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13,700 | 25,599,440 | We found that : ( 1 ) there is consistent evidence for thermal and widespread mechanical pain hypersensitivity in the acute stage of whiplash , ( 2 ) there is no evidence for pain hypersensitivity in the acute and subacute stage of idiopathic neck pain , although the body of evidence is small , and ( 3 ) hyperalgesia and spinal cord hyperexcitability have been detected in early stages of nonspecific low back pain , although evidence about widespread effects are conflicting . | Alterations in sensory processing have been demonstrated in chronic low back and neck pain .
However , it has not been yet systematic ally summarized how early these changes occur in spinal pain .
This systematic review examines the available literature measuring somatosensory function in acute ( < 6 weeks ) and subacute ( 6 - 12 weeks ) spinal pain . | Hypersensitivity to a variety of sensory stimuli is a feature of persistent whiplash associated disorders ( WAD ) . However , little is known about sensory disturbances from the time of injury until transition to either recovery or symptom persistence . Quantitative sensory testing ( pressure and thermal pain thresholds , the brachial plexus provocation test ) , the sympathetic vasoconstrictor reflex and psychological distress ( GHQ‐28 ) were prospect ively measured in 76 whiplash subjects within 1 month of injury and then 2 , 3 and 6 months post‐injury . Subjects were classified at 6 months post‐injury using scores on the Neck Disability Index : recovered ( < 8 ) , mild pain and disability ( 10–28 ) or moderate/severe pain and disability ( > 30 ) . Sensory and sympathetic nervous system tests were also measured in 20 control subjects . All whiplash groups demonstrated local mechanical hyperalgesia in the cervical spine at 1 month post‐injury . This hyperalgesia persisted in those with moderate/severe symptoms at 6 months but resolved by 2 months in those who had recovered or reported persistent mild symptoms . Only those with persistent moderate/severe symptoms at 6 months demonstrated generalised hypersensitivity to all sensory tests . These changes occurred within 1 month of injury and remained unchanged throughout the study period . Whilst no significant group differences were evident for the sympathetic vasoconstrictor response , the moderate/severe group showed a tendency for diminished sympathetic reactivity . GHQ‐28 scores of the moderate/severe group were higher than those of the other two groups . The differences in GHQ‐28 did not impact on any of the sensory measures . These findings suggest that those with persistent moderate/severe symptoms at 6 months display , soon after injury , generalised hypersensitivity suggestive of changes in central pain processing mechanisms . This phenomenon did not occur in those who recover or those with persistent mild symptoms Objective of the investigation : In a 6-month prospect i ve study of 141 consecutive acute whiplash-injured participants , and 40 acute , ankle-injured controls , pain and tenderness in the neck/head , and at a distant control site , were measured . Basic procedures : Muscle palpation and pressure algometry in five head/neck muscle-pairs were performed after 1 week and 1 , 3 and 6 months after injury . Algometry was performed at a distant control site . Main findings : Whiplash-injured patients had lowered pressure-pain-detection thresholds and higher palpation-score initially in the neck/head , but the groups were similar after 6 months , and the control site was not sensitized . Principal conclusion : Focal , but not generalized , sensitization to musculoskeletal structure is present until 3 months , but not 6 months , after whiplash injury , and probably does not play a major role in the development of late whiplash syndrome . Pressure algometry and palpation are useful clinical tools in the evaluation of neck and jaw pain in acute whiplash injury & NA ; Widespread sensory hypersensitivity is present in acute whiplash and is associated with poor recovery . Decreased nociceptive flexion reflex ( NFR ) thresholds ( spinal cord hyperexcitability ) are a feature of chronic whiplash but have not been investigated in the acute to chronic injury stage . This study compared the temporal development of sensory hypersensitivity and NFR responses from soon after injury to either recovery or to transition to chronicity . It also aim ed to identify predictors of persistent spinal cord hyperexcitability . Pressure and cold pain thresholds , NFR responses ( threshold and pain VAS ) were prospect ively measured in 62 participants at <3 weeks , 3 and 6 months post whiplash injury and in 22 healthy controls on two occasions a month apart . Pain levels and psychological distress ( GHQ‐28 ; IES ) were measured at baseline . Whiplash participants were classified at 6 months post‐injury using the Neck Disability Index : recovered ( ≤8 % ) , mild pain and disability ( 10–28 % ) or moderate/severe pain and disability ( ≥30 % ) . All whiplash groups demonstrated spinal cord hyperexcitability ( lowered NFR thresholds ) at 3 weeks post‐injury . This hyperexcitability persisted in those with moderate/severe symptoms at 6 months but resolved in those who recovered or reported lesser symptoms at 6 months . In contrast generalized sensory hypersensitivity ( pressure and cold ) was only ever present in those with persistent moderate/severe symptoms and remained unchanged throughout the study period . This suggests different mechanisms underlie sensory hypersensitivity and NFR responses . In multivariate analyses only initial NDI scores ( p = 0.003 ) were a unique predictor of persistent spinal cord hyperexcitability indicating possible ongoing peripheral nociception following whiplash injury Objectives : To investigate sensory changes present in patients with chronic whiplash-associated disorders and chronic idiopathic neck pain using a variety of quantitative sensory tests to better underst and the pain processing mechanisms underlying persistent symptoms . Methods : A case control study was used with 29 subjects with chronic whiplash-associated disorders , 20 subjects with chronic idiopathic neck pain , and 20 pain-free volunteers . Pressure pain thresholds were measured over the articular pillars of C2-C3 , C5-C6 , the median , radial , and ulnar nerve trunks in the arm and over a remote site , the muscle belly of tibialis anterior . Heat pain thresholds , cold pain thresholds , and von Frey hair sensibility were measured over the cervical spine , tibialis anterior , and deltoid insertion . Anxiety was measured with the Short-Form of the Spielberger State Anxiety Inventory . Results : Pressure pain thresholds were decreased over cervical spine sites in both subject groups when compared with controls ( P < 0.05 ) . In the chronic whiplash-associated disorders group , pressure pain thresholds were also decreased over the tibialis anterior , median , and radial nerve trunks ( P < 0.001 ) . Heat pain thresholds were decreased and cold pain thresholds increased at all sites ( P < 0.03 ) . No differencesin heat pain thresholds or cold pain thresholds were evident in the idiopathic neck pain group at any site compared with the control group ( P > 0.27 ) . No abnormalities in von Frey hair sensibility were evident in either neck pain group ( P > 0.28 ) . Discussion : Both chronic whiplash-associated disorders and idiopathic neck pain groups were characterized by mechanical hyperalgesia over the cervical spine . Whiplash subjects showed additional widespread hypersensitivity to mechanical pressure and thermal stimuli , which was independent of state anxiety and may represent changes in central pain processing mechanisms . This may have implication s for future treatment approaches Objectives ( 1 ) To investigate the development of hypoesthesia from soon after the whiplash injury to 6 months postinjury and ( 2 ) to determine differences in detection thresholds between those with initial features of poor recovery and those without these signs . Methods Fifty-two participants with acute whiplash-associated disorders ( WAD ) ( < 1 mo ) were classified as either “ high-risk ” ( n=17 ; Neck Disability Index > 30 ; sensory hypersensitivity ) or “ low risk ” ( n=35 ; without these signs ) . Detection thresholds to electrical , thermal , and vibration stimuli and psychological distress were prospect ively measured within 1 month of injury and then 3 and 6 months postinjury . Detection thresholds were also measured in the 38 controls . Results Both WAD groups showed hypoesthesia ( vibration , electrical , and cold ) at 1 month postinjury . Vibration and electrocutaneous hypoesthesia persisted to 3 and 6 months only in the high-risk WAD group . Heat detection thresholds were not different between the groups at 1 month postinjury but were elevated in the high-risk group at 3 and 6 months . Both WAD groups were distressed at 1 month but this decreased by 3 months in the low-risk group . The differences in the Impact of Event Scale did not impact on any of the sensory measures . Discussion Sensory hypoesthesia is a feature of acute WAD but persists only in those at higher risk of poor recovery . These findings suggest the involvement of the central inhibitory mechanisms that may be sustained by ongoing nociception UNLABELLED Whiplash injury and chronic whiplash syndrome represent major health problems in certain western communities , pain being the main symptom . Sensitization of the nociceptive system may play a role for non-recovery after whiplash injury . AIMS This study examined if tolerance to endure pain stimuli may predict outcome in whiplash injury . In a prospect i ve fashion , 141 acute whiplash patients exposed to rear-end car collision ( WAD grade 1 - 3 ) and 40 ankle-injured controls were followed and exposed to a cold pressor test , respectively , 1 week , 1 , 3 , 6 and 12 months after the injury . VAS score of pain and discomfort was obtained before , during and after immersion of the dominant h and into cold water for 2 min . The McGill Pain Question naire showed that ankle-injured controls had higher initial pain scores than the corresponding whiplash group , while whiplash-injured subjects had higher scores at 6 months ; pain scores being similar at other time points . No difference was found in cold pressor pain between recovered whiplash patients and ankle-injured subjects . Non-recovery was only encountered in whiplash injury . Eleven non-recovered whiplash patients ( defined as : h and icap after 1 year ) showed reduced time to peak pain from 1 week to 3 months ( P<0.001 ) , 6 months ( P<0.01 ) , but not 12 months after the injury . A larger pain area was seen in non-recovered vs. recovered whiplash-injured subjects during the entire observation period ( P<0.001 ) . Non-recovery after whiplash was associated with initially reduced cold pressor pain endurance and increased peak pain , suggesting that dysfunction of central pain modulating control systems plays a role in chronic pain after acute whiplash injury OBJECTIVE To describe the natural course of patients with acute neck pain presenting in general practice and to identify prognostic factors for recovery and sick leave . DESIGN We conducted a prospect i ve cohort study with a 1-year follow-up in general practice . Question naires were collected at baseline and after 6 , 12 , 26 , and 52 weeks . Days of sick leave were dichotomized into two groups : below and above 7 days of sick leave . Logistic regression was used to identify prognostic factors for recovery and sick leave . PATIENTS Consecutive patients with nonspecific neck pain lasting no longer than 6 weeks were invited to participate . RESULTS One hundred eighty-seven patients were included and 138 ( 74 % ) provided follow-up data . After 1 year , 76 % of the patients stated to be fully recovered or much improved , although 47 % reported to have ongoing neck pain . Almost half of the patients on sick leave at baseline returned to work within 7 days . Multivariate analysis showed that the highest association with recovery was the advice of the general practitioner ( GP ) " to wait and see " ( odds ratio [ OR ] 6.7 , 95 % confidence interval [ CI ] 1.6 - 31.8 ) . For sick leave , referral by the GP , for physical therapy or to a medical specialist , showed the highest association ( OR 2.8 , 95 % CI 1.0 - 8.4 ) . CONCLUSION Acute neck pain had a good prognosis for the majority of patients , but still a relatively high proportion of patients reported neck pain after 1-year follow-up . The advice given by the GP " to wait and see " was associated with recovery , and " referral " was associated with prolonged sick leave SUMMARY Objective : To determine the impact of the lidocaine patch 5 % on pain qualities associated with low-back pain ( LBP ) through use of the Neuropathic Pain Scale ( NPS ) . Patients and methods : Patients were enrolled in an open-label , non-r and omized , prospect i ve , 6-week study involving 8 clinical trial sites in the United States . Eligible patients had non-radicular LBP and reported moderate-to-severe pain on the NPS at study enrollment . Patients were stratified to 3 groups based on the duration of their LBP , defined as acute/sub-acute ( < 3 months ) , short-term chronic ( 3–12 months ) , or long-term chronic LBP ( > 12 months ) . The lidocaine patch 5 % was applied to the area of maximal pain , using no more than a total of 4 patches changed every 24 h. Effectiveness was measured by change from baseline to Week 2 and Week 6 in 4 composite measures of the NPS : NPS-10 , NPS-4 , NPS-8 , and NPS-non-allodynia . Safety was assessed by adverse events ( AEs ) , dermal assessment of application site(s ) , and skin sensory testing . Results : In the combined patient population ( n = 71 ) , 6 weeks of treatment with lidocaine patch 5 % significantly improved all 4 NPS composite measures at both Week 2 and Week 6 ( p < 0.001 ) . Separate analyses by subgroups revealed differential improvements in the 4 composite measures . Eleven patients ( 15.5 % ) experienced treatment-related AEs that were primarily mild-to-moderate and dermal in nature . Conclusions : In patients with moderate-to-severe LBP , 2 weeks and 6 weeks of treatment with the lidocaine patch 5 % significantly reduces the intensity of pain qualities as measured by all 4 NPS composite measures . Lidocaine patch 5 % is well tolerated with few systemic AEs and may provide beneficial pain relief for patients receiving multidisciplinary treatment without increasing risks for adverse drug interactions . Pain scales such as the NPS offer the ability to measure various pain qualities experienced by LBP patients and may allow clinicians to assess the treatment impact of different medications & NA ; In subjects who largely refrained from health care treatment , neck and low back pain declined rapidly after a new pain episode , with the exception of some important subgroups . & NA ; In this prospect i ve cohort study we aim ed to describe the natural course of acute neck and low back pain in a general population of Norway . We screened 9056 subjects aged 20–67 years who participated in a general health survey for a new episode of neck or low back pain the previous month . The screening identified 219 subjects who formed the cohort for this study . Pain intensity was reported on a numeric rating scale ( 0–10 ) at 1 , 2 , 3 , 6 , and 12 months after start of the new pain episode . The course of pain was described for neck and low back pain , different baseline pain levels , age groups , and number of pain sites at baseline . Use of medication and health care was described and associations between pain intensity and seeking health care were estimated . Pain declined rapidly within 1 month after a new pain episode , with a reduction of 0.91 ( 95 % confidence interval [ CI ] 0.50–1.32 ) for neck pain and 1.40 ( 95 % CI 0.82–1.99 ) for low back pain with little change thereafter . However , pain remained unchanged over the follow‐up year for those with equal pain in the neck and low back areas at baseline and for those reporting 4 or more pain sites at baseline . Only 1 in 5 sought health care for their complaints . Still , the course of pain was comparable to effect sizes reported in interventional studies . This study thus contributes natural course reference data for comparisons of pain outcome in clinical trials and practice Cervical pain is a prominent symptom in both acute whiplash injury and late whiplash syndrome . However , no systematic analysis of post-traumatic pain development covering several weeks has yet been performed in whiplash patients . It was the aim of the present study to analyse the duration and course of post-traumatic muscle pain due to whiplash injury in a prospect i ve follow-up examination with short investigation intervals . A recovery of initially increased muscle pain after whiplash injury within 1 month was hypothesized . Pressure pain of the splenius and trapezius muscles was recorded using PC-interactive pressure algesimetry . Whiplash patients were investigated during the acute injury stage and after 3 , 4 , and 6 weeks and compared with matched controls . We found significantly increased pressure pain of the splenius and trapezius muscles in the acute stage of whiplash injury . After 4 weeks patients ' scores of pain parameters were comparable to those of healthy control subjects . Within the patient group the first changes of pressure pain were observed within 3 ( splenius ) and 4 weeks ( trapezius ) . For most patients the recovery dynamics lasted 4 - 6 weeks . A minority of patients did not show any improvement after 6 weeks . The present study shows that the dynamics of pressure pain due to whiplash injury can be quantified by means of PC-interactive pressure algesimetry . Our results confirm the clinical experience that the acute post-traumatic cervical syndrome normally subsides within weeks |
13,701 | 24,164,814 | There is evidence that mothers of very preterm infants of low-birth-weight experience major depression for up to 12 months following PTB .
Sound interventions implemented during and following infant hospitalization and grounded in coping and self-regulation had a small to moderate effect in reducing maternal depression and anxiety and parenting stress for up to 2 months and 12 months respectively . | Early behavioral and educational interventions have been developed to reduce maternal symptoms of psychological trauma ( depression , anxiety , parenting stress , acute stress disorder , and posttraumatic stress disorder ) following preterm birth ( PTB ) .
Aims of this systematic review were to critically assess study methodology and provide a synthesis of existing r and omized control trial ( RCT ) interventions and to estimate effects of the interventions in reducing the maternal symptoms across studies . | Objective : This study tested the efficacy of a brief intervention ( Cues program ) with mothers of very low birth weight ( VLBW < 1500 g ) infants . The primary hypothesis was that mothers in the Cues program would report lower levels of anxiety compared with mothers in the control group . Secondary hypotheses examined whether Cues mothers would report less stress , depression , and role restriction , and exhibit more sensitive interactive behavior , than control group mothers . Methods : A total of 121 mothers of VLBW infants were r and omly assigned to either the experimental ( Cues ) intervention or an attention control ( Care ) condition . The Cues program combined training to reduce anxiety and enhance sensitivity . The control group received general information about infant care . Both programs were initiated during the neonatal intensive care unit stay . Maternal anxiety , stress , depression , and demographic variables were evaluated at baseline , prior to r and omization . Postintervention outcomes were assessed during a home visit when the infant was ∼6 to 8 weeks of corrected age . Results : Although mothers in the Cues group demonstrated greater knowledge of the content of the experimental intervention than mothers in the Care group , the groups did not differ in levels of anxiety , depression , and symptoms of posttraumatic stress . They were similar in their reports of parental role restrictions and stress related to the infant 's appearance and behavior . Cues and Care group mothers were equally sensitive in interaction with their infants . Conclusion : Nonspecific attention was as effective as an early skill-based intervention in reducing maternal anxiety and enhancing sensitive behavior in mothers of VLBW infants Objective To test whether a cognitive – behaviour therapy intervention program reduces the prevalence of depression during the first postnatal year in mothers of very preterm babies BACKGROUND Postnatal and antenatal depression are a focus of considerable clinical and research attention , but little is known about the patterns of anxiety across this period . METHODS Self-reported anxiety and depression were assessed at 18 and 32 weeks gestation and 8 weeks and 8 months postnatally in a prospect i ve longitudinal study of a community sample of women in Engl and ( n=8323 ) . RESULTS The majority of cases of postnatal depression were preceded by antenatal depression ; similarly , postnatal anxiety was preceded by antenatal anxiety . Despite the stability of anxiety and depression across this period , there was a mean decrease in both anxiety and depression . Finally , antenatal anxiety predicted postnatal depression at 8 weeks and 8 months , even after controlling for antenatal depression ( OR=3.22 , p<0.001 ) . LIMITATIONS Data were based on self-report only and there was evidence of selective attrition . CONCLUSION The findings confirm that antenatal anxiety occurs frequently , overlaps with depression and increases the likelihood of postnatal depression Prenatal psychosocial predictors of infant birth weight and length of gestation were investigated in a prospect i ve study of 120 Hispanic and 110 White pregnant women . Hypotheses specifying that personal re sources ( mastery , self-esteem , optimism ) , prenatal stress ( state and pregnancy anxiety ) , and sociocultural factors ( income , education , ethnicity ) would have different effects on birth outcomes were tested using structural equation modeling . Results confirmed that women with stronger re sources had higher birth weight babies ( beta = .21 ) , whereas those reporting more stress had shorter gestations ( beta = -.20 ) . Re sources were also associated with lower stress ( beta = -.67 ) , being married , being White , having higher income and education , and giving birth for the first time . There was no evidence that re sources buffered the effects of stress . The importance of personal re sources in pregnancy is highlighted along with implication s for underst and ing the etiology of adverse birth outcomes Thirty mothers of preterm infants requiring neonatal intensive care unit ( NICU ) hospitalization were assigned r and omly to one of three groups to assess differences in treatment effectiveness of facilitating parental adaptation to the NICU stresses . Groups consisted of : ( a ) a treatment group receiving videotape training in active problem-focused coping strategies ; ( b ) a treatment group receiving videotape training in emotion-focused strategies to help manage anxiety ; and ( c ) a control group receiving promotional information about the hospital and the NICU . On pretreatment measures most of the mothers exhibited little distress , a finding unlike those for the majority of NICU studies . On posttreatment follow-up both the problem-focused and emotion-focused treatment groups were significantly less anxious than the controls and lower levels of depression were observed for the emotion-focused group . Findings suggest that the coping interventions examined were cost efficient and appear promising in facilitating mothers ' coping with NICU stresses OBJECTIVE To examine how family-based interventions in the neonatal intensive care unit ( NICU ) may change parental knowledge and behaviors and decrease stress . METHODS Eighty-four high-risk mother-infant dyads were r and omly assigned to two intervention and one control groups . Group 1 ( n = 28 ) participated in a demonstration of infant reflexes , attention , motor skills , and sleep-wake states . Group 2 ( n = 31 ) viewed educational material s. Group 3 ( n = 25 ) , controls , participated in an informal discussion . Parent-infant interactions ( Nursing Child Assessment Feeding Scale ) were videotaped . Mothers completed measures of stress ( Parenting Stress Index ) and knowledge of infant cues ( Knowledge of Preterm Infant Behavior Scale ) . RESULTS Mothers in both intervention groups evidence d greater knowledge and more contingent and sensitive interactions with their infants than did the control group . Stress also differed across groups , and all mothers reported scores above norms . CONCLUSIONS In a high-risk sample , short-term , family-based NICU interventions may enhance mothers ' knowledge , sensitivity , contingency , and stress The birth of a very small preterm infant ( ⩽ 1500 grams ) can be a traumatizing experience for many parents . A developmental risk model is presented that is the background to an early attachment-oriented preventive psychotherapeutic intervention . This comprehensive parent-centered intervention program is composed of supportive group psychotherapy , attachment-oriented focal individual psychotherapy , a home visit and video-based sensitivity training . The intervention aims at improving parental coping , the process of attachment and parent-infant interaction . In a prospect i ve longitudinal design mothers were r and omly assigned to a control ( N = 44 ) and an intervention group ( N = 43 ) after preterm delivery . Results show that the percentage of secure ( control vs. intervention group : 77.8 % vs. 59.4 % ) and insecure ( control vs. intervention group : 8.3 % vs. 31.3 % avoidant , 13.9 % vs. 9.4 % ambivalent ) attachment quality in high-risk preterm infants is comparable to results from studies with term infants . There was no significant statistical difference in terms of quality of attachment of the preterm infants between the control group and the intervention group . However , only in the control group , impaired neurological development corresponded significantly with an insecure quality of attachment , but not in the intervention group , although there were significantly more neurologically impaired infants in the intervention group . This result is discussed as an effect of the intervention program 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 BACKGROUND . Preterm birth has been associated with increased parenting stress in early infancy , and some reports have found this to be a risk factor for later behavioral problems . There are , however , few studies and conflicting results . Information about the fathers is scarce . OBJECTIVES . Our goal was to study the effects of an early-intervention program on parenting stress after a preterm birth until 1 year corrected age . METHODS . A r and omized , controlled trial was conducted including infants with a birth weight < 2000 g treated at the University Hospital of North Norway Trust , which serves the 2 northern-most counties in Norway , to examine the effects of a modified version of the Mother-Infant Transaction Program on parenting stress measured by the Parenting Stress Index . A term control group was also recruited . The Parenting Stress Index was administered to the mothers at 6 and 12 months ’ corrected age and to the fathers at 12 months ’ corrected age . The intervention consisted of 8 sessions shortly before discharge and 4 home visits by specially trained nurses focusing on the infant ’s unique characteristics , temperament , and developmental potential and the interaction between the infant and the parents . RESULTS . Seventy-one infants were included in the preterm intervention group , and 69 were included in the preterm control group . The preterm groups were well balanced . Seventy-four infants were included in the term control group . Compared with the preterm controls , both the mothers and fathers in the preterm intervention group reported significant lower scores in child domain , parent domain , and total stress on all occasions except the mother-reported child domain at 12 months . These differences were not related to birth weight or gestational age . The level of stress among the preterm intervention group was comparable to their term peers . Both parents in the intervention group reported consistently lower scores within the distractibility/hyperactivity , reinforces parents , competence , and attachment subscales compared with the preterm control group . There were no differences in mean summary stress scores between the mothers and fathers in the 2 preterm groups at 12 months , but the intraclass correlation coefficient was higher in the intervention group . CONCLUSIONS . This early-intervention program reduces parenting stress among both mothers and fathers of preterm infants to a level comparable to their term peers . We are now study ing whether this will result in long-term beneficial effects PURPOSE : To determine whether significant symptoms of acute stress disorder ( ASD ) are present in mothers of premature infants in the neonatal intensive care unit ( NICU ) . SUBJECTS : Forty mothers of premature infants born less than 33 weeks and admitted into NICU . DESIGN : Prospect i ve , cohort , within-subjects . METHODS : Mothers completed the Stanford Acute Stress Reaction Question naire , Edinburgh Postnatal Depression Scale , and the Acute Stress Disorder Interview to explore the number and severity of stress-related symptoms at 2 separate time periods , 7 to 10 days after birth , and 1 month after birth . RESULTS : Twenty-eight percent of the mothers met diagnostic criteria of ASD at 7 to 10 days after birth , and at 1 month after birth ASD symptoms persisted . The majority of the mothers described premature birth as a traumatic stressor . The most commonly met criteria were dissociation and anxiety . Significant symptoms of depression were found in 43 % of mothers and persisted 1 month after birth . Rates of depression and moderate to severe symptoms of ASD were significantly related in mothers at 1 week and at 1 month after birth . CONCLUSIONS : The premature birth experience is traumatic for mothers and may lead to various emotional responses including stress-related symptoms such as depression and /or ASD . Mothers with significant symptoms of depression and those with symptoms of stress seem to be more at risk for developing symptoms of ASD OBJECTIVE . Although low birth weight premature infants and parents are at high risk for adverse health outcomes , there is a paucity of studies that test early NICU interventions with parents to prevent the development of negative parent-infant interaction trajectories and to reduce hospital length of stay . Our objective was to evaluate the efficacy of an educational-behavioral intervention program ( ie , Creating Opportunities for Parent Empowerment ) that was design ed to enhance parent-infant interactions and parent mental health outcomes for the ultimate purpose of improving child developmental and behavior outcomes . DESIGN , SETTING , AND PARTICIPANTS . A r and omized , controlled trial was conducted with 260 families with preterm infants from 2001 to 2004 in 2 NICUs in the northeast United States . Parents completed self-administered instruments during hospitalization , within 7 days after infant discharge , and at 2 months ' corrected age . Blinded observers rated parent-infant interactions in the NICU . INTERVENTION . All participants received 4 intervention sessions of audiotaped and written material s. Parents in the Creating Opportunities for Parent Empowerment program received information and behavioral activities about the appearance and behavioral characteristics of preterm infants and how best to parent them . The comparison intervention contained information regarding hospital services and policies . MAIN OUTCOME MEASURES . Parental stress , depression , anxiety , and beliefs ; parent-infant interaction during the NICU stay ; NICU length of stay ; and total hospitalization were measured . RESULTS . Mothers in the Creating Opportunities for Parent Empowerment program reported significantly less stress in the NICU and less depression and anxiety at 2 months ' corrected infant age than did comparison mothers . Blinded observers rated mothers and fathers in the Creating Opportunities for Parent Empowerment program as more positive in interactions with their infants . Mothers and fathers also reported stronger beliefs about their parental role and what behaviors and characteristics to expect of their infants during hospitalization . Infants in the Creating Opportunities for Parent Empowerment program had a 3.8-day shorter NICU length of stay ( mean : 31.86 vs 35.63 days ) and 3.9-day shorter total hospital length of stay ( mean : 35.29 vs 39.19 days ) than did comparison infants . CONCLUSIONS . A reproducible educational-behavioral intervention program for parents that commences early in the NICU can improve parent mental health outcomes , enhance parent-infant interaction , and reduce hospital length of stay OBJECTIVE To determine the efficacy of an individualized , family-based intervention with preterm infants and their families . DESIGN R and omized , repeated measures intervention outcome study . SETTING Level III neonatal intensive care nursery . PATIENTS R and om sample of 34 preterm infants < or = 1500 g and their families . INTERVENTIONS Individualized , family-based intervention during the hospitalization and transition to home addressed problems identified by parents in four domains including : infant behavior and characteristics , family organization and functioning , caregiving environment , and home discharge and community re sources . MEASUREMENTS AND MAIN RESULTS St and ardized question naires were administered at baseline and discharge to mothers , and predischarge bottle-feeding interactions were videotaped and coded by two blinded observers . Results were in favor of intervention ( Int ) versus control ( Con ) mothers ( baseline ; discharge ) ( P < .05 ) on the Parental Stressor Scale Sights and Sounds subscale ( Int 2.4 + /- 1.0 ; 2.0 + /- 0.8 vs Con 2.4 + /- 0.9 ; 2.6 + /- 0.8 ) ; Child 's Appearance and Behavior subscale ( Int 2.8 + /- 1.0 ; 2.5 + /- 1.1 vs Con 2.8 + /- 0.8 ; 3.1 + /- 0.6 ) ; and Total Stressor Score ( Int 93.9 + /- 36.6 ; 72.3 + /- 41.8 vs Con 87.5 + /- 26.7 ; 87.8 + /- 26.2 ) . On the Beck Depression Inventory , intervention mothers had significant decreases in depressive symptoms ( 39 % ; 11 % ) vs control mothers ( 31 % ; 44 % ) . Maternal self-esteem in both groups improved over time . There were no significant group differences in family environment . During feeding interactions , intervention infants grimaced ( P < .001 ) and gagged ( P < .05 ) less than controls . Intervention mothers less frequently interrupted feedings ( P < .001 ) ; less frequently stimulated infant sucking ( P < .01 ) ; smiled more ( P < .001 ) ; vocalized more ( P < .01 ) ; demonstrated greater sensitivity to infant behavior ( P < .001 ) , better quality of physical contact ( P < .001 ) , and more positive affect ( P < .01 ) . CONCLUSIONS Individualized , family-based intervention appears to reduce maternal stress and depression , and to enhance early mother-infant feeding interactions . Further research is needed to determine whether these short-term beneficial effects persist beyond the newborn period Objective . To ascertain whether a trauma-preventive psychological intervention program for parents of premature infants during hospitalization in a level III NICU may reduce the severity of symptomatic response to the traumatic impact of premature birth . Methods . Mothers of premature infants were enrolled consecutively in a sequential control group design . Intervention group mothers received a structured psychological intervention in the first days after birth . Each mother could make use of additional psychological support if required and was actively approached at critical times during her infant 's NICU stay . Control group mothers did not receive psychological intervention but could ask for counseling by the hospital minister . At discharge , mothers of both groups answered a question naire covering key outcome variables ( symptoms of traumatization , emotions at discharge , and sample and control variables ) . Results . At discharge , intervention group mothers ( N = 25 ) showed significantly lower levels of symptomatic response to the traumatic stressor “ premature birth ” than those in the control group ( N = 25 ; mean overall symptom level 25.2 [ SD : 13.9 ] vs 37.5 [ SD : 19.2 ] ) . Conclusions . This intervention program for parents after premature birth , combining early crisis intervention , psychological aid throughout the infant 's hospitalization , and intense support at critical times , reduced the symptoms of traumatization relating to premature birth Twenty-four low birth weight children who had received an experimental intervention ( LBWE ) during the neonatal period , 31 control children who had received no treatment ( LBWC ) , and 36 normal birth weight children were compared . The intervention involved seven hospital sessions and four home sessions in which a nurse helped mothers adapt to their LBW babies . At age 9 , LBWE children scored significantly higher than LBWC children on the Kaufman Mental Processing Composite , Sequential , Simultaneous , Achievement , Arithmetic , and Riddles scales , after statistical adjustments for socioeconomic status . The LBWE children had also advanced more rapidly in school than had LBWC children . Parent ( Child Behavior Checklist ) and teacher ( Teacher 's Report Form ) ratings of school functioning were more favorable for LBWE than LBWC children , with especially strong effects on Teacher 's Report Form scores for academic performance and the attention problems syndrome . At age 9 , LBWE children were not significantly inferior to normal birth weight children on any measure . These results bear out a progressive divergence between the LBWE and LBWC children that first became statistically significant in cognitive scores at age 3 . The findings suggest that the intervention prevented cognitive lags among LBW children and that this eventually had a favorable effect on academic achievement , behavior , and advancement in school . The progression from no significant differences between LBWE and LBWC children on early cognitive and achievement scores to significant and pervasive differences in later functioning argues for long-term follow-up periods to evaluate properly the power of behavioral interventions to compensate for biological risks |
13,702 | 24,332,136 | Overall , staged multivessel PCI improved short- and long-term survival and reduced repeat PCI . | BACKGROUND Patients with ST-segment elevation myocardial infa rct ion ( STEMI ) and multivessel coronary artery disease who undergo primary percutaneous coronary intervention ( PCI ) are most commonly treated with PCI to the culprit lesion only .
Whether a strategy of complete revascularization in these patients is superior is unknown .
We performed a meta- analysis comparing the benefits and risks of routine culprit-only PCI vs multivessel PCI in STEMI . | Background Complete revascularization after coronary artery bypass surgery is a logical goal and improves symptomatic outcome and survival . However , the impact of complete revascularization in patients with three-vessel coronary disease with varying severities of angina and left ventricular dysfunction has not been clearly defined . Methods and Results The study was performed as a retrospective analysis of 3,372 nonr and omized surgical patients from the Coronary Artery Surgery Study ( CASS ) Registry who had three-vessel coronary disease . Group 1 ( 894 patients ) had class I or II angina ( Canadian Cardiovascular Society criteria ) and group 2 ( 2,478 patients ) had class III or IV angina . In group 1 , adjusted cumulative 4-year survivals according to the number of vessels bypassed were 85 % ( one vessel ) , 94 % ( two vessels ) , 96 % ( three vessels ) , and 96 % ( more than three vessels ) ( log rank , p = 0.022 ) . Adjusted event-free survival ( death , myocardial infa rct ion , definite angina , or reoperation ) was not influenced by the number of vessels bypassed , nor was the anginal status among patients remaining alive after 5 years . In group 2 , adjusted cumulative 5-year survivals were 78 % ( one vessel ) , 85 % ( two vessels ) , 90 % ( three vessels ) , and 87 % ( more than three vessels ) ( log rank , p = 0.074 ) . Adjusted event-free survivals after 6 years were 23 % ( one vessel ) , 23 % ( two vessels ) , 29 % ( three vessels ) , and 31 % ( more than three vessels ) ( p = 0.025 ) ; at 5 years , those with more complete revascularization were more likely to be asymptomatic or free of severe angina . Among group 2 patients with ejection fractions < 0.35 , 6-year survival was 69 % for those with grafts to three or more vessels versus 45 % for those with grafts to two vessels ( p = 0.04 ) . Placing grafts to three or more vessels was independently associated with improved survival and event-free survival in group 2 but not group 1 patients . The case – fatality rates among 529 patients experiencing a myocardial infa rct ion during follow-up was significantly higher for patients with less complete revascularization . Conclusions Complete revascularization ( grafts to three or more vessels ) in patients with three-vessel coronary disease appears to most benefit those with severe angina and left ventricular dysfunction Background — The impact of incomplete revascularization ( IR ) on adverse outcomes after percutaneous coronary intervention remains inconclusive , and few studies have examined mortality during follow-ups longer than 5 years . The objective of this study is to test the hypothesis that IR is associated with higher risk of long-term ( 8-year ) mortality after stenting for multivessel coronary disease . Methods and Results — A total of 13 016 patients with multivessel disease who had undergone stenting procedures with bare metal stents in 1999 to 2000 were identified in the New York State 's Percutaneous Coronary Intervention Reporting System . A logistic regression model was fit to predict the probability of achieving complete revascularization ( CR ) in these patients using baseline risk factors ; then , the CR patients were matched to the IR patients with similar likelihoods of achieving CR . Each patient 's vital status was followed through 2007 using the National Death Index , and the difference in long-term mortality between IR and CR was compared . It was found that CR was achieved in 29.2 % ( 3803 ) of the patients . For the 3803 pair-matched patients , the respective 8-year survival rates were 80.8 % and 78.5 % for CR and IR ( P=0.04 ) , respectively . The risk of death was marginally significantly higher for IR ( hazard ratio=1.12 ; 95 % confidence interval , 1.01–1.26 , P=0.04 ) . The 95 % bootstrap confidence interval for the hazard ratio was 0.98 to 1.32 . Conclusions — IR may be associated with higher risk of long-term mortality after stenting with BMS in patients with multivessel disease . More prospect i ve studies are needed to further test this association BACKGROUND For the treatment of myocardial infa rct ion with ST-segment elevation , primary angioplasty is considered superior to fibrinolysis for patients who are admitted to hospitals with angioplasty facilities . Whether this benefit is maintained for patients who require transportation from a community hospital to a center where invasive treatment is available is uncertain . METHODS We r and omly assigned 1572 patients with acute myocardial infa rct ion to treatment with angioplasty or accelerated treatment with intravenous alteplase ; 1129 patients were enrolled at 24 referral hospitals and 443 patients at 5 invasive-treatment centers . The primary study end point was a composite of death , clinical evidence of reinfa rct ion , or disabling stroke at 30 days . RESULTS Among patients who underwent r and omization at referral hospitals , the primary end point was reached in 8.5 percent of the patients in the angioplasty group , as compared with 14.2 percent of those in the fibrinolysis group ( P=0.002 ) . The results were similar among patients who were enrolled at invasive-treatment centers : 6.7 percent of the patients in the angioplasty group reached the primary end point , as compared with 12.3 percent in the fibrinolysis group ( P=0.05 ) . Among all patients , the better outcome after angioplasty was driven primarily by a reduction in the rate of reinfa rct ion ( 1.6 percent in the angioplasty group vs. 6.3 percent in the fibrinolysis group , P<0.001 ) ; no significant differences were observed in the rate of death ( 6.6 percent vs. 7.8 percent , P=0.35 ) or the rate of stroke ( 1.1 percent vs. 2.0 percent , P=0.15 ) . Ninety-six percent of patients were transferred from referral hospitals to an invasive-treatment center within two hours . CONCLUSIONS A strategy for reperfusion involving the transfer of patients to an invasive-treatment center for primary angioplasty is superior to on-site fibrinolysis , provided that the transfer takes two hours or less Background Few reports described outcomes of complete compared with infa rct -related artery (IRA)-only revascularisation in patients with ST-elevation myocardial infa rct ion ( STEMI ) and multivessel coronary artery disease ( CAD ) . Moreover , no studies have compared the simultaneous treatment of non-IRA with the IRA treatment followed by an elective procedure for the other lesions ( staged revascularisation ) . Methods The outcomes of 214 consecutive patients with STEMI and multivessel CAD undergoing primary angioplasty were studied . Before the first angioplasty patients were r and omly assigned to three different strategies : culprit vessel angioplasty-only ( COR group ) ; staged revascularisation ( SR group ) and simultaneous treatment of non-IRA ( CR group ) . Results During a mean follow-up of 2.5 years , 42 ( 50.0 % ) patients in the COR group experienced at least one major adverse cardiac event ( MACE ) , 13 ( 20.0 % ) in the SR group and 15 ( 23.1 % ) in the CR group , p<0.001 . Inhospital death , repeat revascularisation and re-hospitalisation occurred more frequently in the COR group ( all p<0.05 ) , whereas there was no significant difference in re-infa rct ion among the three groups . Survival free of MACE was significantly reduced in the COR group but was similar in the CR and SR groups . Conclusions Culprit vessel-only angioplasty was associated with the highest rate of long-term MACE compared with multivessel treatment . Patients scheduled for staged revascularisation experienced a similar rate of MACE to patients undergoing complete simultaneous treatment of non-IRA AIMS To examine the incidence of and propensity for non-culprit interventions performed at the time of the primary percutaneous coronary intervention ( PCI ) and its association with 90-day outcomes . METHODS AND RESULTS We examined the incidence , propensity for , and associated 90-day outcomes following non-culprit interventions performed at the time of primary PCI among ST-elevation myocardial infa rct ion patients with multi-vessel coronary artery disease ( MVD ) . Of the 5373 patients who underwent primary PCI in the APEX-AMI trial , 2201 had MVD . Of those , 217 ( 9.9 % ) underwent non-infa rct -related arteries ( IRA ) PCI , whereas 1984 ( 90.1 % ) underwent PCI of the IRA alone . Ninety-day death and death/CHF/shock were higher in the non-IRA group compared with the IRA-only PCI group ( 12.5 vs. 5.6 % , P ( log-rank ) < 0.001 and 17.4 vs. 12.0 % , P ( log-rank ) = 0.020 , respectively ) . After adjusting for patient and procedural characteristics as well as propensity for performing non-IRA PCI , this procedure remained independently associated with an increased hazard of 90-day mortality [ adjusted hazard ratio 2.44 , 95 % CI ( 1.55 - 3.83 ) , P < 0.001 ] . CONCLUSION Non-culprit coronary interventions were performed at the time of primary PCI in 10 % of MVD patients and were significantly associated with increased mortality . Our data support current guideline recommendations discouraging the performance of such procedures in stable primary PCI patients . Prospect i ve r and omized study of this issue may be warranted BACKGROUND Rapid recanalization of infa rct -related artery ( IRA ) has become the major target during primary percutaneous coronary intervention ( PCI ) for patients with ST-elevation myocardial infa rct ion ( MI ) , but strategy for treatment of non-IRA lesions in this setting remains unclear . This study aim ed to compare long-term effects between PCI for IRA only and that for both IRA and non-IRA in ST-elevation MI patients with multi-vessel disease . METHODS A total of 242 eligible patients with ST-elevation MI and at least two diseased coronary arteries ( luminal narrowing > or = 70 % ) undergoing primary PCI were included . Of them , 149 patients underwent primary PCI for IRA only ( group 1 ) , and 93 received primary PCI for IRA followed by elective PCI for non-IRA 7 to 15 days after acute myocardial infa rct ion ( AMI ) ( group 2 ) . Drug-eluting stents ( DESs ) were deployed in more than 90 % of the patients . RESULTS The two groups did not differ with respect to baseline clinical and angiographic characteristics . No significant differences were observed in 12-month clinical follow-up results regarding major adverse cardiac events ( 11.5 % vs 15.1 % , P > 0.05 ) and target lesion revascularization ( 8.1 % vs 7.6 % , P > 0.05 ) between the two groups . However , patients in group 1 had higher rates of recurrent angina ( 10.1 % vs 2.1 % , P < 0.05 ) and depressed left ventricular ejection fraction evaluated by echocardiography ( 0.56 + /- 0.22 vs 0.63 + /- 0.25 , P < 0.05 ) . CONCLUSION With the use of DESs , complete revascularization with elective PCI for non-IRA after primary PCI may exert a beneficial effect on long-term symptomatology and left ventricular function in patients with ST-elevation MI and multi-vessel disease BACKGROUND The success of thrombolytic therapy for acute myocardial infa rct ion is limited by bleeding complications , the impossibility of reperfusing all occluded coronary arteries , recurrent myocardial ischemia , and the relatively small number of patients who are appropriate c and i date s for this therapy . We hypothesized that these problems could be overcome by the use of immediate percutaneous transluminal coronary angioplasty ( PTCA ) , without previous thrombolytic therapy . METHODS At 12 clinical centers , 395 patients who presented within 12 hours of the onset of myocardial infa rct ion were treated with intravenous heparin and aspirin and then r and omly assigned to undergo immediate PTCA ( without previous thrombolytic therapy , 195 patients ) or to receive intravenous tissue plasminogen activator ( t-PA , 200 patients ) followed by conservative care . Radionuclide ventriculography was performed to assess ventricular function within 24 hours and at six weeks . RESULTS Among the patients r and omly assigned to PTCA , 90 percent underwent the procedure ; the success rate was 97 percent , and no patient required emergency coronary-artery bypass surgery . The in-hospital mortality rates in the t-PA and PTCA groups were 6.5 and 2.6 percent , respectively ( P = 0.06 ) . In a post hoc analysis , the mortality rates in the subgroups classified as " not low risk " were 10.4 and 2.0 percent , respectively ( P = 0.01 ) . Reinfa rct ion or death in the hospital occurred in 12.0 percent of the patients treated with t-PA and 5.1 percent of those treated with PTCA ( P = 0.02 ) . Intracranial bleeding occurred more frequently among patients who received t-PA than among those who underwent PTCA ( 2.0 vs. 0 percent , P = 0.05 ) . The mean ( + /- SD ) ejection fractions at rest ( 53 + /- 13 vs. 53 + /- 13 percent ) and during exercise ( 56 + /- 13 vs. 56 + /- 14 percent ) were similar in the t-PA and PTCA groups at six weeks . By six months , reinfa rct ion or death had occurred in 32 patients who received t-PA ( 16.8 percent ) and 16 treated with PTCA ( 8.5 percent , P = 0.02 ) . CONCLUSIONS As compared with t-PA therapy for acute myocardial infa rct ion , immediate PTCA reduced the combined occurrence of nonfatal reinfa rct ion or death , was associated with a lower rate of intracranial hemorrhage , and result ed in similar left ventricular systolic function Background Recanalization of the culprit lesion is the main goal of primary angioplasty for acute ST-segment elevation myocardial infa rct ion ( STEMI ) . Patients presenting with acute myocardial infa rct ion and multivessel disease are , therefore , usually subjected to staged procedures , with the primary percutaneous coronary intervention ( PCI ) confined to recanalization of the infa rct -related artery ( IRA ) . Theoretically at least , early relief of stenoses of non-infa rct related arteries could promote collateral circulation , which could help to limit the infa rct size . However , the safety and feasibility of such an approach has not been adequately established . Methods In this single-center prospect i ve study we examined 73 consecutive patients who had an acute STEMI and at least one or more lesions ≥ 70 % in a major epicardial vessel other than the infa rct related artery . In the first 28 patients , forming the multi-vessel ( MV ) PCI group , all lesions were treated during the primary procedure . In the following 45 patients , forming the culprit-only ( CO ) PCI group , only the culprit lesion was treated during the initial procedure , followed by either planned-staged or ischemiadriven revascularization of the non-culprit lesions . Fluoroscopy time and contrast dye amount were compared between both groups , and patients were followed up for one year for major adverse cardiac events ( MACE ) and other significant clinical events . Results The two groups were well balanced in terms of clinical characteristics , number of diseased vessels and angiographic characteristics of the culprit lesion . In the MV-PCI group , 2.51 lesions per patient were treated using 2.96 ± 1.34 stents ( 1.00 lesions and 1.76 ± 1.17 stents in the CO-PCI group , both p < 0.001 ) . The fluoroscopy time increased from 10.3 ( 7.2–16.9 ) min in the CO-PCI group to 12.5 ( 8.5–19.3 ) min in the MV-PCI group ( p = 0.22 ) , and the amount of contrast used from 200 ( 180–250 ) ml to 250 ( 200–300 ) ml , respectively ( p = 0.16 ) . Peak CK and CK-MB were significantly lower in patients of the MV-PCI group ( 843 ± 845 and 135 ± 125 vs 1652 ± 1550 and 207 ± 155 U/l , p < 0.001 and 0.01 , respectively ) . Similar rates of major adverse cardiac events at one year were observed in the two groups ( 24 % and 28 % in multi-vessel and culprit treatment groups , p = 0.73 ) . The incidence of new revascularization in both infa rct - and noninfa rct -related arteries was also similar ( 24 % and 28 % , respectively , p = 0.73 ) . Conclusion We may state from this limited experience that a multi-vessel stenting approach for patients with acute STEMI and multi-vessel disease is feasible and probably safe during routine clinical practice . Our data suggest that this approach may help to limit the infa rct size . However , larger studies , perhaps using drug-eluting stents , are still needed to further evaluate the safety and efficiency of this procedure , and whether it is associated with a lower need of subsequent revascularization and lower costs BACKGROUND Immediate angioplasty and the administration of a thrombolytic agent followed by conservative treatment are two approaches to the management of acute myocardial infa rct ion , but these methods have not been compared prospect ively . METHODS We enrolled 108 patients with acute myocardial infa rct ion in a r and omized trial design ed to test the hypothesis that immediate angioplasty ( without previous thrombolytic therapy ) may result in greater myocardial salvage than the administration of a thrombolytic agent followed by conservative treatment . The primary end point was the change in the size of the perfusion defect as assessed at admission and discharge by tomographic imaging with technetium-99 m sestamibi , a myocardial perfusion agent that can measure myocardium at risk and final infa rct size . RESULTS End-point data were available for 56 patients r and omly assigned to receive tissue plasminogen activator ( mean [ + /- SD ] time to start of infusion , 232 + /- 174 minutes after the onset of chest pain ) and 47 patients r and omly assigned to receive angioplasty ( first balloon inflation at 277 + /- 144 minutes ) . In the case of anterior infa rct ion , myocardial salvage as assessed by imaging with technetium-99 m sestamibi was 27 + /- 21 percent of the left ventricle for 22 patients in the thrombolysis group , as compared with 31 + /- 21 percent for 15 patients in the angioplasty group . For infa rcts in all other locations , myocardial salvage was 7 + /- 13 percent for 34 patients in the thrombolysis group and 5 + /- 10 percent for 32 patients in the angioplasty group . After adjustment for infa rct location , the difference in mean salvage between groups was 0 ( P = 0.98 ) , with a 95 percent confidence interval of + /- 6 percent of the left ventricle . CONCLUSIONS In patients with acute myocardial infa rct ion , immediate angioplasty does not appear to result in greater myocardial salvage than the administration of a thrombolytic agent followed by conservative treatment , although a small difference between these two therapeutic approaches can not be excluded Objective Predictors of 30-day mortality may differ from predictors of mortality at 1 year among 30-day survivors of ST-elevation myocardial infa rct ion ( STEMI ) treated with primary percutaneous coronary intervention ( PCI ) . We aim ed to evaluate the predictors of 30-day and 1-year mortality in unselected patients with STEMI treated with PCI . Methods Individual patient data from 4732 patients with STEMI , who were treated with primary PCI during an 11-year study period , were recorded prospect ively . Patient characteristics , 30-day , and 1-year outcome were evaluated . Results At 30-day follow-up , 219 patients ( 4.6 % ) died ; and out of the 4513 30-day survivors , 109 patients ( 2.8 % ) died at 1 year . Patients who died were older , had a higher risk profile . Higher rates of Killip class greater than 2 on admission , multivessel disease , and , more often , lower left ventricular ejection fraction were observed in patients who died . Mortality rate was 7.6 % at 30 days among the females when compared with 3.7 among the males , P value less than 0.001 . Age and sex-adjusted multivariate analysis revealed that previous myocardial infa rct ion , diabetes , Killip class greater than 2 , post-PCI thrombolysis in myocardial infa rct ion flow less than 3 , and left ventricular ejection fraction less than 30 % were strong predictors of both 30-day and 1-year mortality . However , multivessel disease , anterior myocardial infa rct location and in-hospital reinfa rct ion , ischemic time , and pre-PCI thrombolysis in myocardial infa rct ion flow less than 3 were particularly strong predictors of 30-day mortality . Conclusion Despite the fact that most characteristics of 30-day and 1-year mortality among 30-day survivors are similar , we found that variables that affect mortality beyond the acute phase may not necessarily be the same as those that influence early mortality BACKGROUND Despite the widespread use of intravenous thrombolytic therapy and of immediate percutaneous transluminal coronary angioplasty for the treatment of acute myocardial infa rct ion , r and omized comparisons of the two approaches to reperfusion are lacking . We report the results of a prospect i ve , r and omized trial comparing immediate coronary angioplasty ( without previous thrombolytic therapy ) with intravenous streptokinase treatment . METHODS A total of 142 patients with acute myocardial infa rct ion were r and omly assigned to receive one of the two treatments . The left ventricular ejection fraction was measured by radionuclide scanning before hospital discharge . Quantitative coronary angiography was performed to assess the degree of residual stenosis in the infa rct -related arteries . RESULTS A total of 72 patients were assigned to receive streptokinase and 70 patients to undergo immediate angioplasty . Angioplasty was technically successful in 64 of the 65 patients who underwent the procedure . Infa rct ion recurred in nine patients assigned to receive streptokinase , but in none of those assigned to receive angioplasty ( P = 0.003 ) . Fourteen patients in the streptokinase group had unstable angina after their infa rct ion , but only four in the angioplasty group ( P = 0.02 ) . The mean ( + /- SD ) left ventricular ejection fraction as measured before discharge was 45 + /- 12 percent in the streptokinase group and 51 + /- 11 percent in the angioplasty group ( P = 0.004 ) . The infa rct -related artery was patent in 68 percent of the patients in the streptokinase group and 91 percent of those in the angioplasty group ( P = 0.001 ) . Quantitative coronary angiography revealed stenosis of 36 + /- 20 percent of the luminal diameter in the angioplasty group , as compared with 76 + /- 19 percent in the streptokinase group ( P < 0.001 ) . CONCLUSIONS Immediate angioplasty after acute myocardial infa rct ion was associated with a higher rate of patency of the infa rct -related artery , a less severe residual stenotic lesion , better left ventricular function , and less recurrent myocardial ischemia and infa rct ion than was intravenous streptokinase BACKGROUND Primary percutaneous coronary intervention ( PCI ) is shown to be the most effective reperfusion strategy in acute myocardial infa rct ion . The aim of this multicentre national r and omized mortality trial was to test whether the nationwide change in treatment guidelines ( transportation of all patients to PCI centres ) was warranted . METHODS The PRAGUE-2 study r and omized 850 patients with acute ST elevation myocardial infa rct ion presenting within < 12 h to the nearest community hospital without a catheter laboratory to either thrombolysis in this hospital ( TL group , n=421 ) or immediate transport for primary percutaneous coronary intervention ( PCI group , n=429 ) . The primary end-point was 30-day mortality . Secondary end-points were : death/reinfa rct ion/stroke at 30 days ( combined end-point ) and 30-day mortality among patients treated within 0 - 3 h and 3 - 12 h after symptom onset . Maximum transport distance was 120 km . RESULTS Five complications ( 1.2 % ) occurred during the transport . R and omization-balloon time in the PCI group was 97+/-27 min , and r and omization-needle time in the TL group was 12+/-10 min . Mortality at 30 days was 10.0 % in the TL group compared to 6.8 % mortality in the PCI group ( P=0.12 , intention-to-treat analysis ) . Mortality of 380 patients who actually underwent PCI was 6.0 % vs 10.4 % mortality in 424 patients who finally received TL ( P<0.05 ) . Among 299 patients r and omized > 3 h after the onset of symptoms , the mortality of the TL group reached 15.3 % compared to 6 % in the PCI group ( P<0.02 ) . Patients r and omized within <3 h of symptom onset ( n=551 ) had no difference in mortality whether treated by TL ( 7.4 % ) or transferred to PCI ( 7.3 % ) . A combined end-point occurred in 15.2 % of the TL group vs 8.4 % of the PCI group ( P<0.003 ) . CONCLUSIONS Long distance transport from a community hospital to a tertiary PCI centre in the acute phase of AMI is safe . This strategy markedly decreases mortality in patients presenting > 3 h after symptom onset . For patients presenting within <3 h of symptoms , TL results are similar results to long distance transport for PCI DESIGN : Prospect i ve r and omized , multicentre study . RATIONALE : Recanalisation of the culprit lesion is the main goal of primary angioplasty for acute myocardial infa rct ion . With the exception of cardiogenic shock , staged procedures are performed in the presence of multivessel disease . The study hypothesis is that with modern non-thrombogenic stents ( heparin coated ) complete revascularization with multivessel treatment can be safely achieved during the primary angioplasty procedure with a lower need of subsequent revascularization procedures and at a lower cost . ENDPOINTS : PRIMARY : 12-month incidence of repeat revascularization ( any revascularization , infa rct related artery as well as non-infa rct -related artery ) . SECONDARY : ( 1 ) in hospital repeat revascularization , reinfa rct ion and death ; ( 2 ) total hospital cost ( including a 12 months follow-up period ) . METHODS : 69 patients with ST elevation Acute Myocardial Infa rct ion ( AMI ) , < 12 hours after symptoms onset , undergoing primary angioplasty , with documented multivessel disease and both culprit lesion and 1 to 3 other lesions suitable for stent implantation . Unbalanced r and omization between culprit lesion treatment only ( n = 17 ) and complete multivessel treatment ( n = 52 , with 71 additional lesions treated ) . RESULTS : The two groups were well balanced in terms of clinical characteristics , number of diseased vessels and angiographic characteristics of the culprit lesion . In the complete multivessel treatment group 2.36 ± 0.64 lesions per patient were treated using 2.73 ± 0.78 heparin coated stents ( 1.00 lesions and 1.29 ± 0.61 stents in the culprit treatment group , bothp < 0.001 ) . The duration of the procedure increased from 53 ± 21 min ( culprit treatment group ) to 69 ± 32 min ( p = 0.032 ) and the amount of contrast used from 242 ± 102 ml ( culprit treatment group ) to 341 ± 163 ml ( multivessel complete treatment),p = 0.025 . A similar low incidence of in-hospital major adverse cardiac events was observed in the 2 groups ( 0 and 3.8 % in culprit and multivessel treatment groups , p = 0.164 ) . The increase in the incidence of new revascularisation in the culprit treatment group at 12 month follow-up was not significant ( 35 vs 17%,p = 0.247 ) but was sufficient to compensate the initial higher in-hospital cost , with a similar 12 month hospital cost in the 2 groups ( € 22 330 ± € 13 653 vs € 20 382 ± € 11 671,p = 0.231 ) . CONCLUSION : Multivessel treatment during primary PTCA was safe in this controlled trial . However , when only the culprit lesion was initially treated , the need for subsequent clinical ly driven revascularization remained low and no clinical or economical advantages were obtainable with a more aggressive initial approach . In clinical practice , a staged approach to multivessel treatment during primary angioplasty avoids to treat unnecessarily non clinical ly relevant lesions . ( Int J Cardiovasc Intervent 2004 ; 6 : 128 - 133 |
13,703 | 18,479,499 | This review confirms previous research demonstrating that FOBT screening reduces the risk of CRC mortality .
The results also indicate that there is no difference in all-cause mortality between the screened and nonscreened population | BACKGROUND AND AIMS : Reducing mortality from colorectal cancer ( CRC ) may be achieved by the introduction of population -based screening programs .
The aim of the systematic review was to up date previous research to determine whether screening for CRC using the fecal occult blood test ( FOBT ) reduces CRC mortality and to consider the benefits , harms , and potential consequences of screening . | All 68,308 inhabitants of Göteborg born between 1918 and 1931 were r and omly divided into a test and a control group . The subjects in the test group were invited to perform Hemoccult II fecal occult blood testing on 3 days and to repeat the test after 16 to 24 months . In the prevalence screening 21,347 ( 63 % ) performed the test , and in the rescreening 19,991 ( 60 % ) . Investigation of the 942 ( 4.4 % ) with positive tests in the prevalence screening showed 47 cancers and 129 subjects with adenomas > or = 1.0 cm . In the rescreening 5.1 % had a positive test , and 34 cancers and 122 subjects with adenomas ( > or = 1.0 cm ) were found among those . Cancer had also been diagnosed in 19 subjects in the interval between the two screening occasions and in 15 subjects among the non-responders . Forty-four cancers had been diagnosed in the control group during the same period . Cancers detected by screening were at a less advanced stage than in the control group . It is too early to show any effect of screening on mortality from colorectal cancer To which groups of patients can the results of clinical trials be applied ? This question is often inappropriately answered by reference to the trial entry criteria . Instead , the benefit and harm ( adverse events , discomfort of treatment , etc ) of treatment could be assessed separately for individual patients . Patients at greatest risk of a disease will have the greatest net benefit as benefit to patients usually increases with risk while harm remains comparatively fixed . To assess net benefit , the relative risks should come from ( a meta- analysis of ) r and omised trials ; the risk in individual patients should come from multivariate risk equations derived from cohort studies . However , before making firm conclusions , the assumptions of fixed adverse effects and constant reduction in relative risk need to be checked BACKGROUND Although tests for occult blood in the feces are widely used to screen for colorectal cancers , there is no conclusive evidence that they reduce mortality from this cause . We evaluated a fecal occult-blood test in a r and omized trial and documented its effectiveness . METHODS We r and omly assigned 46,551 participants 50 to 80 years of age to screening for colorectal cancer once a year , to screening every two years , or to a control group . Participants who were screened su bmi tted six guaiac-impregnated paper slides with two smears from each of three consecutive stools . About 83 percent of the slides were rehydrated . Participants who tested positive underwent a diagnostic evaluation that included colonoscopy . Vital status was ascertained for all study participants during 13 years of follow-up . A committee determined causes of death . A single pathologist determined the stage of each tissue specimen . Differences in mortality from colorectal cancer , the primary study end point , were monitored with the sequential log-rank statistic . RESULTS The 13-year cumulative mortality per 1000 from colorectal cancer was 5.88 in the annually screened group ( 95 percent confidence interval , 4.61 to 7.15 ) , 8.33 in the biennially screened group ( 95 percent confidence interval , 6.82 to 9.84 ) , and 8.83 in the control group ( 95 percent confidence interval , 7.26 to 10.40 ) . The rate in the annually screened group , but not in the biennially screened group , was significantly lower than that in the control group . Reduced mortality in the annually screened group was accompanied by improved survival in those with colorectal cancer and a shift to detection at an earlier stage of cancer . CONCLUSIONS Annual fecal occult-blood testing with rehydration of the sample s decreased the 13-year cumulative mortality from colorectal cancer by 33 percent BACKGROUND : It has recently been suggested that all-cause mortality is a more appropriate end point than disease specific mortality in cancer screening trials , and that disease specific mortality is biased in favour of screening . This suggestion is based partly on supposed inconsistencies between all-cause mortality results and disease specific results in cancer screening trials , and alleged increases in deaths from causes other than breast cancer among breast cancer cases diagnosed among women invited to screening . METHODS : We used data from the Swedish Two-County Trial of mammographic screening for breast cancer , in which 77 080 women were r and omised to an invitation to screening and 55 985 to no invitation . We estimated relative risks ( RRs ) ( invited v control ) of death from breast cancer , death from other causes within the breast cancer cases , and death from all causes within the breast cancer cases . RRs were adjusted for age and took account of the longer follow up of breast cancer cases in the invited group due to lead time . RESULTS : There was a significant 31 % reduction in breast cancer mortality in the invited group ( RR 0.69 , 95 % confidence interval ( CI ) 0.58–0.80 ; p<0.001 ) . There was no significant increase in deaths from other causes among breast cancer cases in the invited group ( RR 1.12 , 95 % CI 0.96–1.31 ; p=0.14 ) . A significant 19 % reduction in deaths from all causes was observed among breast cancer cases in the group invited to screening ( RR 0.81 , 95 % CI 0.72–0.90 ; p<0.001 ) . A more conservative estimation gave a significant 13 % reduction ( RR 0.87 , 95 % CI 0.78–0.97 ; p=0.01 ) . These findings are consistent with the magnitude of the reduction in breast cancer mortality . CONCLUSIONS : Invitation to screening was associated with a reduction in deaths from all causes among breast cancer cases , consistent with high participation rates in screening . There is no significant evidence of bias in cause of death classification in the Two-County Trial , and as breast cancer mortality is the targeted clinical outcome in breast cancer screening , it is the appropriate end point in a breast cancer screening trial . All-cause mortality is a poor and inefficient surrogate for breast cancer mortality BACKGROUND There is growing evidence that faecal-occult-blood ( FOB ) screening may reduce colorectal cancer ( CRC ) mortality , but this reduction in CRC mortality has not been shown in an unselected population -based r and omised controlled trial . The aim of this study was to assess the effect of FOB screening on CRC mortality in such a setting . METHODS Between February , 1981 , and January , 1991 , 152,850 people aged 45 - 74 years who lived in the Nottingham area of the UK were recruited to our study . Participants were r and omly allocated FOB screening ( 76,466 ) or no screening ( controls ; 76,384 ) . Controls were not told about the study and received no intervention . Screening-group participants were sent a Haemoccult FOB test kit with instructions from their family doctor . FOB tests were not rehydrated and dietary restrictions were imposed only for retesting borderline results . Individuals with negative FOB tests at the first screening , together with those who tested positive but in whom no neoplasia was found on colonoscopy , were invited to take part in further screening every 2 years . Screening was stopped in February , 1995 , by which time screening-group participants had been offered FOB tests between three and six times . Screening-group participants who had a positive test were offered full colonoscopy . All participants were followed up until June , 1995 . The primary outcome measure was CRC mortality . FINDINGS Of the 152,850 individuals recruited to the study , 2599 could not be traced or had emigrated and were excluded from the analysis . Thus , there were 75,253 participants in the screening group and 74,998 controls . 44,838 ( 59.6 % ) screening-group participants completed at least one screening . 28,720 ( 38.2 % ) of these individuals completed all the FOB tests they were offered and 16,118 ( 21.4 % ) completed at least one screening but not all the tests they were offered . 30,415 ( 40.4 % ) did not complete any test . Of 893 cancers ( 20 % stage A ) diagnosed in screening-group participants ( CRC incidence of 1.49 per 1000 person-years ) , 236 ( 26.4 % ) were detected by FOB screening , 249 ( 27.9 % ) presented after a negative FOB test or investigation , and 400 ( 44.8 % ) presented in non-responders . The incidence of cancer in the control group ( 856 cases , 11 % stage A ) was 1.44 per 1000 person-years . Median follow-up was 7.8 years ( range 4.5 - 14.5 ) . 360 people died from CRC in the screening group compared with 420 in the control group-a 15 % reduction in cumulative CRC mortality in the screening group ( odds ratio=0.85 [ 95 % ; CI 0.74 - 0.98 ] , p = 0.026 ) . INTERPRETATION Our findings together with evidence from other trials suggest that consideration should be given to a national programme of FOB screening to reduce CRC mortality in the general population BACKGROUND In 1993 , a r and omized controlled trial in Minnesota showed , after 13 years of follow-up , that annual fecal occult blood testing was effective in reducing colorectal cancer mortality by at least 33 % . Biennial screening ( i.e. , every 2 years ) result ed in only a 6 % mortality reduction . Two European trials ( in Engl and and in Denmark ) subsequently showed statistically significant 15 % and 18 % mortality reductions with biennial screening . Herein , we provide up date d results -through 18 years of follow-up -- from the Minnesota trial that address the apparent inconsistent findings among the trials regarding biennial screening . METHODS From 1976 through 1977 , a total of 46551 study subjects , aged 50 - 80 years , were recruited and r and omly assigned to an annual screen , a biennial screen , or a control group . A screen consisted of six guaiac-impregnated fecal occult blood tests ( Hemoccult ) prepared in pairs from each of three consecutive fecal sample s. Participants with at least one of the six tests that were positive were invited for a diagnostic examination that included colonoscopy . All participants were followed annually to ascertain incident colorectal cancers and deaths . RESULTS The numbers of deaths from all causes were similar among the three study groups . Cumulative 18-year colorectal cancer mortality was 33 % lower in the annual group than in the control group ( rate ratio , 0.67 ; 95 % confidence interval [ CI ] = 0.51 - 0.83 ) . The biennial group had a 21 % lower colorectal cancer mortality rate than the control group ( rate ratio , 0.79 ; 95 % CI = 0.62 - 0.97 ) . A marked reduction was also noted in the incidence of Dukes ' stage D cancers in both screened groups in comparison with the control group . CONCLUSION The results from this study , together with the other two published r and omized trials of fecal occult blood screening , are consistent in demonstrating a substantial , statistically significant reduction in colorectal cancer mortality from biennial screening Background : Three large r and omised trials have shown that screening for colorectal cancer using faecal occult blood ( FOB ) tests can reduce the mortality from this disease . Two national pilot studies have recently been launched in the UK to investigate the feasibility of population screening for colorectal cancer in the National Health Service . The largest of the r and omised trials was conducted in Nottingham and r and omised 152 850 individuals between the ages of 45 and 74 years to receive biennial Haemoccult ( FOB ) test kit ( intervention group ) or to a control group . Aims : We have compared the mortality in the intervention group compared with the control group . Methods : The 152 850 r and omised individuals were followed up through local health records and central flagging ( Office for National Statistics ) over a median follow up period of 11 years . Results : At a median follow up of 11 years there was a 13 % reduction in colorectal cancer mortality ( 95 % confidence interval 3–22 % ) in the intervention group despite an uptake at first invitation of only approximately 50 % . The mortality reduction for those accepting screening was 27 % . The reduction in mortality was independent of sex and site of tumour . There was no significant difference in mortality from causes other than colorectal cancer between the intervention and control groups . Conclusions : Although the reduction in colorectal cancer mortality was sustained , further follow up of this population is required to determine whether a significant reduction in the incidence of colorectal cancer will be achieved BACKGROUND The most widely accepted end point in r and omized cancer screening trials is disease-specific mortality . The validity of this end point , however , rests on the assumption that cause of death can be determined accurately . An alternative end point is all-cause mortality , which depends only on the accurate ascertainment of deaths and when they occur . We compared disease-specific and all-cause mortality in published r and omized cancer-screening trials to indirectly assess the validity of the disease-specific mortality end point . METHODS We examined all 12 published r and omized trials of cancer screening for which both end points were available ( seven of mammography , three of fecal occult blood detection , and two of chest x-ray screening for lung cancer ) . For each r and omized trial , we subtracted disease-specific mortality observed in the screened group from that observed in the control group and all-cause mortality in the screened group from that in the control group . We then compared the differences in these two mortality measures . RESULTS In five of the 12 trials , differences in the two mortality rates went in opposite directions , suggesting opposite effects of screening . In four of these five trials , disease-specific mortality was lower in the screened group than in the control group , whereas all-cause mortality was the same or higher . In two of the remaining seven trials , the mortality rate differences were in the same direction but their magnitudes were inconsistent ; i.e. , the difference in all-cause mortality exceeded the disease-specific mortality in the control group . Thus , results of seven of the 12 trials were inconsistent in their direction or magnitude . CONCLUSION Major inconsistencies were identified in disease-specific and all-cause mortality end points in r and omized cancer screening trials . Because all-cause mortality is not affected by bias in classifying the cause of death , it should be examined when interpreting the results of r and omized cancer-screening trials Background : Three r and omised trials have demonstrated reduction in mortality from colorectal cancer ( CRC ) by repeated screening with faecal occult blood tests , including the trial presented here , which is the only one still in progress . Aims : To evaluate reduction in mortality after seven screening rounds and the possible influence of compliance on mortality from CRC . Methods : At Funen in Denmark , r and om allocation to biennial screening with Hemoccult-II in 30 967 subjects aged 45–75 years and 30 966 controls was performed in 1985 from a population of 137 485 of the same age . Only participants who completed the first screening round were invited for further screening . Colonoscopy was offered if the test was positive . The primary end point was death from CRC , and the 10 year results were published in 1996 . Results : From the beginning of the first screening to the seventh round , mean age increased from 59.8 to 70.0 years in the screening and control groups , and the male/female ratio decreased from 0.92 to 0.81 . Those who accepted screening were younger than non-responders . Positivity rates varied from 0.8 % to 3.8 % , the cumulative ratio of a positive test was 5.1 % after seven rounds , and 4.8 % of patients had at least one colonoscopy . Mortality from CRC was significantly less in the screening group ( relative risk ( RR ) 0.82 ( 0.69–0.97 ) ) , and the reduction in mortality was most pronounced above the sigmoid colon . After seven rounds , RR was reduced to less than 0.70 compared with controls . Mortality rates from causes other than CRC did not differ . Non-responders had a significantly increased risk of death from CRC compared with those who accepted the full programme . Subjects who accepted the first screening , but not subsequent ones , demonstrated a tendency towards increased risk . Conclusions : The persistent reduction in mortality from CRC in a biennial screening program with Hemoccult-II , and a reduction in RR to less than 0.70 in those adhering to the programme , support attempts to introduce larger scale population screening programmes . The smaller effect on mortality from CRC in the rectum and sigmoid colon suggests evaluation by additional flexible sigmoidoscopy with longer intervals BACKGROUND & AIMS Several r and omized population -based studies have shown that screening for colorectal cancer ( CRC ) by fecal occult blood tests ( FOBTs ) can reduce CRC mortality . The aim of this French population -based study was to assess whether a similar benefit could be obtained in countries characterized by high performances in the diagnosis and management of CRC . METHODS Small-sized geographic areas , including 91,199 individuals aged 45 - 74 years , were allocated to either FOBT screening or no screening . Six screening rounds were performed . The FOBT was performed without diet restriction and was sent to a central analysis center and processed without rehydration . Screening group participants who had a positive test result were offered a full colonoscopy . The entire population was followed up for 11 years after study entry . RESULTS Acceptability of the test was 52.8 % at the first screening round and varied between 53.8 % and 58.3 % in the successive rounds . Positivity rates were 2.1 % initially and 1.4 % on average in the successive rounds . CRC mortality was significantly lower in the screening population compared with the control population ( mortality ratio , 0.84 ; 95 % confidence interval , 0.71 - 0.99 ) . The reduction in CRC mortality was more pronounced in those who participated at least once ( mortality ratio , 0.67 ; 95 % confidence interval , 0.56 - 0.81 ) . CONCLUSIONS Our findings , together with the results of other trials , suggest that biennial screening by FOBTs can reduce CRC mortality regardless of the quality of the health system and support attempts to introduce large-scale screening programs into the general population AIMS To determine the harm that ensues from faecal occult blood ( FOB ) screening for colorectal cancer . METHODS 150 251 people were r and omly allocated either to receive biennial Haemoccult FOB tests ( n = 75 253 ) or not to be contacted ( n=74 998 ) . Study group patients returning positive tests were offered colonic investigation ; 1774 underwent complete investigation of the colon . RESULTS There was no significant difference in the stage at presentation of interval versus control group cancers . Survival in the interval cancer group was significantly prolonged compared with the control group . Sensitivity for colonoscopy or flexible sigmoidoscopy and double contrast barium enema ( DCBE ) was 96.7 % . There were no complications of DCBE but seven ( 0.5 % ) complications of colonoscopy , of which six required surgical intervention . There were no colonoscopy related deaths . No patients without colorectal cancer died within 30 days of colonic investigation . Five patients died within 30 days of surgery for screen detected colorectal neoplasia and a further two died without having surgery . Six patients died after 30 days but within two years of surgery for screen detected benign adenomas or stage A cancers ; in all cases the cause of death was not related to colorectal cancer . CONCLUSIONS There was investigation related morbidity but no mortality and little to support overdiagnosis bias . The group returning falsely negative tests had a better outcome compared with the whole control group . There is a negative side to any screening programme but mortality reduction in this and other trials suggests that a national programme of colorectal cancer screening should be given consideration BACKGROUND AND PURPOSE : In an ongoing r and omized screening study of 68,306 patients for early detection of colorectal neoplasm , those with positive Hemoccult II ® tests ( Smith Kline Diagnostic , Sunnyvale , CA ) were examined with a flexible sigmoidoscope ( FS ; 60 cm ) and doublecontrast barium enema ( DCE ) . The aim of this study was to determine the rate of complications to the work-up . METHODS : A total of 2,108 FS , 1,987 DCE , 190 colonoscopies , and 104 laparotomies were performed because of a positive Hemoccult ® . RESULTS : One patient 's large bowel was perforated during diagnostic endoscopy . Four perforations of the large bowel occurred during endoscopic polypectomy ( 0.8 percent of 513 adenomas removed ) , and one case of bleeding occurred 12 days after polypectomy . No complications occurred in connection with the 1,987 DCE . Five of 104 laparotomized patients underwent relaparotomy , 3 after removal of a colorectal carcinoma , and 2 of 4 patients with diverticular disease . All five patients healed but required a longer stay at the hospital . CONCLUSIONS : Complications occurred in 0.3 percent of the endoscopies , and 5 percent of patients had to undergo laparotomy again . No mortality occurred . If mortality attributable to colorectal cancer will decrease because of screening , we find the complication rate is acceptable BACKGROUND Case-control studies and a voluntary-based follow-up study have suggested that repeated screening with faecal-occult-blood ( FOB ) tests can lead to a reduction in mortality from colorectal cancer ( CRC ) . The aim of this r and omised study was to compare mortality rates after FOB tests every 2 years during a 10-year period with those of unscreened similar controls . METHODS 140,000 people aged 45 - 75 years lived in Funen , Denmark , in August , 1985 , and were considered for inclusion in our study . Before r and omisation we excluded individuals who had CRC or precursor adenomas and those who had taken part in a previous pilot study . R and omisation of 137,485 people in blocks of 14 allocated three per 14 to the screening group ( 30,967 ) , three per 14 to the control group ( 30,966 ) , and eight not to be enrolled in the study ( 75,552 ) . Controls were not told about the study and continued to use health-care facilities as normal . Hemoccult-II blood tests ( with dietary restrictions but without rehydration ) were sent to screening-group participants . Only those participants who completed the first screening round were invited for further screening -- five rounds of screening during a 10-year period . Participants with positive tests were asked to attend to full examination and were offered colonoscopy whenever possible . The primary endpoint was death from CRC . FINDINGS Of the 30,967 screening-group participants , 20,672 ( 67 % ) completed the first screening round and were invited for further screening ; more than 90 % accepted repeated screenings . During the 10-year study , 481 people in the screening group had a diagnosis of CRC , compared with 483 unscreened controls . There were 205 deaths attributable to CRC in the screening group , compared with 249 deaths in controls . CRC mortality , including deaths attributable to complications from CRC treatment , was significantly lower in the screening group than in controls ( mortality ratio 0.82 [ 95 % CI 0.68 - 0.99 ] ) p = 0.03 ) . INTERPRETATION Our findings indicate that biennial screening by FOB tests can reduce CRC mortality . This study is being continued to improve its statistical power and to assess the effect of the removal of more precursor adenomas in the screening-group participants than in controls on CRC incidence Background : Two large true population studies in Europe have shown a significant reduction in mortality from colorectal cancer ( CRC ) by screening with a faecal occult blood test . In one trial conducted in Funen County , 61,933 individuals ( aged 45–75 years ) were r and omly allocated either to a control group or to receive a biennial Hemoccult‐II test . Methods : These individuals were followed from 1985 to 2002 and 9 screening rounds were performed . Results : First screening was accepted by 67 % ( 20,672 ) . Positivity rates varied between 0.8 % and 3.8 % , and the cumulative proportion of the test group having colonoscopy was 5.3 % . Screen‐detected CRC was early ( Dukes ' A ) in 36 % compared to 11 % among controls . Incidence of CRC was unchanged , but mortality was reduced by 11 % . This figure increased to 43 % in persons participating in all 9 rounds . No more than 8,558 were screened at the 9th round . Patients with CRC detected between screenings had better survival than controls . Death rates from causes other than CRC among participants never became higher than among controls . Conclusion : The lesser reduction in mortality from CRC of 11 % compared to 18 % after 5 screening rounds may be explained by the decrease in the number screened . Efficacy in those screened supports the introduction of countrywide screening in Denmark , but it must be ascertained that acceptability , proportion of early CRC and logistics all reach the same st and ard as in the r and omized trial |
13,704 | 11,386,888 | Seven of the 8 studies examining the effect of early endoscopy on length of stay as a measure of re source utilization demonstrated a significant reduction compared with that of delayed endoscopy .
The overwhelming majority of existing data suggest that early endoscopy is safe and effective for all risk groups . | BACKGROUND While the effectiveness of upper endoscopy has been established for acute nonvariceal upper gastrointestinal tract hemorrhage , its optimal timing has not been clearly defined .
Early endoscopy has been advocated for its ability to achieve prompt diagnosis , risk stratification , and therapeutic hemostasis .
OBJECTIVE To determine whether early vs delayed endoscopy improves patient and economic outcomes for all risk groups with nonvariceal upper gastrointestinal tract hemorrhage . | In an 11 month period , 95 patients with acute upper gastrointestinal hemorrhage underwent early fiberoptic endoscopy . Patients were r and omized into two groups before endoscopy depending on whether the results of the procedure were revealed immediately or after 4 days . No attempt was made to influence the treatment or diagnostic plan . The groups were comparable with respect to historical features surrounding the bleeding episode and the anatomic site of hemorrhage . There were no significant differences in any aspect of patient management or outcome between groups . Important changes in diagnostic or treatment plan were made after learning the results of endoscopy in only 12 % of the patients , half of whom were bleeding briskly at the time of endoscopy . It is concluded that the natural history of acute upper gastrointestinal hemorrhage ( for example , the spontaneous cessation of bleeding ) precludes endoscopy from having a significant effect on patient management BACKGROUND Time to treatment with thrombolytic therapy is a critical determinant of mortality in acute myocardial infa rct ion . Little is known about the relationship between the time to treatment with direct coronary angioplasty and clinical outcome . The objectives of this study were to determine both the time required to perform direct coronary angioplasty in the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes ( GUSTO-IIb ) trial and its relationship to clinical outcome . METHODS AND RESULTS Patients r and omized to direct coronary angioplasty ( n=565 ) were divided into groups based on the time between study enrollment and first balloon inflation . Patients r and omized to angioplasty who did not undergo the procedure were also analyzed . The median time from study enrollment to first balloon inflation was 76 minutes ; 19 % of patients assigned to angioplasty did not undergo an angioplasty procedure . The 30-day mortality rate of patients who underwent balloon inflation < /=60 minutes after study enrollment was 1.0 % ; 61 to 75 minutes after enrollment , 3.7 % ; 76 to 90 minutes after enrollment , 4.0 % ; and > /=91 minutes after enrollment , 6.4 % . The mortality rate of patients assigned to angioplasty who never underwent the procedure was 14.1 % ( P=0.001 ) . Logistic regression analysis revealed that the time from enrollment to first balloon inflation was a significant predictor of mortality within 30 days ; after adjustment for differences in baseline characteristics , the odds of death increased 1.6 times ( P=0.008 ) for a movement from each time interval to the next . CONCLUSIONS The time to treatment with direct PTCA , as with thrombolytic therapy , is a critical determinant of mortality CONTEXT Upper gastrointestinal tract hemorrhage ( UGIH ) is a common and potentially life-threatening disorder . Re source utilization can vary without adverse effect on patient outcome . Clinical practice guidelines are a potential solution to reduce variation in practice while improving patient outcomes . OBJECTIVE To vali date prospect ively the safety , acceptability , and impact of a clinical practice guideline defining the medically appropriate length of stay ( LOS ) for patients hospitalized with UGIH . DESIGN Prospect i ve , controlled time-series study with an alternate-month design . Outcome surveyors and patients were blinded to study group allocation . GUIDELINE : A retrospectively vali date d scoring system using 4 independent variables : hemodynamics , time from bleeding , comorbidity , and esophagogastroduodenoscopy ( EGD ) findings to predict risk of adverse events . The quantitative risk for the low-risk subset was 0.6 % ( 95 % confidence interval [ CI ] , 0.0%-2.0 % ) for subsequent complications and 0 % ( 95 % CI , 0.0%-0.9 % ) for life-threatening complications from this retrospective evaluation . SETTING A 1000-bed , not-for-profit , university-affiliated teaching hospital . PATIENTS Consecutive adult patients hospitalized for acute UGIH . INTERVENTION Concurrent feedback of guideline recommendation ( same-day hospital discharge ) to physicians caring for patients at low risk for complication . No risk information was provided during control months . RESULTS Seventy percent ( 209/299 ) of UGIH patients achieved low-risk status according to the guideline and were therefore potentially suitable for early discharge from the hospital . Providing real-time quantitative risk information ( intervention group only ) was associated with an increase in guideline compliance from 30 % to 70 % ( P<.001 ) and a decrease in mean ( SD ) LOS from 4.6 ( 3.5 ) days to 2.9 ( 1.3 ) days ( mean reduction of 1.7 days per patient ; P<.001 ) . No differences in complications , patient health status , or patient satisfaction were found when measured 1 month after discharge . An independent variable predicting decreased hospital LOS for low-risk UGIH patients was early EGD . CONCLUSIONS Implementation of the clinical practice guideline safely reduced hospital LOS for selected low-risk patients with acute UGIH . Further prospect i ve validation in other setting s is warranted A prospect i ve study was conducted to see whether emergent esophagogastroduodenoscopy ( EGD ) in patients with active upper gastrointestinal ( GI ) bleeding is associated with more oxygen desaturation than nonemergent EGD . Emergent EGD was performed in the study patients with active upper GI bleeding . Nonemergent EGD was performed in the control patients . Determination of oxygen saturation ( Sao2 ) was measured by pulse oximeter . A decrease in Sao2 of > 4 % was more frequent in the study patients ( 26 % , 13 of 50 ) than in controls ( 6 % , 3 of 50 ) ( P < .01 ) . During EGD , mean oxygen saturation decreased significantly in both groups of patients . After EGD , mean oxygen saturation did not recover toward the pre-endoscopy insertion level in the study group ( P < .01 ) . A linear association was found that oxygen desaturation = 5.46 + 0.15 ( status ) -0.06 ( baseline oxygen saturation ) . Emergent EGD for active upper GI bleeding in the emergency department tends to be associated with more frequent significant oxygen desaturation than nonemergent EGD . Continuous oxygen supplementation and oxygen saturation monitoring may be used during emergent nonse date d EGD in the emergency department BACKGROUND From January 1993 to December 1994 , we conducted a prospect i ve study to investigate the evolutionary change of rebleeding risk in bleeding peptic ulcers . To obviate possible confounding factors that would influence decision making for discharge of patients , subjects with coexistent acute illnesses , systemic bleeding disorders , alcoholism , and use of nonsteroidal anti-inflammatory drugs were excluded . METHODS Emergency endoscopies were performed in patients with hematemesis or a melena within 24 hours of admission . Ulcer lesions were divided into six categories according to endoscopic findings . The residual risks of rebleeding of each type of ulcers were calculated for 10 days , and the critical point of acceptable rebleeding risk after discharge was set at 3 % . RESULTS Three hundred ninety-two patients with bleeding peptic ulcers completed the study . The ulcers , characterized by clean bases , red or black spots , adherent clots , nonbleeding visible vessels without local therapy , nonbleeding visible vessels with local therapy , and bleeding visible vessels with local therapy took 0 , 3 , 3 , 4 , 4 , and 3 days , respectively , to decrease rebleeding risk to below the critical point . All episodes of fatal rebleeding ( n = 4 ) occurred within 24 hours after admission . CONCLUSIONS Patients with clean-based ulcers can be discharged in the first day of admission . The optimal duration required for hospitalization of patients with ulcers characterized by nonbleeding visible vessels at initial endoscopy is 4 days . The remaining patients with ulcers marked by other bleeding stigmata may be discharged after a 3-day observation BACKGROUND The impact of upper endoscopy in patients with upper gastrointestinal hemorrhage treated in community practice is unknown . Thus we examined the effectiveness of endoscopy performed within 24 hours of admission ( early endoscopy ) . METHODS Medical records of 909 consecutive hospitalized patients with upper gastrointestinal hemorrhage who underwent endoscopy at 13 hospitals in a large metropolitan area were review ed . We evaluated unadjusted and severity-adjusted associations of early endoscopy with recurrent bleeding or surgery to control hemorrhage , length of hospital stay , and associations of endoscopic therapy in patients with bleeding ulcers or varices . RESULTS Early endoscopy was performed in 64 % of patients and compared with delayed endoscopy and was associated with clinical ly significant reductions in adjusted risk of recurrent bleeding or surgery ( odds ratio [ OR ] 0.70 : 95 % CI [ 0.44 , 1.13 ] ) and a 31 % decrease in adjusted length of stay ( 95 % CI : [ 24 % , 37 % ] ) . In patients at high risk for recurrent bleeding , the use of early endoscopic therapy to control hemorrhage was associated with reductions in recurrent bleeding or surgery ( OR 0.21 : 95 % CI [ 0.10 , 0.47 ] ) and length of stay ( -31 % : 95 % CI [ -44 % , -14 % ) . CONCLUSION In this study of community-based practice , the routine use of endoscopy , and in selected cases endoscopic therapy , performed early in the clinical course of patients with upper gastrointestinal hemorrhage was associated with reductions in length of stay and , possibly , the risk of recurrent bleeding and surgery OBJECTIVES Patients with an ulcer and active bleeding or a nonbleeding , visible vessel are high-risk for further bleeding and should receive aggressive therapy . In this study , we tried to identify clinical parameters that predict these high-risk groups . METHODS Over a 7-month period , 16 clinical parameters were analyzed prospect ively in 316 patients with bleeding peptic ulcer . A multivariate analysis was used to find the independent predictors for the high-risk patients . RESULTS A total of 114 patients ( 36 % ) was found to have a spurting hemorrhage ( eight patients ) , oozing hemorrhage ( 27 patients ) , or a nonbleeding visible vessel ( 79 patients ) . Using an univariate analysis , a statistically significant predictor was the appearance of coffee ground fluid or blood from the nasogastric tube . This predictor also emerged as an independent factor ( odds ratio , 0.4333 ; 95 % confidence interval , 0.263 - 0.714 ) . CONCLUSIONS Patients with bleeding peptic ulcer who have coffee ground fluid or blood from the nasogastric tube should receive an emergency endoscopy and aggressive treatment Aims —To assess changes in practice and outcome in acute upper gastrointestinal haemorrhage following the feedback of data , the reemphasis of national guidelines , and specific recommendations following an initial survey . Design —A prospect i ve , multicentre , audit cycle . Forty five hospitals from three health regions participed in two phases of the audit cycle . Patients —Phase I : 2332 patients with acute upper gastrointestinal haemorrhage ; phase II : 1625 patients with upper gastrointestinal haemorrhage . Methods — Patients were evaluated with respect to management ( with reference to the recommendations in the national guidelines ) , mortality , and length of hospital stay . Results —Following the distribution of data from the first phase of the National Audit and the formulation of specific recommendations for improving practice , the proportion of hospitals with local guidelines or protocol s for the management of upper gastrointestinal haemorrhage rose from 71 % ( 32/45 ) to 91 % ( 41/45 ) ; 12 of the 32 hospitals with guidelines during the first phase revised their guidelines following the initial survey . There was a small but significant increase in the proportion of all patients who underwent endoscopy ( from 81 % to 86 % ) , the proportion who underwent endoscopy within 24 hours of admission ( from 50 % to 56 % ) , and the use of central venous pressure monitoring in patients with organ failure requiring blood transfusion or those with profound shock ( from 30 % to 43 % ) . There was , however , no change in the use of high dependency beds or joint medical/surgical management in high risk cases . There was no significant change in crude or risk st and ardised mortality ( 13.4 % in the first phase and 14.4 % in the second phase ) . Conclusions —Although many of the participating hospitals have made efforts to improve practice by producing or updating guidelines or protocol s , there has been only a small demonstrable change in some areas of practice during the National Audit . The failure to detect any improvement in mortality may reflect this lack of change of practice , but may also reflect the fact that a large proportion of the deaths in this unselected study are not preventable ; only a very large study could hope to demonstrate a significant change out of the context of a clinical trial PURPOSE The outcome of patients with upper gastrointestinal hemorrhage is greatly influenced by recurrence of bleeding , but it may be possible to identify patients who have a low risk for rebleeding , and can be discharged after a short hospitalization . To examine the effect of an early discharge protocol ( length of hospital stay < or =3 days ) , we conducted a 2-year prospect i ve study in patients with upper gastrointestinal bleeding at low risk for rebleeding , as selected by clinical and endoscopic criteria . METHODS During the first year of the study , patients were managed according to the st and ard criteria by any of six surgical teams ( control period ) . During the second year , patients were managed by only one surgical team under the early discharge protocol guidelines ( study period ) . RESULTS Overall , 488 of 942 ( 52 % ) patients were considered as low risk . Early discharge was achieved in 26 of 230 ( 11 % ) patients in the control period and in 191 of 258 ( 74 % ) in the study period ( P < 0.001 ) . Age and number of compensated comorbidities did not affect the rate of early discharge . Length of hospital stay was reduced from ( mean + /- SD ) 6 + /- 2.7 days ( control period ) to 3 + /- 2.3 days ( study period , P < 0.001 ) . No differences were observed in rates of rebleeding , need for surgery , readmission or mortality . By contrast , no differences in lengths of stay were observed during that time period among patients admitted with coronary artery disease , colorectal cancer , or acute pancreatitis . CONCLUSION Most patients with upper gastrointestinal bleeding who are at low risk for rebleeding can be discharged early , leading to important cost savings BACKGROUND Low risk of rebleeding has been observed in patients with gastrointestinal bleeding due to peptic ulcer without high-risk stigmata of recent hemorrhage . We aim ed to evaluate the safety and acceptability of an aggressive early discharge policy in those patients admitted with upper gastrointestinal bleeding due to duodenal ulcers without high-risk stigmata of recent hemorrhage . METHOD Retrospective analysis was carried out in bleeding ulcer patients less than 60 years of age with stable vital signs and no stigmata or only flat spots on endoscopy . A prospect i ve study was then performed that included only duodenal ulcer patients less than 60 years of age with stable vital signs , no concomitant serious medical illness , and no stigmata of recent hemorrhage . These patients were discharged on the same day that endoscopy was performed . RESULTS During a period of 18 months , 72 patients satisfied the criteria in the retrospective study . The mean hospital stay was 1.4 days ( range , 1 to 5 ) . There were no episodes of rebleeding nor significant drops in hemoglobin level 2 weeks after discharge ( 10.8 gm/dL + /- 1.4 vs 11.0 gm/dL + /- 1.5 ) . Seventy-five patients were recruited into the prospect i ve study . None of them had rebleeding nor significant drops in hemoglobin 1 week after discharge ( 12.1 gm/dL + /- 1.8 vs 11.7 gm/dL + /- 2.5 ) . CONCLUSION We conclude that patients with gastrointestinal bleeding who have clean-based duodenal ulcers and are stable on admission can be safely discharged on the same day as endoscopy BACKGROUND Thrombolytic therapy for acute ischemic stroke has been approached cautiously because there were high rates of intracerebral hemorrhage in early clinical trials . We performed a r and omized , double-blind trial of intravenous recombinant tissue plasminogen activator ( t-PA ) for ischemic stroke after recent pilot studies suggested that t-PA was beneficial when treatment was begun within three hours of the onset of stroke . METHODS The trial had two parts . Part 1 ( in which 291 patients were enrolled ) tested whether t-PA had clinical activity , as indicated by an improvement of 4 points over base-line values in the score of the National Institutes of Health stroke scale ( NIHSS ) or the resolution of the neurologic deficit within 24 hours of the onset of stroke . Part 2 ( in which 333 patients were enrolled ) used a global test statistic to assess clinical outcome at three months , according to scores on the Barthel index , modified Rankin scale , Glasgow outcome scale , and NIHSS : RESULTS In part 1 , there was no significant difference between the group given t-PA and that given placebo in the percentages of patients with neurologic improvement at 24 hours , although a benefit was observed for the t-PA group at three months for all four outcome measures . In part 2 , the long-term clinical benefit of t-PA predicted by the results of part 1 was confirmed ( global odds ratio for a favorable outcome , 1.7 ; 95 percent confidence interval , 1.2 to 2.6 ) . As compared with patients given placebo , patients treated with t-PA were at least 30 percent more likely to have minimal or no disability at three months on the assessment scales . Symptomatic intracerebral hemorrhage within 36 hours after the onset of stroke occurred in 6.4 percent of patients given t-PA but only 0.6 percent of patients given placebo ( P < 0.001 ) . Mortality at three months was 17 percent in the t-PA group and 21 percent in the placebo group ( P = 0.30 ) . CONCLUSIONS Despite an increased incidence of symptomatic intracerebral hemorrhage , treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months The benefit of early endoscopy in the management of peptic ulcer bleeding remains controversial . In this study we looked at the role of early endoscopy in bleeding peptic ulcer patients with clear , " coffee grounds , " or bloody nasogastric aspirate . A consecutive series of 325 patients with peptic ulcer bleeding were included ( 218 patients with clear aspirate , 77 patients with coffee-grounds aspirate , and 30 patients with bloody aspirate ) . They were r and omized to receive early endoscopy ( within 12 h of arrival at the emergency room ) or delayed endoscopy ( 12 h after arrival at the emergency room ) . Early endoscopy did not benefit patients with clear or coffee-grounds aspirate . However , combined with endoscopic therapy , it did significantly benefit patients with bloody aspirate in reducing the need for blood transfusion ( mean , 450 ml vs. 666 ml ; p < 0.001 ) and hospital stay ( mean , 4 vs. 14.5 days , p < 0.001 ) . Early endoscopy and endoscopic therapy are not needed in bleeding peptic ulcer patients with clear or coffee-grounds nasogastric aspirate . However , early endoscopy and endoscopic therapy benefit patients with bloody nasogastric aspirate Cardiopulmonary events account for many of the serious gastrointestinal endoscopy complications . Pulse oximetry monitoring detects hypoxemia to allow prevention of complications . Alternatively , prophylaxis by continuous nasal oxygen during the procedure may offset any tendency toward oxygen desaturation . We monitored patients with major upper gastrointestinal hemorrhage by pulse oximetry during emergency upper endoscopy on room air or while receiving supplemental nasal oxygen ( 2 l/min ) . Desaturation ( SpO2 < 90 % ) occurred in 80 % of patients undergoing emergency procedures on room air but in only 25 % of those receiving supplemental oxygen . For comparison , patients without significant cardiac or pulmonary disease undergoing elective procedures were studied on room air and desaturation only occurred in 29 % . Thus , arterial oxygen desaturation as measured by pulse oximetry occurs more often during emergency than elective endoscopy . Supplemental oxygen decreases desaturation during emergency endoscopy but does not abolish it . We recommend that supplemental oxygen be used during emergency endoscopy to decrease desaturation , but it should not substitute for patient monitoring BACKGROUND AND STUDY AIMS Stigmata of hemorrhage in bleeding peptic ulcers have prognostic characteristics . In the present study , the evolution of these stigmata was studied prospect ively using daily endoscopic examinations . PATIENTS AND METHODS From January 1989 to October 1989 , 778 consecutive patients with bleeding peptic ulcers underwent endoscopy within 24 hours of admission . The bleeding peptic ulcers were assigned by three endoscopists to five categories , those with : a ) active bleeding , b ) a nonbleeding visible vessel , c ) adherent clot , d ) dot , or e ) a clean base . Actively bleeding ulcers were treated by epinephrine injection . Ulcers with nonbleeding visible vessels , adherent clots , or dots were left untreated . Daily endoscopic examinations were carried out for three subsequent days , or until the ulcer base became clean . RESULTS On day 0 , there were 56 actively bleeding ulcers ( 7 % ) , 62 ulcers with visible vessels ( 8 % ) , 104 with adherent clots ( 13 % ) , 182 with flat dots ( 23 % ) , and 374 with a white base ( 48 % ) . On the subsequent three days , 24 of 62 ulcers with visible vessels ( 39 % ) , 30 of 104 with adherent clots ( 29 % ) , 24 of 182 with dots ( 13 % ) , and 19 of 374 with a clean base ( 5 % ) on day 0 re-bled endoscopically or clinical ly , or both . The overall rebleeding risk was 9.9 % , 4.9 % , and 2.7 % on days 1 , 2 , and 3 , respectively . CONCLUSIONS Stigmata of hemorrhage in bleeding peptic ulcers are predictive of rebleeding . They represent intermediate phases in the evolution of bleeding vessels into clean-based ulcers . The associated rebleeding risk diminishes as the vessel disappears from the ulcer base To determine whether routine early endoscopy is beneficial to patients with upper-gastrointestinal-tract bleeding that ceases during hospitalization , we r and omly assigned 206 patients to routine endoscopy ( 100 patients ) or no routine endoscopy ( 106 ) . Patients in the latter group underwent endoscopy only if recurrent bleeding occurred during hospitalization or if x-ray films disclosed gastric ulcer or suggested neoplasia . All patients were initially treated with an empiric antacid regimen . When the two groups were compared ( experimental versus control ) , there were no significant differences in overall hospital deaths ( 11 versus eight ) , recurrence of bleeding ( 33 versus 32 ) , number of transfusions required to treat recurrent bleeding ( mean + /- S.E.M. , 7.4 + /- 1.2 versus 6.3 + /- 0.7 units ) , deaths after recurrent bleeding ( eight versus five ) , or duration of hospital stay . During the 12 months after discharge , there were also no significant differences in frequency of readmission to the hospital , incidence of further gastrointestinal bleeding , number of hemorrhage-related deaths , or frequency of gastrointestinal surgery . We conclude that endoscopy should not be a routine procedure in patients with upper-gastrointestinal-tract bleeding that ceases during treatment The effects of immediate vs. delayed refeeding and the prognostic value of endoscopic findings in patients with major upper gastrointestinal hemorrhage were assessed in a prospect i ve r and omized study . Entry criteria were clinical evidence of major hemorrhage and endoscopic evidence of a Mallory-Weiss tear or an ulcer with a clean base , flat spot , or clot . Two hundred fifty-eight patients were r and omly assigned to groups receiving a regular diet immediately or nothing by mouth for 36 hours , then clear liquids for 12 hours , and a regular diet thereafter . Outcomes in the immediate and delayed refeeding groups were comparable : rebleeding occurred in 4 % vs. 5 % ; urgent intervention , 2 % vs. 2 % ; and deaths , 1 % vs. 1 % , respectively . Rebleeding occurred in 2 ( 2 % ) of 96 patients with cleanbased ulcers , 5 ( 8 % ) of 65 with ulcers with spots , 3 ( 14 % ) of 21 with ulcers with clots ( P = 0.05 , 3 x 2 chi2 test ) , and 1 ( 2 % ) of 66 with Mallory-Weiss tears . It is concluded that the time of refeeding does not influence the hospital course of patients with a low risk of recurrent bleeding . Patients with clean-based ulcers or nonbleeding Mallory-Weiss tears may be refed and discharged home immediately after stabilization BACKGROUND Nearly half of patients hospitalized with unstable angina eventually receive a non-cardiac-related diagnosis , yet 5 percent of patients with myocardial infa rct ion are inappropriately discharged from the emergency department . We evaluated the safety , efficacy , and cost of admission to a chest-pain observation unit ( CPU ) located in the emergency department for such patients . METHODS We performed a community-based , prospect i ve , r and omized trial of the safety , efficacy , and cost of admission to a CPU as compared with those of regular hospital admission for patients with unstable angina who were considered to be at intermediate risk for cardiovascular events in the short term . A total of 424 eligible patients were r and omly assigned to routine hospital admission ( a monitored bed under the care of the cardiology service ) or admission to the CPU ( where patients were cared for according to a strict protocol including aspirin , heparin , continuous ST-segment monitoring , determination of creatine kinase isoenzyme levels , six hours of observation , and a study of cardiac function ) . The CPU was managed by the emergency department staff . Patients whose test results were negative were discharged , and the others were hospitalized . Primary outcomes ( nonfatal myocardial infa rct ion , death , acute congestive heart failure , stroke , or out-of-hospital cardiac arrest ) and use of re sources were compared between the two groups . RESULTS The 212 patients in the hospital-admission group had 15 primary events ( 13 myocardial infa rct ions and 2 cases of congestive heart failure ) , and the 212 patients in the CPU group had 7 events ( 5 myocardial infa rct ions , 1 death from cardiovascular causes , and 1 case of congestive heart failure ) . There was no significant difference in the rate of cardiac events between the two groups ( odds ratio for the CPU group as compared with the hospital-admission group , 0.50 ; 95 percent confidence interval , 0.20 to 1.24 ) . No primary events occurred among the 97 patients who were assigned to the CPU and discharged . Re source use during the first six months was greater among patients assigned to hospital admission than among those assigned to the CPU ( P<0.01 by the rank-sum test ) . CONCLUSIONS A CPU located in the emergency department can be a safe , effective , and cost-saving means of ensuring that patients with unstable angina who are considered to be at intermediate risk of cardiovascular events receive appropriate care BACKGROUND Many patients with upper gastrointestinal ( GI ) bleeding have a benign outcome and could receive less intensive and costly care if accurately identified . We sought to determine whether early endoscopy performed shortly after admission in the emergency department could significantly reduce the health care use and costs of caring for patients with nonvariceal upper GI bleeding without adversely affecting the clinical outcome . METHODS All eligible patients with upper GI bleeding and stable vital signs were r and omized after admission to undergo endoscopy in 1 to 2 days ( control ) or early endoscopy in the emergency department . Patients with low-risk findings on early endoscopy were discharged directly from the emergency department . Clinical outcomes and costs were prospect ively assessed for 30 days . RESULTS We r and omized 110 consecutive stable patients with nonvariceal upper GI bleeding during the 12-month study period . The baseline demographic features , endoscopic findings , and the clinical outcomes were no different between the two groups . However the findings of the early endoscopy allowed us to immediately discharge 26 of 56 ( 46 % ) patients r and omized to that group . No patient discharged from the emergency department suffered an adverse outcome . The hospital stay ( median of 1 day [ interquartile range of 0 to 3 days ] vs. 2 days [ interquartile range of 2 to 3 days ] , p = 0.0001 ) and the cost of care ( $ 2068 [ interquartile range of $ 928 to $ 3960 ] versus $ 3662 [ interquartile range of $ 2473 to $ 7280 ] , p = 0.00006 ) were significantly less for the early endoscopy group . CONCLUSIONS Early endoscopy performed shortly after admission in the emergency department safely triaged 46 % of patients with nonvariceal upper GI bleeding to outpatient care , which significantly reduced hospital stay and costs |
13,705 | 27,158,893 | However , subsequent observational cohort studies and meta-analyses have not confirmed these fears , and the findings of the EAGLES trial do not support a causal link between varenicline and neuropsychiatric disorders , including suicidal ideation and suicidal behaviour .
The evidence is not conclusive , however , in people with past or current psychiatric disorders .
Lower dose regimens also conferred benefits for cessation , while reducing the incidence of adverse events .
Limited evidence suggests that varenicline may have a role to play in relapse prevention .
The most frequently recorded adverse effect of varenicline is nausea , but mostly at mild to moderate levels and tending to subside over time . | BACKGROUND Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms ( acting as an agonist ) and reducing smoking satisfaction ( acting as an antagonist ) .
OBJECTIVES To review the efficacy of nicotine receptor partial agonists , including varenicline and cytisine , for smoking cessation .
Early concerns about a possible association between varenicline and depressed mood , agitation , and suicidal behaviour or ideation led to the addition of a boxed warning to the labelling in 2008 .
Concerns have also been raised that varenicline may slightly increase cardiovascular events in people already at increased risk of those illnesses . | Genotype scores that predict relevant clinical outcomes may detect other disease features and help direct prevention efforts . We report data that vali date a previously established v1.0 smoking cessation quit success genotype score and describe striking differences in the score in individuals who display differing developmental trajectories of use of common addictive substances . In a cessation study , v1.0 genotype scores predicted ability to quit with P=0.00056 and area under receiver-operating characteristic curve 0.66 . About 43 % vs 13 % quit in the upper vs lower genotype score terciles . Latent class growth analyses of a developmentally assessed sample identified three latent classes based on substance use . Higher v1.0 scores were associated with ( a ) higher probabilities of participant membership in a latent class that displayed low use of common addictive substances during adolescence ( P=0.0004 ) and ( b ) lower probabilities of membership in a class that reported escalating use ( P=0.001 ) . These results indicate that : ( a ) we have identified genetic predictors of smoking cessation success , ( b ) genetic influences on quit success overlap with those that influence the rate at which addictive substance use is taken up during adolescence and ( c ) individuals at genetic risk for both escalating use of addictive substances and poor abilities to quit may provide especially urgent focus for prevention efforts 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 INTRODUCTION Dianicline is a α4β2 nicotinic acetylcholine receptor partial agonist , a class of drugs that includes varenicline and cytisine . Varenicline is efficacious for smoking cessation , while cytisine has not been studied systematic ally . The efficacy of dianicline has not been previously tested in an adequately powered study . METHODS In a r and omized , double-blind , parallel group placebo-controlled trial , 602 generally healthy cigarette smokers were assigned to dianicline ( n = 300 ) or placebo ( n = 302 ) for 7 weeks followed by a 19-week off drug follow-up period . RESULTS Exhaled carbon monoxide and cotinine-confirmed continuous abstinence rates for Weeks 4 - 7 were 24.0 % for dianicline versus 20.5 % for placebo ( odds ratio 1.22 ; 95 % CI , 0.83 - 1.80 ; p = .307 ) . For Weeks 4 - 26 , the abstinence rates were 16.7 % for dianicline versus 13.9 % for placebo ( odds ratio 1.24 ; 95 % CI , 0.79 - 1.93 ; p = .366 ) . Craving for a cigarettes was reduced by dianicline compared with placebo after 7 weeks ( p = .0175 ) . Nicotine withdrawal symptoms measured by the Hughes and Hatsukami Minnesota Withdrawal Scale were lower for dianicline compared with placebo in the first 3 weeks of treatment during which time quit rates were also higher in the dianicline-treated group . CONCLUSIONS Dianicline did not increase cigarette smoking abstinence rates beyond the initial phase of treatment . However , self-reported craving and nicotine withdrawal symptoms were reduced BACKGROUND Varenicline is approved as an aid to smoking cessation in adults aged > or = 18 years . OBJECTIVE The goal of this study was to characterize the multiple-dose pharmacokinetics , safety , and tolerability of varenicline in adolescent smokers . METHODS This multicenter , r and omized , double-blind , placebo-controlled , parallel-group study enrolled healthy 12- to 16-year-old smokers ( > or =3 cigarettes daily ) into high-body-weight ( > 55 kg ) and low-body-weight ( < or = 55 kg ) groups . Subjects were r and omized to receive 14 days of treatment with a high dose of varenicline , a low dose of varenicline , or placebo . The varenicline doses in the high-body-weight group were 1 mg BID and 0.5 mg BID ; the varenicline doses in the low-body-weight group were 0.5 mg BID and 0.5 mg once daily . The apparent renal clearance ( CL/F ) and volume of distribution ( V/F ) of varenicline and the effect of body weight on these parameters were estimated using nonlinear mixed-effects modeling . RESULTS The high-body-weight group consisted of 35 subjects ( 65.7 % male ; 77.1 % white ; mean age , 15.2 years ) . The low-body-weight group consisted of 37 subjects ( 37.8 % male ; 48.6 % white ; mean age , 14.3 years ) . The pharmacokinetic parameters of varenicline were dose proportional over the dose range from 0.5 to 2 mg/d . The CL/F for a 70-kg adolescent was 10.4 L/h , comparable to that in a 70-kg adult . The estimated varenicline V/F was decreased in individuals of small body size , thus predicting a varenicline C(max ) approximately 30 % greater in low-body-weight subjects than in high-body-weight subjects . In high-body-weight subjects , steady-state varenicline exposure , as represented by the AUC(0 - 24 ) , was 197.0 ng . h/mL for varenicline 1 mg BID and 95.7 ng . h/mL for varenicline 0.5 mg BID , consistent with values reported previously in adult smokers at the equivalent doses . In low-body-weight subjects , varenicline exposure was 126.3 ng . h/mL for varenicline 0.5 mg BID and 60.1 ng . h/mL for varenicline 0.5 mg once daily , values at the lower end of the range observed previously in adults at doses of 1 mg BID and 0.5 mg BID , respectively . Among high-body-weight subjects , adverse events ( AEs ) were reported by 57.1 % of subjects in both the high- and low-dose varenicline groups and by 14.3 % of subjects in the placebo group ; among low-body-weight subjects , AEs were reported by 64.3 % , 73.3 % , and 12.5 % of subjects in the high-dose varenicline , low-dose varenicline , and placebo groups , respectively . The most common AEs were nausea , headache , vomiting , and dizziness . Psychiatric AEs that were considered treatment related included abnormal dreams in 2 subjects and mild , transient anger in 1 subject . Of the AEs reported by > or = 1 subject in any treatment group , > or = 92 % were mild in intensity . No subject discontinued the study because of an AE . CONCLUSIONS Varenicline steady-state exposure in study subjects weighing > 55 kg was similar to that observed previously in adults . The body-weight effect on varenicline pharmacokinetics , which result ed in higher exposure in individuals of smaller body size ( < or = 55 kg ) , was adequately offset by administration of half the varenicline dose recommended in adults . Varenicline was generally well tolerated during the 14-day treatment period . Clinical Trials Identification Number : NCT00463918 Background — Smoking cessation is a key component of secondary cardiovascular disease prevention . Varenicline , a partial & agr;4&bgr;2 nicotinic acetylcholine receptor agonist , is effective for smoking cessation in healthy smokers , but its efficacy and safety in smokers with cardiovascular disease are unknown . Methods and Results — A multicenter , r and omized , double-blind , placebo-controlled trial compared the efficacy and safety of varenicline with placebo for smoking cessation in 714 smokers with stable cardiovascular disease . Participants received varenicline ( 1 mg twice daily ) or placebo , along with smoking-cessation counseling , for 12 weeks . Follow-up lasted 52 weeks . The primary end point was carbon monoxide – confirmed continuous abstinence rate for weeks 9 through 12 ( last 4 weeks of treatment ) . The continuous abstinence rate was higher for varenicline than placebo during weeks 9 through 12 ( 47.0 % versus 13.9 % ; odds ratio , 6.11 ; 95 % confidence interval [ CI ] , 4.18 to 8.93 ) and weeks 9 through 52 ( 19.2 % versus 7.2 % ; odds ratio , 3.14 ; 95 % CI , 1.93 to 5.11 ) . The varenicline and placebo groups did not differ significantly in cardiovascular mortality ( 0.3 % versus 0.6 % ; difference , −0.3 % ; 95 % CI , −1.3 to 0.7 ) , all-cause mortality ( 0.6 % versus 1.4 % ; difference , −0.8 % ; 95 % CI , −2.3 to 0.6 ) , cardiovascular events ( 7.1 % versus 5.7 % ; difference , 1.4 % ; 95 % CI , −2.3 to 5.0 ) , or serious adverse events ( 6.5 % and 6.0 % ; difference , 0.5 % ; 95 % CI , −3.1 to 4.1 ) . As a result of adverse events , 9.6 % of varenicline and 4.3 % of placebo participants discontinued study drug . Conclusions — Varenicline is effective for smoking cessation in smokers with cardiovascular disease . It was well tolerated and did not increase cardiovascular events or mortality ; however , trial size and duration limit definitive conclusions about safety . Clinical Trial Registration Information— URL : http://www . clinical trials.gov/ct2/show/NCT00282984 . Unique identifier : NCT00282984 UNLABELLED There are few data concerning changes in lung function and respiratory symptoms in smokers with chronic obstructive pulmonary disease ( COPD ) weeks to months after quitting smoking . We examined serial changes in spirometry and Clinical COPD Question naire ( CCQ ) scores ( measuring respiratory symptoms and health-related quality of life ) in COPD participants by smoking status during a smoking cessation trial . In this r and omized , double-blind trial , smokers with mild-to-moderate COPD were treated with varenicline 1 mg b.i.d . or placebo for 12 weeks and followed to Week 52 . Primary endpoints of abstinence were previously reported . Secondary endpoints were mean changes from baseline in post-bronchodilator forced expired volume in 1 s ( FEV(1 ) ) and CCQ scores . Change from baseline in post-bronchodilator FEV(1 ) was significantly improved in continuous abstainers ( 121.8 mL ) vs. continuous smokers ( 37.9 mL ) at Week 12 ( P = 0.0069 ) , but not at Weeks 24 or 52 . Mean change from baseline at Week 12 in CCQ Total Score was significantly better in continuous abstainers ( -1.04 ) vs. continuous smokers ( -0.53 ; P < 0.0001 ) : this improvement was sustained at Weeks 24 and 52 . In a 1-year cessation trial of smokers with COPD , continuous abstinence compared with continuous smoking significantly improved post-bronchodilator FEV(1 ) at Week 12 ( although the difference narrowed subsequently ) and CCQ Total Scores at Week 12 , with sustained improvement thereafter . ( TRIAL REGISTRY http://www . clinical trials.gov ; trial identifier : NCT00285012 ) BACKGROUND Currently available smoking cessation therapies have limited success rates . Varenicline tartrate is a novel , selective nicotinic receptor partial agonist developed specifically for smoking cessation . This study evaluated the efficacy , tolerability , and safety of 3 varenicline doses for smoking cessation . Bupropion hydrochloride was included as an active control . METHODS A phase 2 , multicenter , r and omized , double-blind , placebo-controlled study of healthy smokers ( 18 - 65 years old ) . Subjects were r and omized to varenicline tartrate , 0.3 mg once daily ( n = 128 ) , 1.0 mg once daily ( n = 128 ) , or 1.0 mg twice daily ( n = 127 ) , for 6 weeks plus placebo for 1 week ; to 150-mg sustained-release bupropion hydrochloride twice daily ( n = 128 ) for 7 weeks ; or to placebo ( n = 127 ) for 7 weeks . RESULTS During the treatment phase , the continuous quit rates for any 4 weeks were significantly higher for varenicline tartrate , 1.0 mg twice daily ( 48.0 % ; P<.001 ) and 1.0 mg once daily ( 37.3 % ; P<.001 ) , than for placebo ( 17.1 % ) . The bupropion rate was 33.3 % ( P = .002 vs placebo ) . The carbon monoxide-confirmed continuous quit rates from week 4 to week 52 were significantly higher in the varenicline tartrate , 1.0 mg twice daily , group compared with the placebo group ( 14.4 % vs 4.9 % ; P = .002 ) . The bupropion rate was 6.3 % ( P = .60 vs placebo ) . Discontinuation owing to treatment-emergent adverse events was 15.9 % for bupropion , 11.2 % to 14.3 % for varenicline , and 9.8 % for placebo . No dose-related increases occurred in adverse events for varenicline . CONCLUSIONS Varenicline tartrate demonstrated both short-term ( 1 mg twice daily and 1 mg once daily ) and long-term efficacy ( 1 mg twice daily ) vs placebo . Varenicline was well tolerated and may provide a novel therapy to aid smoking cessation BACKGROUND Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion . Their efficacy relative to nicotine patch largely relies on indirect comparisons , and there is limited information on safety and efficacy in smokers with psychiatric disorders . We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders . METHODS We did a r and omised , double-blind , triple-dummy , placebo-controlled and active-controlled ( nicotine patch ; 21 mg per day with taper ) trial of varenicline ( 1 mg twice a day ) and bupropion ( 150 mg twice a day ) for 12 weeks with 12-week non-treatment follow-up done at 140 centres ( clinical trial centres , academic centres , and outpatient clinics ) in 16 countries between Nov 30 , 2011 , and Jan 13 , 2015 . Participants were motivated-to-quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit . R and omisation was computer generated ( 1:1:1:1 ratio ) . Participants , investigators , and research personnel were masked to treatment assignments . The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events . The main efficacy endpoint was biochemically confirmed continuous abstinence for weeks 9 - 12 . All participants r and omly assigned were included in the efficacy analysis and those who received treatment were included in the safety analysis . The trial is registered at Clinical Trials.gov ( number NCT01456936 ) and is now closed . FINDINGS 8144 participants were r and omly assigned , 4116 to the psychiatric cohort ( 4074 included in the safety analysis ) and 4028 to the non-psychiatric cohort ( 3984 included in the safety analysis ) . In the non-psychiatric cohort , 13 ( 1·3 % ) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group , 22 ( 2·2 % ) of 989 in the bupropion group , 25 ( 2·5 % ) of 1006 in the nicotine patch group , and 24 ( 2·4 % ) of 999 in the placebo group . The varenicline-placebo and bupropion-placebo risk differences ( RDs ) for moderate and severe neuropsychiatric adverse events were -1·28 ( 95 % CI -2·40 to -0·15 ) and -0·08 ( -1·37 to 1·21 ) , respectively ; the RDs for comparisons with nicotine patch were -1·07 ( -2·21 to 0·08 ) and 0·13 ( -1·19 to 1·45 ) , respectively . In the psychiatric cohort , moderate and severe neuropsychiatric adverse events were reported in 67 ( 6·5 % ) of 1026 participants in the varenicline group , 68 ( 6·7 % ) of 1017 in the bupropion group , 53 ( 5·2 % ) of 1016 in the nicotine patch group , and 50 ( 4·9 % ) of 1015 in the placebo group . The varenicline-placebo and bupropion-placebo RDs were 1·59 ( 95 % CI -0·42 to 3·59 ) and 1·78 ( -0·24 to 3·81 ) , respectively ; the RDs versus nicotine patch were 1·22 ( -0·81 to 3·25 ) and 1·42 ( -0·63 to 3·46 ) , respectively . Varenicline-treated participants achieved higher abstinence rates than those on placebo ( odds ratio [ OR ] 3·61 , 95 % CI 3·07 to 4·24 ) , nicotine patch ( 1·68 , 1·46 to 1·93 ) , and bupropion ( 1·75 , 1·52 to 2·01 ) . Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo ( OR 2·07 [ 1·75 to 2·45 ] and 2·15 [ 1·82 to 2·54 ] , respectively ) . Across cohorts , the most frequent adverse events by treatment group were nausea ( varenicline , 25 % [ 511 of 2016 participants ] ) , insomnia ( bupropion , 12 % [ 245 of 2006 participants ] ) , abnormal dreams ( nicotine patch , 12 % [ 251 of 2022 participants ] ) , and headache ( placebo , 10 % [ 199 of 2014 participants ] ) . Efficacy treatment comparison did not differ by cohort . INTERPRETATION The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo . Varenicline was more effective than placebo , nicotine patch , and bupropion in helping smokers achieve abstinence , whereas bupropion and nicotine patch were more effective than placebo . FUNDING Pfizer and GlaxoSmithKline Aims We assessed to what degree smokers who fail to quit on the target quit date ( TQD ) or lapse following TQD eventually achieve success with continued treatment . Design A secondary analysis of pooled data of successful quitters treated with varenicline ( 306 of 696 ) , bupropion ( 199 of 671 ) and placebo ( 121 of 685 ) from two identically- design ed clinical trials of varenicline versus bupropion sustained-release and placebo . Setting Multiple research centers in the US . Participants Adult smokers ( n = 2052 ) r and omized to 12 weeks drug treatment plus 40 weeks follow-up . Measurement The primary end-point for the trials was continuous abstinence for weeks 9–12 . TQD was day 8 . Two patterns of successful quitting were identified . Immediate quitters ( IQs ) were continuously abstinent for weeks 2–12 . Delayed quitters ( DQs ) smoked during 1 or more weeks for weeks 2–8 . Findings Cumulative continuous abstinence ( IQs + DQs ) increased for all treatments during weeks 3–8 . Overall IQs and DQs for varenicline were ( 24 % ; 20 % ) versus bupropion ( 18.0 % , P = 0.007 ; 11.6 % , P < 0.001 ) or placebo ( 10.2 % , P < 0.001 ; 7.5 % , P < 0.001 ) . However , DQs as a proportion of successful quitters was similar for all treatments ( varenicline 45 % ; bupropion 39 % ; placebo 42 % ) and accounted for approximately one-third of those remaining continuously abstinent for weeks 9–52 . No gender differences were observed by quit pattern . Post-treatment relapse was similar across groups . Conclusions Our data support continuing cessation treatments without interruption for smokers motivated to remain in the quitting process despite lack of success early in the treatment Background : Varenicline , a new treatment for smoking cessation , has demonstrated significantly greater efficacy over placebo and sustained release bupropion ( bupropion SR ) . A study was undertaken to compare a 12-week st and ard regimen of varenicline with a 10-week st and ard regimen of transdermal nicotine replacement therapy ( NRT ) for smoking cessation . Methods : In this 52-week , open-label , r and omised , multicentre , phase 3 trial conducted in Belgium , France , the Netherl and s , UK and USA , participants were r and omly assigned ( 1:1 ) to receive varenicline uptitrated to 1 mg twice daily for 12 weeks or transdermal NRT ( 21 mg/day reducing to 7 mg/day ) for 10 weeks . Non-treatment follow-up continued to week 52 . The primary outcome was the biochemically confirmed ( exhaled carbon monoxide ⩽10 ppm ) self-reported continuous abstinence rate ( CAR ) for the last 4 weeks of the treatment period in participants who had taken at least one dose of treatment . Secondary outcomes included CAR from the last 4 weeks of treatment through weeks 24 and 52 , and measures of craving , withdrawal and smoking satisfaction . Results : A total of 376 and 370 participants assigned to varenicline and NRT , respectively , were eligible for analysis . The CAR for the last 4 weeks of treatment was significantly greater for varenicline ( 55.9 % ) than NRT ( 43.2 % ; OR 1.70 , 95 % CI 1.26 to 2.28 , p<0.001 ) . The week 52 CAR ( NRT , weeks 8–52 ; varenicline , weeks 9–52 ) was 26.1 % for varenicline and 20.3 % for NRT ( OR 1.40 , 95 % CI 0.99 to 1.99 , p = 0.056 ) . Varenicline significantly reduced craving ( p<0.001 ) , withdrawal symptoms ( p<0.001 ) and smoking satisfaction ( p<0.001 ) compared with NRT . The most frequent adverse event was nausea ( varenicline , 37.2 % ; NRT , 9.7 % ) . Conclusions : The outcomes of this trial established that abstinence from smoking was greater and craving , withdrawal symptoms and smoking satisfaction were less at the end of treatment with varenicline than with transdermal NRT . Trial registration number : NCT00143325 Background Tobacco cessation medication adherence is one of the few factors shown to improve smoking cessation rates among methadone-maintained smokers , but interventions to improve adherence to smoking cessation medications have not yet been tested among methadone treatment patients . Methadone clinic-based , directly observed therapy ( DOT ) programs for HIV and tuberculosis improve adherence and clinical outcomes , but have not been evaluated for smoking cessation . We describe a r and omized controlled trial to evaluate whether a methadone clinic-based , directly observed varenicline therapy program increases adherence and tobacco abstinence among opioid-dependent drug users receiving methadone treatment . Methods / Design We plan to enroll 100 methadone-maintained smokers and r and omize them to directly observed varenicline dispensed with daily methadone doses or treatment as usual ( self-administered varenicline ) for 12 weeks . Our outcome measures are : 1 ) pill count adherence and 2 ) carbon monoxide-verified tobacco abstinence . We will assess differences in adherence and abstinence between the two treatment arms using repeated measures models . Discussion This trial will allow for rigorous evaluation of the efficacy of methadone clinic-based , directly observed varenicline for improving adherence and smoking cessation outcomes . This detailed description of trial methodology can serve as a template for the development of future DOT programs and can guide protocol s for studies among opioid-dependent smokers receiving methadone treatment . Trial Registration clinical trials.gov Background Smoking is the leading cause of preventable death in the US . While one in five individuals smoke , and 70 % of these indicate a desire to quit , < 5 % of unaided quit attempts succeed . Cessation aids can double or triple the odds of successfully quitting . Models of smoking-cessation behaviour can eluci date the implication s of individual abstinence patterns to allow better tailoring of quit attempts to an individual ’s characteristics . Objective The objectives of this study were to develop and vali date a discrete-event simulation ( DES ) to evaluate the benefits of smoking abstinence using data from the pooled pivotal clinical trials of varenicline versus bupropion or placebo for smoking cessation and to provide a foundation for the development of a lifetime smoking-cessation model . Methods The DES model simulated the outcome of a single smoking-cessation attempt over 1 year , in accordance with the clinical trial timeframes . Pharmaceutical costs were assessed from the perspective of a healthcare payer . The model r and omly sample d patient profiles from the pooled varenicline clinical trials . All patients were physically and mentally healthy adult smokers who were motivated to quit abruptly . The model allowed for comparisons of up to five distinct treatment approaches for smoking cessation . In the current analyses , three interventions corresponding to the clinical trials were evaluated , which included brief counselling plus varenicline 1.0 mg twice daily ( bid ) or bupropion SR 150 mg bid versus placebo ( i.e. brief counselling only ) . The treatment periods in the clinical trials were 12 weeks ( target quit date : day 8) , with a 40-week non-treatment follow-up , and counselling continuing over the entire 52-week period in all treatment groups . The main outcome modelled was the continuous abstinence rate ( CAR ; defined as complete abstinence from smoking and confirmed by exhaled carbon monoxide ≤10 ppm ) at end of treatment ( weeks 9–12 ) and long-term follow-up ( weeks 9–52 ) , and total time abstinent from smoking over the course of 52 weeks . The model also evaluated costs and cost-effectiveness outcomes . Results For the varenicline , bupropion and placebo cohorts , respectively , the model predicted CARs for weeks 9–12 of 44.3 % , 30.4 % and 18.6 % compared with observed rates of 44.0 % , 29.7 % and 17.7 % ; over weeks 9–52 , predicted CARs in the model compared with observed rates in the pooled clinical studies were 22.9 % , 16.4 % and 9.4 % versus 22.4 % , 15.4 % and 9.3 % , respectively . Total mean abstinence times accrued in the model varenicline , bupropion and placebo groups , respectively , were 3.6 , 2.6 and 1.5 months and total pharmaceutical treatment costs were $ US261 , $ US442 and $ US0 ( year 2008 values ) over the 1-year model period . Using cost per abstinent-month achieved as a measure of cost effectiveness , varenicline dominated bupropion and yielded an incremental cost-effectiveness ratio of $ US124 compared with placebo . Conclusion The model accurately replicated abstinence patterns observed in the clinical trial data using individualized predictions and indicated that varenicline was more effective and may be less costly than bupropion . This simulation incorporated individual predictions of abstinence and relapse , and provides a framework for lifetime modelling that considers multiple quit attempts over time in diverse patient population s using a variety of quit attempt strategies Pre clinical research and learning theory suggest that a longer duration of varenicline treatment prior to the target quit date ( TQD ) would reduce smoking rates before cessation and improve abstinence outcomes . A double‐blind r and omized controlled trial tested this hypothesis in 60 smokers r and omized to either an Extended run‐in group ( 4 weeks of pre‐TQD varenicline ) or a St and ard run‐in group ( 3 weeks of placebo , 1 week of pre‐TQD varenicline ) ; all the participants received 11 weeks of post‐TQD varenicline and brief counseling . During the pre‐quit run‐in , the reduction in smoking rates was greater in the Extended run‐in group than in the St and ard run‐in group ( 42 % vs. 24 % , P < 0.01 ) , and this effect was greater in women than in men ( 57 % vs. 26 % , P = 0.001 ) . The rate of continuous abstinence during the final 4 weeks of treatment was higher among women in the Extended group compared to women in the St and ard run‐in group ( 67 % vs. 35 % ) . Although these data suggest that extension of varenicline treatment reduces smoking during the pre‐quit period and may further enhance cessation rates , confirmatory evidence is needed from phase III clinical trials Rationale Varenicline , an approved smoking cessation pharmacotherapy , also shows promise as a potential treatment for alcohol dependence . However , varenicline has not been tested in heavy drinkers , and it remains to be determined whether varenicline could reduce alcohol craving and consumption in smokers who are trying to quit smoking . Objectives We conducted a preliminary study to examine the effect of varenicline on drinking behavior and the effects of extended varenicline pretreatment on smoking . Methods Thirty heavy drinking smokers received smoking cessation counseling and were r and omly assigned to receive either an extended 4-week pretreatment with varenicline 2 mg daily or the usual 1-week pretreatment . Those in the extended pretreatment group received active medication for 8 weeks ( i.e. , 4 weeks of active pre-treatment followed by 4 weeks of active treatment ) , and participants in the usual pretreatment group received active medication after a placebo lead in ( i.e. , 3 weeks of placebo followed by active medication for 5 weeks ) . Results Participants who received varenicline during the first 3 weeks reported significantly greater reductions in alcohol craving and numerically fewer heavy drinking days compared to those who received placebo , and these differences persisted during the open-label phase . Extended pretreatment was associated with numerically greater reductions in cigarette smoking over the entire study period . There were no differences , however , in smoking abstinence rates following the smoking quit date between the two groups . Conclusions Findings from this preliminary study suggest that varenicline may be a promising strategy for concurrently reducing heavy drinking and promoting smoking changes in heavy drinkers INTRODUCTION Varenicline , a first-line non-nicotine medication , has not been evaluated in Black smokers , and limited attention has been paid to pharmacotherapy adherence in smoking cessation trials . This pilot study estimated quit rates for Black smokers treated with varenicline and tested a behavioral intervention to aid varenicline adherence . METHODS Seventy-two Black smokers ( > 10 cigarettes per day ; cpd ) were r and omly assigned to adherence support ( AS ; n = 36 ) or st and ard care ( n = 36 ) . All participants received 3 months of varenicline and a single counseling session focused on making a quit plan . AS participants received 5 additional counseling sessions to encourage medication use . Outcome measures included salivary cotinine , and carbon monoxide confirmed smoking abstinence , reductions in self-reported cpd , and pill counts of varenicline adherence at Months 1 , 2 , and 3 . RESULTS Sixty-one participants ( 84.7 % ) completed follow-up at Month 3 . Participants were female ( 62.5 % ) , 46.8 years of age , and smoked 16.3 cpd . No treatment group differences were found on the smoking or adherence outcome measures ( p > .05 ) . Collapsing across treatment , varenicline adherence was adequate ( 86.1 % ) , yet despite a reduction of 12.2 ( 6.5 ) cpd from baseline to Month 3 ( p < 0.001 ) , only 23.6 % were confirmed quit at Month 3 . Participants who were quit at Month 3 had higher varenicline adherence rates ( 95.8 % ) than those who continued to smoke ( 80.8 % , p ≤ .05 ) . CONCLUSIONS Studies are needed to examine the efficacy of varenicline among Black smokers . Interventions to facilitate adherence to pharmacotherapy warrant further attention as adherence is linked to improved tobacco abstinence 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 There is substantial scope for improvement in the current arsenal of smoking cessation methods and techniques : even when front-line cessation treatments are utilized , smokers are still more likely to fail than to succeed . Studies testing the incremental benefit of using nicotine patch for 1–4 weeks prior to quitting have shown pre-quit nicotine patch use produces a robust incremental improvement over st and ard post-quit patch treatment . The primary objective of the current study is to test the mechanism of action of two pre-quit smoking cessation medications — varenicline and nicotine patch — in order to learn how best to optimize these pre-quit treatments . Methods / Design The study is a three group , r and omized , open-label controlled clinical trial . Participants ( n = 216 interested quitters ) will be r and omized to receive st and ard patch treatment ( 10 weeks of patch starting from a design ated quit day ) , pre-quit patch treatment ( two weeks of patch treatment prior to a quit day , followed by 10 weeks post-quit treatment ) or varenicline ( starting two weeks prior to quit day followed by 10 weeks post-quit ) . Participants will use study -specific modified smart-phones to monitor their smoking , withdrawal symptoms , craving , mood and social situations in near real-time over four weeks ; two weeks prior to an assigned quit date and two weeks after this date . Smoking and abstinence will be assessed at regular study visits and biochemically verified . Discussion Underst and ing how nicotine patches and varenicline influence abstinence may allow for better tailoring of these treatments to individual smokers . Trial registration Australian New Zeal and Clinical Trials Registry , ACTRN12614000329662 ( Registered : 27 March 2014 ) IMPORTANCE Some cigarette smokers may not be ready to quit immediately but may be willing to reduce cigarette consumption with the goal of quitting . OBJECTIVE To determine the efficacy and safety of varenicline for increasing smoking abstinence rates through smoking reduction . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled , multinational clinical trial with a 24-week treatment period and 28-week follow-up conducted between July 2011 and July 2013 at 61 centers in 10 countries . The 1510 participants were cigarette smokers who were not willing or able to quit smoking within the next month but willing to reduce smoking and make a quit attempt within the next 3 months . Participants were recruited through advertising . INTERVENTIONS Twenty-four weeks of varenicline titrated to 1 mg twice daily or placebo with a reduction target of 50 % or more in number of cigarettes smoked by 4 weeks , 75 % or more by 8 weeks , and a quit attempt by 12 weeks . MAIN OUTCOMES AND MEASURES Primary efficacy end point was carbon monoxide-confirmed self-reported abstinence during weeks 15 through 24 . Secondary outcomes were carbon monoxide-confirmed self-reported abstinence for weeks 21 through 24 and weeks 21 through 52 . RESULTS The varenicline group ( n = 760 ) had significantly higher continuous abstinence rates during weeks 15 through 24 vs the placebo group ( n = 750 ) ( 32.1 % for the varenicline group vs 6.9 % for the placebo group ; risk difference ( RD ) , 25.2 % [ 95 % CI , 21.4%-29.0 % ] ; relative risk ( RR ) , 4.6 [ 95 % CI , 3.5 - 6.1 ] ) . The varenicline group had significantly higher continuous abstinence rates vs the placebo group during weeks 21 through 24 ( 37.8 % for the varenicline group vs 12.5 % for the placebo group ; RD , 25.2 % [ 95 % CI , 21.1%-29.4 % ] ; RR , 3.0 [ 95 % CI , 2.4 - 3.7 ] ) and weeks 21 through 52 ( 27.0 % for the varenicline group vs 9.9 % for the placebo group ; RD , 17.1 % [ 95 % CI , 13.3%-20.9 % ] ; RR , 2.7 [ 95 % CI , 2.1 - 3.5 ] ) . Serious adverse events occurred in 3.7 % of the varenicline group and 2.2 % of the placebo group ( P = .07 ) . CONCLUSIONS AND RELEVANCE Among cigarette smokers not willing or able to quit within the next month but willing to reduce cigarette consumption and make a quit attempt at 3 months , use of varenicline for 24 weeks compared with placebo significantly increased smoking cessation rates at the end of treatment , and also at 1 year . Varenicline offers a treatment option for smokers whose needs are not addressed by clinical guidelines recommending abrupt smoking cessation . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01370356 BACKGROUND The selective nicotinic acetylcholine receptor partial agonist , varenicline tartrate , represents a novel type of therapy for smoking cessation . This study evaluated the efficacy , safety , and tolerability of 4 varenicline dose regimens , 2 with progressive dosing over the first week ( eg , titrated ) and 2 with a fixed dosing schedule ( eg , non-titrated ) , for promoting smoking cessation . METHODS This multicenter , double-blind , placebo-controlled study r and omized healthy smokers ( aged 18 - 65 years ) to varenicline tartrate , 0.5 mg twice daily nontitrated ( n = 129 ) , 0.5 mg twice daily titrated ( n = 130 ) , 1.0 mg twice daily nontitrated ( n = 129 ) , 1.0 mg twice daily titrated ( n = 130 ) , or placebo ( n = 129 ) for 12 weeks to aid in smoking cessation . A 40-week follow-up period assessed long-term efficacy . The primary efficacy measures were the carbon monoxide-confirmed 4-week continuous quit rates by pooled dosage group for weeks 4 through 7 and 9 through 12 and the continuous abstinence rates for weeks 9 through 52 . RESULTS Weeks 9 through 12 continuous quit rates were greater in the 1.0-mg group ( 49.4 % ) and the 0.5-mg group ( 44.0 % ) vs placebo ( 11.6 % ; P<.001 vs both doses ) . Weeks 9 through 52 abstinence rates were greater in the 1.0-mg group ( 22.4 % ; P<.001 ) and the 0.5-mg group ( 18.5 % ; P<.001 ) vs placebo ( 3.9 % ) . Varenicline was generally well tolerated , with nausea occurring in 16 % to 42 % of varenicline-treated subjects . Reports of nausea were lower for the titrated vs nontitrated dosing and infrequently led to medication discontinuation . CONCLUSION Varenicline tartrate , 0.5 mg and 1.0 mg twice daily , is efficacious for smoking cessation BACKGROUND Varenicline was developed to aid smoking cessation by reducing smoking reinforcement . The present study tests this reinforcement-reduction hypothesis among smokers preparing to quit . METHOD After a one-week baseline , treatment-seeking smokers were r and omized to receive three weeks of varenicline or placebo ( Weeks 2 - 4 ) . During each of the four weeks of the study , smokers completed a hypothetical cigarette purchase task ( CPT ) via h and held devices in their natural environment . Behavioral economic measures of simulated smoking if cigarettes were free ( dem and intensity ) , sensitivity of consumption to increasing price ( elasticity ) , and price at which purchases would drop to 0 ( breakpoint ) were estimated . RESULTS The exponential dem and equation fit the purchase task data well across subjects and time . As predicted , dem and intensity decreased and sensitivity to price ( elasticity ) increased over time . However , changes in dem and intensity did not differ by treatment group . Contrary to our hypothesis that varenicline would increase sensitivity to price , the placebo group tended to become more elastic in their purchases during Weeks 2 and 3 ; the groups did not differ in elasticity at Week 4 . Breakpoint did not vary by group , time , or their interaction . CONCLUSION Simulated smoking dem and can be validly assessed in the natural environment of treatment-seeking smokers . Simulated dem and indices of smoking reinforcement diminished as smokers approached their target quit date . However , there was no evidence that varenicline facilitated these changes over a three-week period , leaving open the mechanisms by which varenicline reduces smoking rate prior to cessation and improves long-term abstinence ABSTRACT BACKGROUND Varenicline may be associated with greater mood disturbance and side-effects among smokers with psychiatric history , but empirical evidence is limited . Differential treatment effectiveness by psychiatric history may also exist . OBJECTIVE To compare mood , prevalence and intensity of treatment side-effects , and abstinence among people with a probable history of major depression ( DH+ ) or not ( DH− ) who took varenicline and received behavioral smoking cessation treatment . DESIGN Smokers participated in a r and omized behavioral intervention effectiveness trial . Treatment side-effects and outcomes were compared between DH+ and DH− participants ( n = 1,117 ) at 2 days and 3 months after the target quit date . PARTICIPANTS Smokers recruited from a large regional health plan . MEASUREMENTS Change in stress and depression scores , prevalence and intensity of treatment side-effects , and abstinence rates . RESULTS All side-effects averaged moderate intensity or less and were similar across DH groups , except DH+ ’s endorsed slightly worse confusion , nausea ( adjusted P = 0.04 ) and trouble sleeping ( adjusted P = 0.008 ) at 21 days . Depression and stress scores declined in both DH groups and an equal proportion of each evidence d new/worsening depressive symptoms . Despite few differences in symptom intensity , more DH+ participants reported recent tension/agitation , irritability/anger , confusion , and depression at 21 days ( adjusted P < 0.05 ) , and depression and anxiety ( adjusted P < 0.01 ) at three months . Nonsmoking rates did not differ by DH group at follow-up . CONCLUSION While some group differences were noted , DH+ smokers did not report qualitatively worse neuropsychiatric symptoms , more new/worsening mood disturbance , or differential abstinence rates compared to DH- smokers Background Smokers need effective support to maximise the chances of successful quit attempts . Current smoking cessation medications , such as nicotine replacement therapy ( NRT ) , bupropion , nortriptyline or varenicline , have been shown to be effective in clinical trials but are underused by smokers attempting to quit due to adverse effects , contraindications , low acceptability and /or high cost . Cytisine is a low-cost , plant-based alkaloid that has been sold as a smoking cessation aid in Eastern Europe for 50 years . A systematic review of trial evidence suggests that cytisine has a positive impact on both short- and long-term abstinence rates compared to placebo . However , the quality of the evidence is poor and insufficient for licensing purpose s in many Western countries . A large , well-conducted placebo-controlled trial ( n = 740 ) of cytisine for smoking cessation has recently been published and confirms the findings of earlier studies , with 12-month continuous abstinence rates of 8.4 % in the cytisine group compared to 2.4 % in the placebo group ( Relative risk = 3.4 , 95 % confidence intervals 1.7 - 7.1 ) . No research has yet been undertaken to determine the effectiveness of cytisine relative to that of NRT . Methods / design A single-blind , r and omised controlled , non-inferiority trial has been design ed to determine whether cytisine is at least as effective as NRT in assisting smokers to remain abstinent for at least one month . Participants ( n = 1,310 ) will be recruited through the national telephone-based Quitline service in New Zeal and and r and omised to receive a st and ard 25-day course of cytisine tablets ( Tabex ® ) or usual care ( eight weeks of NRT patch and /or gum or lozenge ) . Participants in both study arms will also receive a behavioural support programme comprising an average of three follow-up telephone calls delivered over an eight-week period by Quitline . The primary outcome is continuous abstinence from smoking at one month , defined as not smoking more than five cigarettes since quit date . Outcome data will also be collected at one week , two months and six months post-quit date . Discussion Cytisine appears to be effective compared with placebo , and given its ( current ) relative low cost may be an acceptable smoking cessation treatment for smokers , particularly those in low- and middle-income countries . Cytisine 's ' natural ' product status may also increase its acceptability and use among certain groups of smokers , such as indigenous people , smokers in countries where the use of natural medicines is widespread ( e.g. China , India ) , and in those people who do not want to use NRT or anti-depressants to help them quit smoking . However it is important to ascertain the effectiveness of cytisine compared with that of existing cessation treatments . Trial registration Australian New Zeal and Clinical Trials Registry ( ACTRN12610000590066 Many persons who attempt to quit smoking have made previous unsuccessful attempts to quit with pharmacologic aids . An underst and ing of the impact of these previous attempts to quit is vital for selecting medications that may be more successful in a future attempt to quit . In particular , the effect of repeated use of bupropion SR ( Zyban ; INN , amfebutamone ) on abstinence rates has not been studied previously OBJECTIVE The authors evaluated an adaptive smoking cessation treatment strategy in which nicotine patch treatment was initiated before a quit date , and then , depending on initial therapeutic response , either the nicotine patch was continued or alternative pharmacotherapies were provided . METHOD The study was a double-blind , parallel-arm adaptive treatment trial . A total of 606 cigarette smokers started open-label nicotine patch treatment 2 weeks before the quit date . Those whose ad lib smoking did not decrease by > 50 % after 1 week were r and omly assigned to one of three double-blind treatments : nicotine patch alone ( control condition ) ; " rescue " treatment with bupropion augmentation of the patch ; or rescue treatment with varenicline alone . Participants whose precessation smoking decreased > 50 % but who lapsed after the quit date were also r and omly assigned to the two rescue treatments or to nicotine patch alone . Logistic regression analyses compared each rescue treatment against the control condition in terms of abstinence at the end of treatment ( weeks 8 - 11 ) and at 6 months . RESULTS Smokers who did not respond adequately to precessation nicotine patch benefited from bupropion augmentation ; abstinence rates at end of treatment were 16 % with nicotine patch alone and 28 % with bupropion augmentation ( odds ratio=2.04 , 95 % CI=1.03 - 4.01 ) . Switching to varenicline produced less robust effects , but point abstinence at 6 months was 6.6 % with the patch alone and 16.5 % with a switch to varenicline ( odds ratio=2.80 , 95 % CI=1.11 - 7.06 ) . Postquit adaptive changes in treatment had no significant effects on any abstinence outcome . CONCLUSIONS It is possible to rescue a significant portion of smokers who would have failed to achieve abstinence if left on nicotine patch alone by identifying these smokers before their quit date and implementing adaptive changes in treatment AIMS To test the efficacy and safety of varenicline as an aid to smoking cessation in methadone-maintained smokers . DESIGN Multicenter , r and omized , double-blind , placebo-controlled trial with r and om assignment to 12 weeks of varenicline 1 mg twice daily ( n = 57 ) or matched placebo ( n = 55 ) , with in-person and telephone counseling . SETTING Urban methadone programs in the Bronx , New York City , New York , USA . PARTICIPANTS Methadone maintenance patients , smoking ≥5 cigarettes/day , interested in quitting , stable in methadone treatment , without current Axis I psychiatric disorders , suicidal ideation or recent suicide attempts . MEASUREMENTS Seven-day point prevalence abstinence verified by expired carbon monoxide ( CO ) < 8 parts per million at week 12 ( primary outcome ) ; carbon monoxide (CO)-verified abstinence , cigarettes/day , incident Axis I psychiatric illness , suicidal ideation or serious adverse events ( SAEs ) at weeks 2 , 4 , 8 , 12 or 24 ( secondary outcomes ) . FINDINGS Baseline demographic , smoking and clinical factors were similar between groups . Retention at 24 weeks was 90 % . Subjects receiving varenicline were more likely than those receiving placebo to achieve abstinence ( 10.5 versus 0 % , P = 0.03 ; effect size 10.5 % , 95 % confidence interval ( CI ) = 4.4 - 19.3 % ) and to reduce smoking ( median five versus two cigarettes/day , P < 0.001 ) at 12 weeks . These effects were not maintained after drug treatment ceased . Incident psychiatric illness ( OR= 0.84 , 95 % CI = 0.16 , 4.4 ) and suicidality [ odds ratio ( OR ) = 0.88 , 95 % CI 0.2 , 3.9 ] were not different between groups . There were no psychiatric or cardiac SAEs . CONCLUSIONS Varenicline can aid short-term smoking abstinence in methadone-maintained smokers INTRODUCTION This study evaluated the effect of varenicline in combination with counseling to assist long-term nicotine replacement therapy ( NRT ) users to quit NRT . METHODS This was a double-blind , placebo-controlled , r and omized trial of varenicline or placebo for 12 weeks , with 52-week follow-up , performed in 1 hospital-based smoking cessation specialist clinic . At the first visit , 139 ex-smokers and long-term NRT users were allocated to treatment according to a computer-generated list with r and om numbers . Visits were scheduled at Weeks 0 , 2 , 4 , 6 , 9 , 12 , and 52 . At each visit , nurse-led counseling was delivered , carbon monoxide in expired air , plasma cotinine , and body weight were assessed , and subjects were asked about craving , nausea , and dreams . The primary outcome was 12-week point prevalence quit rate ( PPR ) of nicotine replacement therapy use . RESULTS At all time points , the PPR was superior for varenicline versus placebo , although the difference was only statistically significant at 12 and 36 weeks . The PPR was 64.3 % ( varenicline ) versus 40.6 % ( placebo ) at 12 weeks ( p = .006 ) , and 42.9 % ( varenicline ) versus 36.2 % ( placebo ) at 52 weeks ( NS ) . The continuous abstinence rate from Week 9 to Week 12 was 48.6 % ( varenicline ) versus 30.4 % ( placebo ) ( p = .03 ) . Withdrawal symptoms were statistically significantly lower in the varenicline group than the placebo group . CONCLUSION Varenicline for 12 weeks combined with supportive visits was superior to placebo to get long-term NRT users to quit NRT . A larger study is needed to evaluate long-term efficacy The prevalence of smoking in HIV-infected subjects is high . As a smoking cessation aid , varenicline ( Champix ( ® ) , Pfizer , Saint-Laurent , QC , Canada or Chantix ( ® ) , Pfizer , Mission , KS ) has not been previously evaluated in HIV-infected smokers . In this multicenter pilot open label study , varenicline 1.0 mg was used twice daily for 12 weeks with dose titration in the first week . Adverse events ( AEs ) during the treatment period were recorded . Changes from baseline in laboratory tests , vital signs , daily cigarette consumption , nicotine dependence , and withdrawal were measured through week 24 . Self-reported abstinence was vali date d by serum cotinine at week 12 . We enrolled 36 subjects with a mean of 29 pack-years of smoking and a minimum of 4 cigarettes per day . All but 1 were male , 33 ( 92 % ) were white . The most frequently reported AEs were nausea ( 33 % ) , abnormal dreams ( 31 % ) , affect lability ( 19 % ) , and insomnia ( 19 % ) . Six ( 17 % ) subjects discontinued varenicline due to AEs . No grade 3/4 laboratory abnormalities or serious AEs occurred during the study . There was no significant change in HIV viral load . CD4 counts increased by 69 cells/mm3 ( p = 0.001 ) at week 24 . Serum cotinine-verified 4-week continuous abstinence rate through weeks 9 - 12 was 42 % ( 95 % confidence interval [ CI ] : 26 - 58 % ) . AEs and abstinence rates were comparable to those in published r and omized controlled trials conducted in generally healthy HIV-negative smokers . Varenicline was safe and appears effective among HIV-infected smokers in this exploratory study , although AEs were common . The most common AE was nausea , with no adverse effect on HIV treatment outcome . Close monitoring of liver enzymes and blood pressure is recommended for HIV-positive smokers taking varenicline INTRODUCTION Despite tremendous potential public health impact , little work has focused on development of evidence -based smoking cessation treatments for adolescents , including pharmacotherapies . No prior studies have explored the feasibility and safety of varenicline and bupropion XL , 2 potentially promising pharmacotherapies , as smoking cessation treatments in adolescents . METHODS Treatment-seeking older adolescent smokers ( ages 15 - 20 ) were r and omized ( double-blind ) to varenicline ( n = 15 ) or bupropion XL ( n = 14 ) , with 1-week titration and active treatment for 7 weeks . Structured safety , tolerability , and efficacy assessment s ( cotinine-confirmed 7-day point prevalence abstinence ) were conducted weekly . RESULTS There were no serious adverse events . Two participants discontinued bupropion XL due to adverse effects , and none discontinued varenicline . Over the course of treatment , participants receiving varenicline reduced from 14.1 ± 6.3 ( mean ± SD ) to 0.9 ± 2.1 cigarettes/day ( CPD , 4 achieved abstinence ) , while those receiving bupropion XL reduced from 15.8 ± 4.4 to 3.1 ± 4.0 CPD ( 2 achieved abstinence ) . CONCLUSIONS These preliminary results support the feasibility and safety of conducting adequately powered , placebo-controlled efficacy studies of varenicline and bupropion XL for adolescent smoking cessation IMPORTANCE Behavioral approaches and pharmacotherapy are of proven benefit in assisting smokers to quit , but it is unclear whether combining nicotine replacement therapy ( NRT ) with varenicline to improve abstinence is effective and safe . OBJECTIVE To evaluate the efficacy and safety of combining varenicline and a nicotine patch vs varenicline alone in smoking cessation . DESIGN , SETTING , AND PARTICIPANTS R and omized , blinded , placebo-controlled clinical trial with a 12-week treatment period and a further 12-week follow-up conducted in 7 centers in South Africa from April 2011 to October 2012 . Four hundred forty-six generally healthy smokers were r and omized ( 1:1 ) ; 435 were included in the efficacy and safety analyses . INTERVENTIONS Nicotine or placebo patch treatment began 2 weeks before a target quit date ( TQD ) and continued for a further 12 weeks . Varenicline was begun 1 week prior to TQD , continued for a further 12 weeks , and tapered off during week 13 . MAIN OUTCOMES AND MEASURES Tobacco abstinence was established and confirmed by exhaled carbon monoxide measurements at TQD and at intervals thereafter up to 24 weeks . The primary end point was the 4-week exhaled carbon monoxide-confirmed continuous abstinence rate for weeks 9 through 12 of treatment , ie , the proportion of participants able to maintain complete abstinence from smoking for the last 4 weeks of treatment , as assessed using multiple imputation analysis . Secondary end points included point prevalence abstinence at 6 months , continuous abstinence rate from weeks 9 through 24 , and adverse events . Multiple imputation also was used to address loss to follow-up . RESULTS The combination treatment was associated with a higher continuous abstinence rate at 12 weeks ( 55.4 % vs 40.9 % ; odds ratio [ OR ] , 1.85 ; 95 % CI , 1.19 - 2.89 ; P = .007 ) and 24 weeks ( 49.0 % vs 32.6 % ; OR , 1.98 ; 95 % CI , 1.25 - 3.14 ; P = .004 ) and point prevalence abstinence rate at 6 months ( 65.1 % vs 46.7 % ; OR , 2.13 ; 95 % CI , 1.32 - 3.43 ; P = .002 ) . In the combination treatment group , there was a numerically greater incidence of nausea , sleep disturbance , skin reactions , constipation , and depression , with only skin reactions reaching statistical significance ( 14.4 % vs 7.8 % ; P = .03 ) ; the varenicline-alone group experienced more abnormal dreams and headaches . CONCLUSIONS AND RELEVANCE Varenicline in combination with NRT was more effective than varenicline alone at achieving tobacco abstinence at 12 weeks ( end of treatment ) and at 6 months . Further studies are needed to assess long-term efficacy and safety . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01444131 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 IMPORTANCE Combining pharmacotherapies for tobacco-dependence treatment may increase smoking abstinence . OBJECTIVE To determine efficacy and safety of varenicline and bupropion sustained-release ( SR ; combination therapy ) compared with varenicline ( monotherapy ) in cigarette smokers . DESIGN , SETTING , AND PARTICIPANTS R and omized , blinded , placebo-controlled multicenter clinical trial with a 12-week treatment period and follow-up through week 52 conducted between October 2009 and April 2013 at 3 midwestern clinical research sites . Five hundred six adult ( ≥18 years ) cigarette smokers were r and omly assigned and 315 ( 62 % ) completed the study . INTERVENTIONS Twelve weeks of varenicline and bupropion SR or varenicline and placebo . MAIN OUTCOMES AND MEASURES Primary outcome was abstinence rates at week 12 , defined as prolonged ( no smoking from 2 weeks after the target quit date ) abstinence and 7-day point-prevalence ( no smoking past 7 days ) abstinence . Secondary outcomes were prolonged and point-prevalence smoking abstinence rates at weeks 26 and 52 . Outcomes were biochemically confirmed . RESULTS At 12 weeks , 53.0 % of the combination therapy group achieved prolonged smoking abstinence and 56.2 % achieved 7-day point-prevalence smoking abstinence compared with 43.2 % and 48.6 % in varenicline monotherapy ( odds ratio [ OR ] , 1.49 ; 95 % CI , 1.05 - 2.12 ; P = .03 and OR , 1.36 ; 95 % CI , 0.95 - 1.93 ; P = .09 , respectively ) . At 26 weeks , 36.6 % of the combination therapy group achieved prolonged and 38.2 % achieved 7-day point-prevalence smoking abstinence compared with 27.6 % and 31.9 % in varenicline monotherapy ( OR , 1.52 ; 95 % CI , 1.04 - 2.22 ; P = .03 and OR , 1.32 ; 95 % CI , 0.91 - 1.91 ; P = .14 , respectively ) . At 52 weeks , 30.9 % of the combination therapy group achieved prolonged and 36.6 % achieved 7-day point-prevalence smoking abstinence compared with 24.5 % and 29.2 % in varenicline monotherapy ( OR , 1.39 ; 95 % CI , 0.93 - 2.07 ; P = .11 and OR , 1.40 ; 95 % CI , 0.96 - 2.05 ; P = .08 , respectively ) . Participants receiving combination therapy reported more anxiety ( 7.2 % vs 3.1 % ; P = .04 ) and depressive symptoms ( 3.6 % vs 0.8 % ; P = .03 ) . CONCLUSIONS AND RELEVANCE Among cigarette smokers , combined use of varenicline and bupropion , compared with varenicline alone , increased prolonged abstinence but not 7-day point prevalence at 12 and 26 weeks . Neither outcome was significantly different at 52 weeks . Further research is required to determine the role of combination therapy in smoking cessation . TRIAL REGISTRATION clinical trials.gov Identifier : http:// clinical trials.gov/show/NCT00935818 Background : The efficacy of perioperative tobacco interventions on long-term abstinence and the safety of smoking cessation less than 4 weeks before surgery is unclear . Our objective was to determine the efficacy and safety of a perioperative smoking cessation intervention with varenicline to reduce smoking in elective surgical patients . Methods : In a prospect i ve , multicenter , double-blind , placebo-controlled trial , 286 patients were r and omized to receive varenicline or placebo . Both groups received in-hospital and telephone counseling during 12 months . The primary outcome was the 7-day point prevalence abstinence rate 12 months after surgery . Secondary outcomes included abstinence at 3 and 6 months after surgery . Multivariable logistic regression was used to identify independent variables related to abstinence . Results : The 7-day point prevalence abstinence at 12 months for varenicline versus placebo was 36.4 % versus 25.2 % ( relative risk : 1.45 ; 95 % : CI : 1.01–2.07 ; P = 0.04 ) . At 3 and 6 months , the 7-day point prevalence abstinence was 43.7 % versus 31.9 % ( relative risk : 1.37 ; 95 % CI : 1.01 to 1.86 ; P = 0.04 ) , and 35.8 % versus 25.9 % ( relative risk : 1.43 ; 95 % : CI 1.01–2.04 ; P = 0.04 ) for varenicline versus placebo , respectively . Treatment with varenicline ( odds ratio : 1.76 ; 95 % CI : 1.03–3.01 ; P = 0.04 ) , and preoperative nicotine dependence ( odds ratio : 0.82 , 95 % CI : 0.68 to 0.98 ; P = 0.03 ) predicted abstinence at 12 months . The adverse events profile in both groups was similar except for nausea , which occurred more frequently for varenicline versus placebo ( 13.3 % vs. 3.7 % , P = 0.004 ) . Conclusions : A perioperative smoking cessation intervention with varenicline increased abstinence from smoking 3 , 6 , and 12 months after elective noncardiac surgery with no increase in serious adverse events 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 INTRODUCTION Long-term smokeless tobacco ( ST ) use is known to increase the risk for oropharyngeal cancer , heart attack , and stroke . Extant literature on cigarette smokers suggests that smoking reduction increases smoking abstinence among smokers not interested in quitting . Similarly , a reduction strategy may reduce ST exposure and increase ST abstinence rates among ST users not interested in quitting . METHODS We conducted a pilot study to obtain preliminary data on the use of 12 weeks of varenicline as a tobacco reduction strategy among ST users not interested in quitting . RESULTS We enrolled 20 male ST users with a mean age of 42.8 ± 11.7 years who used an average of 3.9 ± 1.7 cans/pouches per week for 18.6 ± 8.6 years . At end of treatment ( 12 weeks ) , 60 % ( 12/20 ) of subjects reduced their ST use by ≥ 50 % and 15 % ( 3/20 ) were biochemically confirmed abstinent from tobacco . At end of study ( 6 months ) , 50 % ( 10/20 ) reduced by ≥ 50 % of baseline use and 10 % ( 2/20 ) were biochemically confirmed abstinent from tobacco . Varenicline reduced ST satisfaction , reward , and craving . Among subjects able to reduce ST , all subjects reported that reduction increased motivation and confidence in being able to maintain reduction and quit . The most common side effects were sleep disturbance ( 25 % ) and nausea ( 15 % ) . DISCUSSION Varenicline may be effective in reducing ST use and achieving ST abstinence among ST users with no plans to quit but who are interested in reducing their ST use IMPORTANCE Given the actions of varenicline tartrate and bupropion hydrochloride sustained-release ( SR ) on neurobiological targets related to affect and reward , it is thought that the modulation of nicotine withdrawal symptoms may contribute to their effectiveness . OBJECTIVE To assess the relative efficacy of varenicline and bupropion SR plus intensive counseling on smoking cessation and emotional functioning . DESIGN AND SETTING Placebo-controlled r and omized clinical trial at a university medical center . PARTICIPANTS In total , 294 community volunteers who wanted to quit smoking . INTERVENTIONS Twelve weeks of varenicline , bupropion SR , or placebo plus intensive smoking cessation counseling ( 10 sessions , for a total of approximately 240 minutes of counseling ) . MAIN OUTCOME MEASURES Prolonged abstinence from smoking and weekly measures of depression , negative affect , and other symptoms of nicotine withdrawal . RESULTS Significant differences were found in abstinence at the end of treatment and through the 3-month postquit follow-up visit , favoring both active medications compared with placebo . At the 6-month postquit follow-up visit , only the varenicline vs placebo comparison remained significant . Varenicline use was also associated with a generalized suppression of depression and reduced smoking reward compared with the other treatments , while both active medications improved concentration , reduced craving , and decreased negative affect and sadness compared with placebo , while having little effect ( increase or decrease ) on anxiety and anger . No differences were noted in self-reported rates of neuropsychiatric adverse events . CONCLUSIONS AND RELEVANCE In a community sample , varenicline exerts a robust and favorable effect on smoking cessation relative to placebo and may have a favorable ( suppressive ) effect on symptoms of depression and other affective measures , with no clear unfavorable effect on neuropsychiatric adverse events . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00507728 Rationale Emerging evidence suggests that the α4β2 form of the nicotinic acetylcholine receptor ( nAChR ) modulates the rewarding effects of alcohol . The nAChR α4β2 subunit partial agonist varenicline ( Chantix ™ ) , which is approved by the Food and Drug Administration for smoking cessation , also decreases ethanol consumption in rodents ( Steensl and et al. , Proc Natl Acad Sci U S A 104:12518–12523 , 2007 ) and in human laboratory and open-label studies ( Fucito et al. , Psychopharmacology ( Berl ) 215:655–663 , 2011 ; McKee et al. , Biol Psychiatry 66:185–190 2009 ) . Objectives We present a r and omized , double-blind , 16-week study in heavy-drinking smokers ( n = 64 r and omized to treatment ) who were seeking treatment for their smoking . The study was design ed to determine the effects of varenicline on alcohol craving and consumption . Outcome measures included number of alcoholic drinks per week , cigarettes per week , amount of alcohol craving per week , cumulative cigarettes and alcoholic drinks consumed during the treatment period , number of abstinent days , and weekly percentage of positive ethyl glucuronide and cotinine screens . Results Varenicline significantly decreases alcohol consumption ( χ2 = 35.32 , p < 0.0001 ) in smokers . Although varenicline has previously been associated with suicidality and depression , side effects were low in this study and declined over time in the varenicline treatment group . Conclusions Varenicline can produce a sustained decrease in alcohol consumption in individuals who also smoke . Further studies are warranted to assess varenicline efficacy in treatment-seeking alcohol abusers who do not smoke and to ascertain the relationship between varenicline effects on smoking and drinking As many as one-half of smokers relapse in the first week following a quit attempt , and subjective reports of cognitive deficits in early abstinence are associated with increased relapse risk . This study examined whether objective cognitive performance after 3 days of abstinence predicts smoking resumption in a 7-day simulated quit attempt . Sixty-seven treatment-seeking smokers received either varenicline or placebo ( r and omized double-blind ) for 21 days . Following medication run-up ( days 1 - 10 ) , there was a 3-day m and atory ( biochemically confirmed ) abstinence period ( days 11 - 13 ) during which working memory ( Letter-N-Back Task ) and sustained attention ( Continuous Performance Task ) were assessed ( day 13 ) . Participants were then exposed to a scheduled smoking lapse and instructed to try to remain abstinent for the next 7 days ( days 15 - 21 ) . Poorer cognitive performance ( slower correct reaction time on Letter-N-Back task ) during abstinence predicted more rapid smoking resumption among those receiving placebo ( p=0.038 ) but not among those receiving varenicline . These data lend further support for the growing recognition that cognitive deficits involving working memory are a core symptom of nicotine withdrawal and a potential target for the development of pharmacological and behavioral treatments INTRODUCTION Measuring adherence to smoking cessation pharmacotherapy is important to evaluating its effectiveness . Blood levels are considered the most accurate measure of adherence but are invasive and costly . Pill counts and self-report are more practical , but little is known about their relationship to blood levels . This study compared the validity of pill count and self-report against plasma varenicline concentration for measuring pharmacotherapy adherence . METHODS Data were obtained from a r and omized pilot study of varenicline for smoking cessation among African American smokers . Adherence was measured on Day 12 via plasma varenicline concentration , pill count , 3-day recall , and a visual analogue scale ( VAS ; adherence was represented on a line with two extremes " no pills " and " all pills " ) . RESULTS The sample consisted of 55 African American moderate to heavy smokers ( average 16.8 cigarettes/day , SD = 5.6 ) and 63.6 % were female . Significant correlations ( p < .05 ) were found between plasma varenicline concentration and pill count ( r = .56 ) , 3-day recall ( r = .46 ) , and VAS ( r = .29 ) . Using plasma varenicline concentration of 2.0 ng/ml as the cutpoint for adherence , pill count demonstrated the largest area under the receiver operating characteristic curve ( AUC = 0.85 , p = .01 ) and had 88 % sensitivity ( 95 % CI = 75.0 - 95.0 ) and 80 % specificity ( 95 % CI = 30.0 - 99.0 ) for detecting adherence . CONCLUSIONS Of 3 commonly used adherence measures , pill count was the most valid for identifying adherence in this sample of African American smokers . Pill count has been used across other health domains and could be incorporated into treatment to identify nonadherence , which , in turn , could maximize smoking cessation pharmacotherapy use and improve abstinence rates INTRODUCTION Combining behavioural support and pharmacotherapy is most effective for smoking cessation and recommended in clinical guidelines . Despite that smoking cessation assistance from the general practitioner can be effective , dissemination of clinical practice guidelines and efforts on upskilling has not lead to the routine provision of smoking cessation advice among general practitioners . Intensive counselling from the practice nurse could contribute to better smoking cessation rates in primary care . However , the effectiveness of intensive counselling from a practice nurse versus usual care from a general practitioner in combination with varenicline is still unknown . MATERIAL S AND METHODS A pragmatic r and omized controlled trial was conducted comparing : ( a ) intensive individual counselling delivered by a practice nurse and ( b ) brief advice delivered by a general practitioner ; both groups received 12-weeks of open-label varenicline . A minimum of 272 adult daily smoking participants were recruited and treated in their routine primary care setting . The primary outcome was defined as prolonged abstinence from weeks 9 to 26 , biochemically vali date d by exhaled carbon monoxide . Data was analysed blinded according to the intention-to-treat principle and participants with missing data on their smoking status at follow-up were counted as smokers . Secondary outcomes included : one-year prolonged abstinence , short-term incremental cost-effectiveness , medication adherence , and baseline predictors of successful smoking cessation . DISCUSSION This trial is the first to provide scientific evidence on the effectiveness , cost-effectiveness , and potential mechanisms of action of intensive practice nurse counselling combined with varenicline under real-life conditions . This paper explains the methodology of the trial and discusses the pragmatic and /or explanatory design aspects . TRIAL REGISTRATION Dutch Trial Register NTR3067 Background Psychiatric adverse drug reactions ( ADRs ) are distressing for patients and have important public health implication s. We identified the drugs with the most frequent spontaneous reports of depression , and fatal and non-fatal suicidal behaviour to the UK ’s Yellow Card Scheme from 1998 to 2011 . Methods We obtained Yellow Card data from the Medicines and Healthcare products Regulatory Agency for the drugs with the most frequent spontaneous reports of depression and suicidal behaviour from 1964 onwards . Prescribing data were obtained from the NHS Information Centre and the Department of Health . We examined the frequency of reports for drugs and estimated rates of reporting of psychiatric ADRs using prescribing data as proxy denominators from 1998 to 2011 , as prescribing data were not available prior to 1998 . Results There were 110 different drugs with ≥ 20 reports of depression , 58 with ≥10 reports of non-fatal suicidal behaviour and 33 with ≥5 reports of fatal suicidal behaviour in the time period . The top five drugs with the most frequent reports of depression were the smoking cessation medicines varenicline and bupropion , followed by paroxetine ( a selective serotonin reuptake inhibitor ) , isotretinoin ( used in acne treatment ) and rimonabant ( a weight loss drug ) . Selective serotonin reuptake inhibitors , varenicline and the antipsychotic medicine clozapine were included in the top five medicines with the most frequent reports of fatal and non-fatal suicidal behaviour . Medicines with the highest reliably measured reporting rates of psychiatric ADRs per million prescriptions dispensed in the community included rimonabant , isotretinoin , mefloquine ( an antimalarial ) , varenicline and bupropion . Robust denominators for community prescribing were not available for two drugs with five or more suicide reports , efavirenz ( an antiretroviral medicine ) and clozapine . Conclusions Depression and suicide-related ADRs are reported for many nervous system and non-nervous system drugs . As spontaneous reports can not be used to determine causality between the drug and the ADR , psychiatric ADRs which can cause significant public alarm should be specifically assessed and reported in all r and omised controlled trials BACKGROUND Placebo-controlled trials indicate that cytisine , a partial agonist that binds the nicotinic acetylcholine receptor and is used for smoking cessation , almost doubles the chances of quitting at 6 months . We investigated whether cytisine was at least as effective as nicotine-replacement therapy in helping smokers to quit . METHODS We conducted a pragmatic , open-label , noninferiority trial in New Zeal and in which 1310 adult daily smokers who were motivated to quit and called the national quitline were r and omly assigned in a 1:1 ratio to receive cytisine for 25 days or nicotine-replacement therapy for 8 weeks . Cytisine was provided by mail , free of charge , and nicotine-replacement therapy was provided through vouchers for low-cost patches along with gum or lozenges . Low-intensity , telephone-delivered behavioral support was provided to both groups through the quitline . The primary outcome was self-reported continuous abstinence at 1 month . RESULTS At 1 month , continuous abstinence from smoking was reported for 40 % of participants receiving cytisine ( 264 of 655 ) and 31 % of participants receiving nicotine-replacement therapy ( 203 of 655 ) , for a difference of 9.3 percentage points ( 95 % confidence interval , 4.2 to 14.5 ) . The effectiveness of cytisine for continuous abstinence was superior to that of nicotine-replacement therapy at 1 week , 2 months , and 6 months . In a prespecified subgroup analysis of the primary outcome , cytisine was superior to nicotine-replacement therapy among women and noninferior among men . Self-reported adverse events over 6 months occurred more frequently in the cytisine group ( 288 events among 204 participants ) than in the group receiving nicotine-replacement therapy ( 174 events among 134 participants ) ; adverse events were primarily nausea and vomiting and sleep disorders . CONCLUSIONS When combined with brief behavioral support , cytisine was found to be superior to nicotine-replacement therapy in helping smokers quit smoking , but it was associated with a higher frequency of self-reported adverse events . ( Funded by the Health Research Council of New Zeal and ; Australian New Zeal and Clinical Trials Registry number , ACTRN12610000590066 . ) Background Some smokers may benefit from a therapy that combines different nicotine replacement therapies ( NRT ) or drugs with different mechanisms of action . The aim of this study was to determine the efficacy of the combined therapy of varenicline and nicotine patches versus varenicline monotherapy . Methods Three hundred forty-one smokers who smoked 20 or more cigarettes per day were recruited from a smoking cessation clinic between February 2012 and June 2013 . The participants were r and omized to receive a varenicline plus nicotine patch of 21 mg every 24 hours ( 170 ) or varenicline plus a placebo patch ( 171 ) . All of the smokers received a st and ard 12-week course of varenicline and an 11-week course of either the placebo patch or the active patch after the target quit day . Both groups received behavioral support . The primary outcome was continuous abstinence for weeks 2 through 12 confirmed by exhaled levels of carbon monoxide . Post hoc subgroup analyses were performed to evaluate the treatment effects for a specific endpoint in subgroups of smokers . Results The combination of the nicotine patch with varenicline was not associated with higher rates of continuous abstinence at 12 weeks ( 39.1 % versus 31.8 % ; odds ratio ( OR ) 1.24 ; 95 % confidence interval ( CI ) 0.8 to 2.6 ) and 24 weeks ( 32.8 % versus 28.2 % ; OR 1.17 ; 95 % CI 0.4 to 1.9 ) . When participants were analyzed by subgroups according to cigarette consumption , the abstinence rates among smokers who smoked more than 29 cigarettes per day at 12 weeks ( OR 1.39 ; 95 % CI 1.2 to 2.5 ) and 24 weeks ( OR 1.46 ; 95 % CI 1.2 to 2.8 ) were significantly higher in the combination group . Other post hoc analyses based on level of dependence and previous quit attempts did not show subgroup differences . No differences between the groups for the reported adverse events were observed ( χ2 value 0.07 ; P 0.79 ) . Conclusions The combination of varenicline with the nicotine patch does not improve abstinence rates at 12 and 24 weeks compared with varenicline used as monotherapy when all smokers were analyzed as a whole , independent of consumption level . Trial registration This study is registered at clinical trial.gov ( NCT01538394 ) Objective To assess the efficacy and safety of varenicline ( a licensed cigarette smoking cessation aid ) in helping users of smokeless tobacco to quit . Design Double blind , placebo controlled , parallel group , multicentre , r and omised controlled trial . Setting Medical clinics ( mostly primary care ) in Norway and Sweden . Participants Men and women aged ≥18 who used smokeless tobacco at least eight times a day , with no abstinence period over three months within one year before screening , who wanted to quit all tobacco use . Participants were excluded if they used any other form of tobacco ( except smokeless tobacco ) or medication to stop smoking within three months of screening or had any pre-existing medical or psychiatric condition . Interventions Varenicline 1 mg twice daily ( titrated during the first week ) or placebo for 12 weeks , with 14 weeks ’ follow-up after treatment . Main outcome measures The primary end point was the four week continuous abstinence rate at the end of treatment ( weeks 9 - 12 ) confirmed with cotinine concentration . A secondary end point was continuous abstinence rate for weeks 9 - 26 . Safety and tolerability were also evaluated . Results 431 participants ( 213 varenicline ; 218 placebo ) were r and omised and received at least one dose of study drug . Participants ’ demographics and baseline use of smokeless tobacco were similar ( 89 % ( 189 ) and 90 % ( 196 ) , respectively , were men ; mean age in both groups was 43.9 ; participants used smokeless tobacco products about 15 times a day , and about 80 % first used smokeless tobacco within 30 minutes after awakening ) . Continuous abstinence rate at week 9 - 12 was higher in the varenicline group than the placebo group ( 59 % ( 125 ) v 39 % ( 85 ) ; relative risk 1.60 , 95 % confidence interval 1.32 to 1.87 , P<0.001 ; risk difference 20 % ; number needed to treat 5 ) . The advantage of varenicline over placebo persisted through 14 weeks of follow-up ( continuous abstinence rate at week 9 - 26 was 45 % ( 95 ) v 34 % ( 73 ) ; relative risk 1.42 , 1.08 to 1.79 , P=0.012 ; risk difference 11 % ; number needed to treat 9 ) . The most common adverse events in the varenicline group compared with the placebo group were nausea ( 35 % ( 74 ) v 6 % ( 14 ) ) , fatigue ( 10 % ( 22 ) v 7 % ( 15 ) ) , headache ( 10 % ( 22 ) v 9 % ( 20 ) ) , and sleep disorder ( 10 % ( 22 ) v 7 % ( 15 ) ) . Few adverse events led to discontinuation of treatment ( 9 % ( 19 ) and 4 % ( 9 ) , respectively ) , and serious adverse events occurred in two ( 1 % ) and three ( 1 % ) participants , respectively . Conclusion Varenicline can help people to give up smokeless tobacco and has an acceptable safety profile . The response rate in the placebo group in this study was high , suggesting a population less resistant to treatment than smokers . Trial Registration NCT00717093 AIM The EUROACTION PLUS trial measured the effectiveness of a nurse-led preventive cardiology programme ( EUROACTION ) offering intensive smoking cessation PLUS optional varenicline for persistent high CVD risk smokers to reduce overall cardiovascular risk compared with usual care ( UC ) in general practice ( GP ) . METHODS AND RESULTS A parallel group r and omized controlled trial in 20 GP in Italy , Netherl and s , Spain , and UK . Six hundred and ninety-six current smokers , ( 137 vascular disease and 559 high total CVD risk ) , were r and omized 350 to EUROACTION PLUS ( EA+ ) and 346 to UC . Specially , trained nurses offered the EUROACTION preventive cardiology programme addressing smoking cessation , diet , physical activity , and risk factor management to reduce overall cardiovascular risk . The primary endpoint was 7 day point prevalence of self-reported abstinence ( vali date d breath carbon monoxide < 10 p.p.m . ) at 16 weeks . Secondary outcomes included dietary habits , physical activity , weight , blood pressure ( BP ) , lipid , and glucose management . One hundred and seventy-seven ( 51 % ) EA+ patients ( 91 % opted to use varenicline ) were abstinent vs. 63 ( 19 % ) in UC ; OR 4.52 ( 95 % CI : 3.20 - 6.39 ) . The Mediterranean diet score of ≥9 in 149 ( 52 % ) EA+ patients vs. 97 ( 37 % ) in UC ; OR 1.84 ( 95 % CI : 1.31 - 2.59 ) . Physical activity target achieved in 46 ( 16 % ) EA+ patients vs. 19 ( 7 % ) in UC ; OR 2.48 ( 95 % CI : 1.41 - 4.36 ) . Target BP ( < 140/90 mm Hg ) achieved in 150 ( 52 % ) EA+ patients vs. 112 ( 43 % ) in UC , OR 1.47 ( 95 % CI : 1.05 - 2.06 ) with no difference in antihypertensive drugs . There were no differences in management of cholesterol or glucose . CONCLUSIONS The EUROACTION preventive cardiology programme in high CVD risk smokers using optional varenicline substantially increased smoking abstinence over 16 weeks and also reduced overall cardiovascular risk compared with UC . REC reference : 09/H0402/85 ; EudraCT number : 2009 - 012451 - 18 ; http://www.controlled-trials.com/IS RCT N22073647 , 12 February 2014 , date last accessed Rationale A network meta- analysis of r and omized trials and real-world comparative studies strongly suggest that varenicline is more effective in aiding smoking cessation than single form nicotine replacement therapy ( NRT ) . Modeling the health benefits attributable to this difference relies on extrapolation to lifetime cessation , but to date , follow-up has only extended to 12 months . Longer term follow-up data are helpful in checking these assumptions . Objectives This study aim ed to compare the sustained abstinence rates of smokers using varenicline versus nicotine patch in their quit attempt up to 36 months . Method Five hundred eighty-seven smokers were recruited at Kaohsiung Veteran General Hospital between Feb 2006 and Aug 2009 . Participants received counseling from a physician and received either varenicline ( N = 296 ) or the nicotine patch ( N = 291 ) for smoking cessation . Both varenicline and nicotine patch users could receive their medications for a maximum of 8 weeks . Participants were followed up by telephone at 3 , 6 , 12 , and 36 months from the first visit . The primary outcome measure was self-reported sustained abstinence up to 36 months . Measures were also taken of smoking characteristics , cigarette dependence , and sociodemographic characteristics . Results Multiple logistic regression of 36-month sustained abstinence on to medication adjusting for other baseline variables showed a significant advantage for varenicline , OR = 7.94 ( 95 % CI 1.87–33.74 ) . Conclusion An 8-week course of varenicline appears to yield higher abstinence rate up to 3 years than a similar length course of nicotine transdermal patch in routine clinical practice where behavioral support is available Background Nicotine replacement therapy ( NRT ) and varenicline are both effective in helping smokers quit . There is growing interest in combining the two treatments to improve treatment outcomes , but no experimental data exist on whether this is efficacious . This double-blind r and omised controlled trial was design ed to evaluate whether adding nicotine patches to varenicline improves withdrawal relief and short-term abstinence rates . Methods 117 participants seeking help to stop smoking were r and omly allocated to varenicline plus placebo patch or varenicline plus nicotine patch ( 15 mg/16 hour ) . Varenicline use commenced one week prior to the target quit date ( TQD ) , patch use started on the TQD . Ratings of urges to smoke and cigarette withdrawal symptoms were collected weekly over 4 weeks post-TQD . Medication use and smoking status were established at 1 , 4 and 12 weeks . Participants lost to follow-up were included as continuing smokers . Results 92 % of participants used both medications during the first week after the TQD . The combination treatment generated no increase in nausea or other adverse effects . It had no overall effect on urges to smoke or on other withdrawal symptoms . The combination treatment did not improve biochemically vali date d abstinence rates at 1 week and 4 weeks post-TQD ( 69 % vs 59 % , p=0.28 and 60 % vs 59 % , p=0.91 , in the nicotine patch and placebo patch arm , respectively ) , or self reported abstinence rates at 12 weeks ( 36 % vs. 29 % , p=0.39 , NS ) . Conclusions The efficacy of varenicline was not enhanced by the addition of nicotine patches , although further trials would be useful to exclude the possibility of type II error . Trial Registration Clinical trials.gov Registration Number : Introduction : Current smoking cessation guidelines recommend setting a quit date prior to starting pharmacotherapy . However , providing flexibility in the date of quitting may be more acceptable to some smokers . The objective of this study was to compare varenicline 1 mg twice daily ( b.i.d . ) with placebo in subjects using a flexible quit date paradigm after starting medication . Methods : In this double-blind , r and omized , placebo-controlled international study , smokers of ≥10 cigarettes/day , aged 18–75 years , and who were motivated to quit were r and omized ( 3:1 ) to receive varenicline 1 mg b.i.d . or placebo for 12 weeks . Subjects were followed up through Week 24 . Subjects were instructed to quit between Days 8 and 35 after starting medication . The primary endpoint was carbon monoxide – confirmed continuous abstinence during Weeks 9–12 , and a key secondary endpoint was continuous abstinence during Weeks 9–24 . Results : Overall , 493 subjects were r and omized to varenicline and 166 to placebo . Continuous abstinence was higher for varenicline than for placebo subjects at the end of treatment ( Weeks 9–12 : 53.1 % vs. 19.3 % ; odds ratio [ OR ] 5.9 ; 95 % CI , 3.7–9.4 ; p < .0001 ) and through 24 weeks follow-up ( Weeks 9–24 : 34.7 % vs. 12.7 % ; OR 4.4 ; 95 % CI , 2.6–7.5 ; p < .0001 ) . Serious adverse events occurred in 1.2 % varenicline ( none were psychiatric ) and 0.6 % placebo subjects . Fewer varenicline than placebo subjects reported depression-related adverse events ( 2.3 % vs. 6.7 % , respectively ) . Conclusions : Varenicline 1 mg b.i.d . using a flexible quit date paradigm had similar efficacy and safety compared with previous fixed quit date studies BACKGROUND Smoking cessation programmes were first introduced in Iran in 1997 . To date a number of types of nicotine replacement therapy have been prescribed . OBJECTIVE To evaluate the effectiveness of varenicline for tobacco cessation . METHODS This was a r and omised parallel clinical study conducted in 2010 . Participants were smokers willing to quit who were visiting a smoking cessation clinic for the first time and were r and omly divided into three groups : all three groups received brief counselling on cessation , Group 2 received nicotine patches and Group 3 was prescribed varenicline for 8 weeks . RESULTS There were 272 participants in the study : 91 in Group 1 , 92 in Group 2 and 89 in Group 3 . At the end of the first month , 128 of the 272 subjects ( 47.1 % ) succeeded in quitting : 17 ( 18.7 % ) in Group 1 , 60 ( 65.2 % ) in Group 2 and 51 ( 57.3 % ) in Group 3 ( P = 0.000 ) . At follow-up after 12 months , 58 subjects ( 21.3 % ) remained smoke-free , of whom 6 ( 6.6 % ) were in Group 1 , 23 ( 25 % ) in Group 2 and 29 ( 32.6 % ) in Group 3 ( P = 0.000 ) . CONCLUSION In the study , varenicline treatment was slightly more effective than but not significantly different from nicotine replacement therapy 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 Prevalence rates of smoking are rising in developing countries . Previous trials evaluating the efficacy and tolerability of the smoking-cessation medication varenicline have used largely participants of Caucasian origin . OBJECTIVE This study was conducted to evaluate the efficacy and tolerability of varenicline in population s of participants from Latin America , Africa , and the Middle East to investigate potential differences in the therapeutic response to varenicline . METHODS This multinational , r and omized , double-blind , placebo-controlled trial was conducted at 42 centers in 11 countries ( Latin America : Brazil , Colombia , Costa Rica , Mexico , and Venezuela ; Africa : Egypt and South Africa ; Middle East : Jordan , Lebanon , Saudi Arabia , and the United Arab Emirates ) . Participants were male and female smokers aged 18 to 75 years who were motivated to stop smoking ; smoked ≥10 cigarettes/d , with no cumulative period of abstinence > 3 months in the previous year ; and who had no serious or unstable disease within the previous 6 months . Subjects were r and omized in a 2:1 ratio to receive varenicline 1 mg or placebo , BID for 12 weeks , with a 12-week nontreatment follow-up . Brief smoking-cessation counseling was provided . The main outcome measures were carbon monoxide-confirmed continuous abstinence rate ( CAR ) at weeks 9 to 12 and weeks 9 to 24 . Adverse events ( AEs ) were recorded for tolerability assessment . RESULTS Overall , 588 subjects ( varenicline , 390 ; placebo , 198 ) were r and omized and treated . The mean ( SD ) ages of subjects in the varenicline and placebo groups were 43.1 ( 10.8 ) and 43.9 ( 10.8 ) years , respectively ; 57.7 % and 65.7 % were male ; and the mean ( SD ) weights were 75.0 ( 16.0 ) and 76.7 ( 16.3 ) kg ( range , 40.0 - 130.0 and 45.6 - 126.0 kg ) . CAR at weeks 9 to 12 was significantly higher with varenicline than with placebo ( 53.59 % vs 18.69 % ; odds ratio [ OR ] = 5.76 ; 95 % CI , 3.74 - 8.88 ; P < 0.0001 ) , and this rate was maintained during weeks 9 to 24 ( 39.74 % vs 13.13 % ; OR = 4.78 ; 95 % CI , 2.97 - 7.68 ; P < 0.0001 ) . Nausea , headache , and insomnia were the most commonly reported AEs with varenicline and were reported numerically more frequently in the varenicline group compared with the placebo group . Serious AEs ( SAEs ) were reported in 2.8 % of varenicline recipients compared with 1.0 % in the placebo group , with 6 subjects reporting psychiatric SAEs compared with none in the placebo group . CONCLUSION Based on these data , varenicline was apparently efficacious and generally well tolerated as a smoking-cessation aid in smokers from selected sites in Latin America , Africa , and the Middle East . Clinical Trials.gov identifier : NCT00594204 Introduction : An employer-based cost-benefit analysis for varenicline versus bupropion was conducted using clinical outcomes from a recently published trial . Methods : A decision tree model was developed based on the net benefit of treatment to produce a nonsmoker at 1 year . Sensitivity analyses were conducted based on quit rates with placebo and varenicline and the cost of varenicline . Results : Estimated 12-month employer cost savings per non-smoking employee were $ 540.60 for varenicline , $ 269.80 for bupropion SR generic , $ 150.80 for bupropion SR br and , and $ 81.80 for placebo . Varenicline was more cost beneficial than placebo , which had quit rates of 16.9 % or less . The quit rate with varenicline would have to be ≤16.9 % to lose cost benefit over bupropion SR generic . Conclusions : The economic benefit of varenicline is improved over bupropion , despite the increased initial cost of varenicline BACKGROUND It has been suggested that anti-smoking therapy gives encouraging results , but this has not been verified by well-r and omized study protocol s. The present study was a r and omized controlled trial of varenicline vs nicotine patch in adult smokers for comparison of efficacy , safety and withdrawal symptoms . METHODS AND RESULTS The 32 adult smokers were r and omly divided into a varenicline group ( VG , n=16 ) and a nicotine patch group ( NG , n=16 ) . The primary endpoints were the 12- and 24-week smoking-abstinence rates , safety and withdrawal symptoms including stress . No significant difference in abstinence rates was observed between the 2 groups over weeks 9 - 12 ( 71.4 % vs 78.6 % in the VG and NG , respectively ) , and weeks 9 - 24 ( 64.3 % vs 71.4 % , respectively ) . The frequencies of inability to concentrate at 2 , 4 , and 8 weeks , and wakeful nights at 2 weeks were higher in the VG than in the NG . Adverse side-effects associated with a gastrointestinal disorder occurred in 14 cases and 1 case in the VG and NG , respectively , and skin allergy was seen in 0 and 9 cases , respectively . CONCLUSIONS The selection of treatment depends on the balance of desired acuteness of cessation of smoking and side-effects , such as psychiatric and gastrointestinal problems or skin allergy This article examines reported symptoms , nonsmoking rates , and medication use among 1,018 smokers using varenicline in a r and omized trial comparing three forms of behavioral support for smoking cessation ( phone , Web , or phone + Web ) . One month after beginning varenicline , 168 people ( 17 % ) had discontinued the medication . Most ( 53 % ) quit due to side effects and other symptoms . The most common side effect among all users was nausea ( reported by 57 % of users ) . At 1 month post medication initiation , those not taking varenicline were more likely to report smoking than those who continued the medication ( 57 % vs. 16 % , p < .001 ) . Women reported more symptoms but did not discontinue medication at higher rates . Participants who received any telephone counseling ( n = 681 ) were less likely to discontinue their medication than those with Web support only ( 15 % vs. 21 % , p < .01 ) . Counseling may improve tolerance of this medication and reduce the rate of discontinuation due to side effects Lung cancer screening with computed tomography has demonstrated a significant reduction in mortality . While these findings are important for the lung cancer research field , the most important risk factor for lung cancer , i.e. smoking , should not be ignored . We performed a pilot study to examine the feasibility of delivering a program that included both tobacco dependence treatment and lung cancer screening . The objectives of this study were to : ( 1 ) estimate the proportion of smokers who complied with a 12-week treatment protocol that included both tobacco dependence treatment and lung cancer screening , ( 2 ) obtain preliminary estimates of abstinence and quit attempts at 4 and 6 months , and ( 3 ) obtain preliminary estimates of the cognitive social health information processing ( C-SHIP ) constructs and how they change following the intervention . In this r and omized pilot study , 18 volunteers completed a 12-week protocol : half received the tobacco dependence treatment program before a CT scan ( BCT ) and the other received the CT scan first , followed by the treatment program ( ACT ) . The treatment protocol included both nurse-delivered telephone counseling and either nicotine replacement therapy or varenicline . Only one person did not complete all follow-up evaluations . At 4 months post enrollment , the carbon monoxide confirmed quit rates were 33.3 % in the BCT arm and 22.2 % in the ACT arm ( 27.8 % overall ) , and all but one had made a 24-h attempt to quit . At 6 months the confirmed abstinence decreased to 22.1 % in the BCT arm and 11.1 % in the ACT arm ( 16.7 % overall ) , and 72.2 % of participants had made a 24-h quit attempt . These preliminary results suggest that it might be better to deliver treatment before the screening test . Future r and omized trials with a larger sample size are needed to confirm these findings BACKGROUND Identifying predictors of smoking relapse helps to eluci date the challenges of long-term smoking cessation and provides direction for improved treatment development . METHODS In this post hoc data analysis , we examined predictors of relapse from end-of-treatment ( week 13 ) through 1-year follow-up ( week 52 ) for treatment-responding participants who achieved the primary efficacy endpoint of 4-week continuous abstinence ( weeks 9 - 12 ) , during two phase III varenicline trials . RESULTS Of 626 smokers classified as treatment responders for all treatment groups across both trials , 301 ( 48 % ) relapsed during follow-up ( weeks 13 - 52 ) . The odds of relapsing were almost 5 times greater ( odds ratio [OR]=4.92 , 95 % confidence interval [ CI ] : 2.77 - 8.97 ; p<.001 ) for treatment responders who did not initiate continuous abstinence until the final 4 weeks of the treatment period compared with those who initiated continuous abstinence by their quit date . Participants who reported > 30 days of abstinence during the year prior to study entry were significantly more likely to relapse than those who reported 0 days of abstinence ( OR=2.38 , 95 % CI : 1.17 - 5.04 ; p=.013 ) . CONCLUSION Results of these analyses suggest that the ability to quit smoking on the initial quit date and maintain abstinence throughout the treatment period is a good prognostic indicator for long-term abstinence . The relationship between post-treatment relapse and longer pretreatment periods of abstinence is counterintuitive , yet not without precedence in the literature 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 CONTEXT The majority of cigarette smokers who achieve abstinence relapse within the first year and require many attempts before achieving permanent abstinence . Evidence to support pharmacological treatment for relapse prevention is insufficient . OBJECTIVE To determine whether smokers who quit after 12 weeks of treatment with varenicline , a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist , maintain greater continuous abstinence rates ( defined as not a single " puff " of a cigarette ) than placebo controls during an additional 12 weeks of treatment and until 52 weeks after treatment initiation . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial conducted at multiple medical clinics in 7 countries with follow-up to 52 weeks after study baseline . Of 1927 cigarette smokers recruited between April 2003 and February 2004 and treated for 12 weeks with open-label varenicline titrated to 1 mg twice per day , 1236 ( 64.1 % ) did not smoke , use tobacco , or use nicotine replacement therapy during the last week of treatment and 62.8 % ( n = 1210 ) were r and omized to additional treatment or placebo . INTERVENTION Participants were r and omly assigned to receive either double-blind varenicline , 1 mg twice per day ( n = 603 ) , or placebo ( n = 607 ) for an additional 12 weeks . MAIN OUTCOME MEASURES Carbon monoxide-confirmed continued abstinence during weeks 13 to 24 and weeks 13 to 52 of the study . RESULTS The carbon monoxide-confirmed continuous abstinence rate was significantly higher for the varenicline group than for the placebo group for weeks 13 to 24 ( 70.5 % vs 49.6 % ; odds ratio [ OR ] , 2.48 ; 95 % confidence interval [ CI ] , 1.95 - 3.16 ; P<.001 ) as well as for weeks 13 to 52 ( 43.6 % vs 36.9 % ; OR , 1.34 ; 95 % CI , 1.06 - 1.69 ; P = .02 ) . Adverse events reported in the open-label period were mostly mild ; no difference in adverse events between varenicline and placebo was observed during the double-blind period . CONCLUSIONS Smokers who achieved abstinence for at least 7 days at the end of 12 weeks of open-label varenicline treatment and were r and omized to receive an additional 12 weeks of varenicline treatment showed significantly greater continuous abstinence in weeks 13 to 24 compared with placebo . This advantage was maintained through the nontreatment follow-up to week 52 . Varenicline may be an efficacious , safe , and well-tolerated agent for maintaining abstinence from smoking . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00143286 INTRODUCTION Long-term smokeless tobacco ( ST ) use is known to increase the risk for oropharyngeal cancer , heart attack , and stroke . Varenicline has recently been demonstrated to increase ST abstinence rates among Swedish snus users . We have conducted a pilot study to obtain preliminary evidence of efficacy of varenicline for the treatment of ST users in Midwestern United States . METHODS We conducted a r and omized , placebo-controlled Phase II clinical trial to evaluate the potential efficacy of 12 weeks of varenicline for the treatment of ST users with an a priori decision rule that a 1-tailed p < .20 for the comparison of the primary endpoint was evidence to conclude that future studies were warranted . Subjects were followed for 6 months after r and omization . RESULTS We r and omized 76 subjects ( 38 varenicline and 38 placebo ) . Subjects were similar at baseline with a mean age of 41 years , and all were male . The biochemically confirmed point prevalence tobacco abstinence rates at end of treatment were 55.3 % for varenicline and 42.1 % for placebo ( p = .126 ) and 47.4 % and 31.6 % ( p = .080 ) , respectively , at 6 months . Point prevalence ST abstinence rates at end of treatment for varenicline were 57.9 % and 42.1 % for placebo ( p = .084 ) and 57.9 % and 31.6 % ( p = .011 ) , respectively , at 6 months . Varenicline was associated with significantly less craving compared with placebo . Varenicline was well tolerated with nausea and sleep disturbance being the most common side effects . CONCLUSIONS Varenicline decreases craving and may be effective for increasing tobacco abstinence rates among ST users . Larger trials may be warranted to confirm these results The efficacy and safety of retreatment with varenicline in smokers attempting to quit were evaluated in this r and omized , double‐blind , placebo‐controlled , multicenter trial ( Australia , Belgium , Canada , the Czech Republic , France , Germany , the United Kingdom , and the United States ) . Participants were generally healthy adult smokers ( ≥10 cigarettes/day ) with ≥1 prior quit attempt ( ≥2 weeks ) using varenicline and no quit attempts in ≤3 months ; they were r and omly assigned ( 1:1 ) to 12 weeks ' varenicline ( n = 251 ) or placebo ( n = 247 ) treatment , with individual counseling , plus 40 weeks ' nontreatment follow‐up . The primary efficacy end point was the carbon monoxide – confirmed ( ≤10 ppm ) continuous abstinence rate for weeks 9–12 , which was 45.0 % ( varenicline ; n = 249 ) vs. 11.8 % ( placebo ; n = 245 ; odds ratio : 7.08 ; 95 % confidence interval : 4.34 , 11.55 ; P < 0.0001 ) . Common varenicline group adverse events were nausea , abnormal dreams , and headache , with no reported suicidal behavior . Varenicline is efficacious and well tolerated in smokers who have previously taken it . Abstinence rates are comparable with rates reported for varenicline‐naive smokers Varenicline is an effective and increasingly prescribed drug for smoking cessation , but has been associated with depressive symptoms and suicidal behavior . However , it remains unclear whether those changes in mood and behavior are directly related to varenicline use , or caused by smoking cessation itself or reflects depression and suicidality rates in smokers , independent of treatment . To investigate the influence of varenicline on mood and behavior independent of smoking and smoking cessation , we assessed the effects of varenicline on emotional processing ( a biomarker of depressogenic effects ) , emotion-potentiated startle reactivity , impulsivity ( linked with suicidal behavior ) , and cognitive performance in non-smoking subjects . We used a r and omized , double-blind design , in which we administered varenicline or placebo to healthy subjects over 7 days ( 0.5 mg/day first 3 days , then 1 mg/day ) . Cognitive and emotional processing was assessed by a battery of computerized tasks and recording of emotion-potentiated startle response . A total of 41 subjects were r and omized , with 38 subjects included in the analysis . The varenicline group did not differ from placebo in terms of negative biases in emotional processing or mood . However , compared with placebo , the varenicline group scored higher on working and declarative memory . In conclusion , short-term varenicline use did not influence negative biases in emotional processing or impulsivity in non-smoking subjects , thereby not supporting direct depressogenic or suicidal risk behavior-inducing effects . In contrast , varenicline may have cognitive-enhancing effects BACKGROUND Smoking remains the primary preventable cause of death and illness in the U.S. Effective , convenient treatment programs are needed to reduce smoking prevalence . PURPOSE This study compared the effectiveness of three modalities of a behavioral smoking-cessation program in smokers using varenicline . METHODS Current treatment-seeking smokers ( n=1202 ) were recruited from a large healthcare organization between October 2006 and October 2007 . Eligible participants were r and omized to one of three smoking-cessation interventions : web-based counseling ( n=401 ) ; proactive telephone-based counseling ( PTC ; n=402 ) ; or combined PTC and web counseling ( n=399 ) . All participants received a st and ard 12-week FDA -approved course of varenicline . Self-report determined the primary outcomes ( 7-day point prevalent abstinence at 3- and 6-month follow-ups ) ; the number of days varenicline was taken ; and treatment-related symptoms . Behavioral measures determined utilization of both the web- and Phone-based counseling . RESULTS Intent-to-treat analyses revealed relatively high percentages of abstinence at 3 months ( 38.9 % , 48.5 % , 43.4 % ) and at 6 months ( 30.7 % , 34.3 % , 33.8 % ) for the web , PTC , and PTC-web groups , respectively . The PTC group had a significantly higher percentage of abstinence than the web group at 3 months ( OR=1.48 , 95 % CI=1.12 , 1.96 ) , but no between-group differences in abstinence outcomes were seen at 6 months . CONCLUSIONS Phone counseling had greater treatment advantage for early cessation and appeared to increase medication adherence , but the absence of differences at 6 months suggests that any of the interventions hold promise when used in conjunction with varenicline Rationale Smoking cessation interventions in outpatient setting s have been demonstrated to be cost effective . Given this evidence , we aim ed to evaluate the effectiveness of varenicline tartrate plus Quitline-counselling compared with Quitline-counselling alone when initiated in the inpatient setting . Methods Adult patients ( 18–75 years ) admitted with a smoking-related illness to three hospitals , were r and omised to receive either 12-weeks of varenicline tartrate plus Quitline-counselling , ( n=196 ) or Quitline-counselling alone , ( n=196 ) , with 12-months follow-up . Results For the primary analysis population ( intention-to-treat ) , the proportion of subjects who remained continuously abstinent were significantly greater in the varenicline plus counselling arm ( 31.1 % , n=61 ) compared with counselling alone ( 21.4 % , n=42 ; RR 1.45 , 95 % CI 1.03 to 2.03 , p=0.03 ) . Conclusions The combined use of varenicline plus counselling when initiated in the inpatient setting has produced a sustained smoking cessation benefit at 12-months follow-up , indicating a successful opportunistic treatment for smokers admitted with smoking related illnesses . Trial registration http://www . clinical trials.gov/ Clinical Trials.gov identification number : NCT01141855 Background There is a significant resumption of smoking following smoking cessation using varenicline . Both smoking cessation medications and counseling have been shown to increase smoking quit rates at one year . Thus , the combination of varenicline and interactive voice response ( IVR ) telephony followed by extended IVR may further improve smoking cessation rates at one and two years . Methods 101 participants were recruited from the community via newspaper advertisement . They attended a group counseling session and were given smoking information booklets from the Canadian Cancer Society . After 12 weeks of varenicline and 9 IVR calls , all participants who had quit smoking were r and omized into 2 groups matched by levels of motivation and addiction as per baseline question naire score . The intervention group continued to receive bi-weekly IVR support for weeks 13 – 52 . The control group no longer received IVR . The primary end-point was self-reported abstinence and exhaled carbon monoxide levels of less than 10 ppm for weeks 12 , 52 and 2 years . Data were analyzed by Fisher ’s exact test or Wilcoxon rank-sum test . Results Of the 101 participants , 44 ( 43 % ) had stopped smoking after 12 weeks of varenicline and 9 IVR calls . Of these , 23 ( 52 % ) were r and omized to receive IVR calls from weeks 13 to 52.At 52 weeks , 26 ( 59 % ) participants remained smoke-free . Of the 23 with IVR , 12 ( 52.2 % ) stopped smoking compared to 14 of 21 ( 66.7 % ) without IVR . At 2 years , 40 of the 44 ( 90.9 % ) r and omized participants were contacted and 24 of the 44 ( 54.5 % ) came in for testing . Fourteen ( 13 % of the original cohort , 30 % who were abstinent at 12 weeks and 53 % who were abstinent at 52 weeks ) remained smoke-free . Five of the 23 ( 21.7 % ) r and omized to IVR and 9 of the 21 ( 42.9 % ) r and omized to no IVR remained smoke-free at 2 years . Conclusions In this pilot study of an apparently healthy population , extended IVR did not affect abstinence rates . There was no relapse prevention benefit in offering 9 months of continued IVR to subjects who had stopped smoking after receiving 3 months of varenicline and IVR treatment . Trial registration Clinical Trial.gov : BACKGROUND With smoking rates far exceeding the general population , methadone-maintained ( MMT ) opiate-dependent smokers experience high rates of tobacco-related health consequences . Previous treatment studies have used nicotine replacement and produced low quit rates . METHODS We test , using a three-group r and omized design , the efficacy of varenicline versus placebo , in comparison with nicotine replacement therapy ( NRT ) that combines nicotine patch prescription plus ad libitum nicotine rescue , for smoking cessation . We recruited methadone-maintained smokers from nine treatment centers in southern New Engl and and provided six months of treatment , and a minimal behavioral intervention at baseline ( NCI 's 5A 's ) . Outcomes included carbon monoxide ( CO ) confirmed 7-day point smoking cessation prevalence at 6 months and self-reported change in mean cigarettes per day . RESULTS The 315 participants had a mean age of 40 , with 50 % male and 79 % non-Hispanic White , smoked an average of 19.6 ( ± 10.4 ) cigarettes/day , and had a mean daily methadone dose of 109 mg . Intent-to-treat analyses , with missing considered to be smoking , showed the rate of CO-confirmed 7-day abstinence at 6-months was 5.4 % overall , with varenicline 3.7 % compared to placebo 2.2 % , and NRT 8.3 % ( p>.05 ) . Adherence rates during the 7-days immediately prior to 6-month assessment were 34.2 % in varenicline , 34.4 % in placebo , and 48.8 % in NRT . Between baseline and 6-months there was an overall self-reported mean reduction of 8.3 cigarettes/day . CONCLUSION Varenicline did not increase quit rates over placebo . Smoking cessation rates in methadone-maintained smokers are low and novel treatment strategies are required INTRODUCTION Methadone maintenance treatment ( MMT ) patients have an exceedingly high prevalence of tobacco use , and interventions that have been specifically developed for this vulnerable sub population have struggled to attain even modest rates of cessation . A significant barrier has been an inability to initiate a quit attempt early in the treatment process and adherence to treatment . METHODS This study examined the extent to which self-efficacy , medication adherence , and other demographic and smoking variables predicted an early quit day in a sample of MMT smokers ( n = 315 ) enrolled in a smoking cessation pharmacotherapy trial . Using logistic regression , we estimated the association of having an early quit day-24hr without smoking during the first month of treatment . RESULTS Only 35.2 % of participants reported a successful early quit day . The likelihood of an early quit day increased significantly ( odds ratio [ OR ] = 1.39 , 95 % CI = 1.04 - 1.86 , p < .05 ) with education level and if a quit attempt was made in the past year ( OR = 2.27 , 95 % CI = 1.33 - 3.87 , p < .01 ) . Compared to the placebo arm , those r and omized to either nicotine replacement therapy ( OR = 3.25 , 95 % CI = 1.30 - 8.10 , p < .01 ) or varenicline ( OR = 3.16 , 95 % CI = 1.26 - 7.92 ) were significantly more likely to have an early quit day . The likelihood of an early quit day was also positively associated with adherence to the medication protocol ( OR = 2.05 , 95 % CI = 1.52 - 2.76 ) . CONCLUSIONS Difficulty in achieving an early quit attempt may help explain the very low cessation rates found in studies of MMT smokers Varenicline is an α4β2 nicotinic acetylcholine receptor partial agonist developed as an aid for smoking cessation . This study evaluated varenicline 's potential for abuse by smokers ( n = 23 ) and nonsmokers ( n = 22 ) . The study useda r and omized , double‐blind , placebo‐controlled , double‐dummy crossover design with five treatment periods : 15 and 30 mg amphetamine , 1 and 3 mg varenicline , and placebo . Following each treatment , the participants were assessedon aspects relating to potential abuse of the drug ( e.g. , drug liking , drug high , and drug monetary value ) . The positive effects measured for 3 mg varenicline were similar to those for the placebo , and significantly lower than those for amphetamine in both smokers and nonsmokers . Unpleasant effects were reported for 3 mg vareniclinein both participant groups . For 1 mg varenicline , the overall patterns were similar , with the exception that thenonsmokers group showed some small positive effects balanced by some negative effects when compared with the effects of placebo . These findings lead to the conclusion that varenicline is unlikely to be abused OBJECTIVE The authors assessed the efficacy and safety of combination treatment with varenicline and sustained-release bupropion for smokers who , based on an assessment of initial smoking reduction prior to the quit date , were deemed unlikely to achieve abstinence using nicotine patch treatment . METHOD In a r and omized , double-blind , parallel-group adaptive treatment trial , the authors identified 222 cigarette smokers who failed to show a reduction of more than 50 % in smoking after 1 week of nicotine patch treatment . Smokers were r and omly assigned to receive 12 weeks of varenicline plus bupropion or varenicline plus placebo . The primary outcome measure was continuous smoking abstinence at weeks 8 - 11 after the target quit date . RESULTS Both treatments were well tolerated . Participants who received the combination treatment had a significantly higher abstinence rate than those who received varenicline plus placebo ( 39.8 % compared with 25.9 % ; odds ratio=1.89 ; 95 % CI=1.07 , 3.35 ) . Combination treatment had a significantly greater effect on abstinence rate in male smokers ( odds ratio=4.26 ; 95 % CI=1.73 , 10.49 ) than in female smokers ( odds ratio=0.94 ; 95 % CI=0.43 , 2.05 ) . It also had a significantly greater effect in highly nicotine-dependent smokers ( odds ratio=3.51 , 95 % CI=1.64 , 7.51 ) than in smokers with lower levels of dependence ( odds ratio=0.71 , 95 % CI=0.28 , 1.80 ) . CONCLUSIONS Among smokers who did not show a sufficient initial response to prequit nicotine patch treatment , combination treatment with varenicline and bupropion proved more efficacious than varenicline alone for male smokers and for smokers with a high degree of nicotine dependence Objective To compare the risk of suicide , self harm , and depression in patients prescribed varenicline or bupropion with those prescribed nicotine replacement therapy . Design Prospect i ve cohort study within the Clinical Practice Research Data link . Setting 349 general practice s in Engl and . Participants 119 546 men and women aged 18 years and over who used a smoking cessation product between 1 September 2006 and 31 October 2011 . There were 81 545 users of nicotine replacement products ( 68.2 % of all users of smoking cessation medicines ) , 6741 bupropion ( 5.6 % ) , and 31 260 varenicline ( 26.2 % ) users . Main outcome measures Outcomes were treated depression and fatal and non-fatal self harm within three months of the first smoking cessation prescription , determined from linkage with mortality data from the Office for National Statistics ( for suicide ) and Hospital Episode Statistics data ( for hospital admissions relating to non-fatal self harm ) . Hazard ratios or risk differences were estimated using Cox multivariable regression models , propensity score matching , and instrumental variable analysis using physicians ’ prescribing preferences as an instrument . Sensitivity analyses were performed for outcomes at six and nine months . Results We detected 92 cases of fatal and non-fatal self harm ( 326.5 events per 100 000 person years ) and 1094 primary care records of treated depression ( 6963.3 per 100 000 person years ) . Cox regression analyses showed no evidence that patients prescribed varenicline had higher risks of fatal or non-fatal self harm ( hazard ratio 0.88 , 95 % confidence interval 0.52 to 1.49 ) or treated depression ( 0.75 , 0.65 to 0.87 ) compared with those prescribed nicotine replacement therapy . There was no evidence that patients prescribed bupropion had a higher risk of fatal or non-fatal self harm ( 0.83 , 0.30 to 2.31 ) or of treated depression ( 0.63 , 0.46 to 0.87 ) compared with patients prescribed nicotine replacement therapy . Similar findings were obtained using propensity score methods and instrumental variable analyses . Conclusions There is no evidence of an increased risk of suicidal behaviour in patients prescribed varenicline or bupropion compared with those prescribed nicotine replacement therapy . These findings should be reassuring for users and prescribers of smoking cessation medicines UNLABELLED Patients who continue to smoke after an acute coronary syndrome ( ACS ) have a significantly increased risk of reinfa rct ion and death compared with those who quit . Varenicline is a first-line smoking cessation therapy with proven efficacy in the general population . However , its efficacy and safety immediately after an ACS are unknown . METHODS The EVITA trial is a multicenter , double-blind , r and omized , placebo-controlled trial ( NCT00794573 ) . The primary objective is to evaluate the efficacy of varenicline after ACS in achieving biochemically vali date d smoking abstinence at 24 weeks . The secondary objectives are to examine the efficacy of varenicline for smoking abstinence and reduction in daily cigarette consumption at 52 weeks and to describe the occurrence of adverse events . Three hundred and two patients motivated to quit smoking were enrolled in the United States and Canada from November 2009 to December 2014 while hospitalized with an ACS . These participants were r and omized ( 1:1 ) to either varenicline ( 1.0 mg twice daily ) or placebo for 12 weeks . The trial includes follow-ups by telephone at weeks 1 , 2 , and 8 and clinic visits at weeks 4 , 12 , 24 , and 52 . Data collected include demographic and clinical characteristics , self-reported smoking , exhaled carbon monoxide ( an indicator of current smoking ) , and adverse events . CONCLUSION The EVITA trial will provide novel information concerning the efficacy and safety of varenicline immediately after ACS . If varenicline is efficacious in this population , it will have a major impact on secondary prevention of recurrent clinical events in patients post-ACS BACKGROUND Tobacco use causes long-term morbidity and mortality . In patients with asthma , the frequency of smokers is high ; however , asthmatic smokers experience more pronounced symptoms , accelerated loss of lung function and treatment resistance . Varenicline is an effective drug in smoking cessation , when investigated in COPD patients and general population s. The aim of the present study was to evaluate the effect of Varenicline on tobacco cessation in young asthmatics . METHODS In a r and omized , placebo-controlled , double-blinded trial , 52 asthmatic current smokers ( age 19 - 40 ) ≥ 10 cigarettes daily and ≥10 packyears ( mean 15.6 ) were recruited to a 12 week treatment period with Varenicline or placebo ( 1:1 ) in parallel design . Evaluation of smoking status , asthma symptom score , general health quality score and methacholine challenge were performed at week 0 , week 6 , week 12 and week 24 . RESULTS In the Varenicline group , at week 12 , 69 % of the patients quit smoking vs. 36 % in the placebo group ( p = 0.017 , intended-to-treat analysis ) , but after 24 weeks , a high relapse rate was present ( quit rates 19 % vs. 16 % , NS ) . After 6 weeks of treatment , significant improvements in airway hyperresponsiveness ( AHR ) in the Varenicline group was found ( from 88 % to 58 % , p = 0.016 ) , whereas no change was observed in the placebo group . Symptom score and general health quality improved in both the Varenicline and the placebo group . CONCLUSION We demonstrated that Varenicline can be used with a high probability of success with tobacco cessation in young smokers with asthma , but relapse rate after end of treatment is high . Quitting smoking can improve asthma control Most smokers do not utilize approved interventions for nicotine dependence , reducing the probability of cessation . Smoking cessation programs typically use recruitment messages emphasizing the health threats of smoking . Augmenting this threat message by describing the genetic aspects of nicotine addiction may enhance enrollment into a cessation program . During telephone recruitment , 125 treatment-seeking smokers were r and omized to receive by phone either a st and ard threat message or a threat plus genetic prime message and were offered open-label varenicline and counseling . There was a greater rate of enrollment into the cessation program for the threat plus genetic prime participants ( 51.7 % ) versus the threat-only participants ( 37.7 % ; p = .03 ) . Smokers who self-identified from racial/ethnic minority groups were less likely to enroll in the cessation program ( p = .01 ) versus smokers who self-identified as Caucasian . These preliminary data suggest that a simple , affordable , and transportable communication approach enhances enrollment of smokers into a smoking cessation program . A larger clinical trial to evaluate a genetic prime message for improving recruitment into smoking cessation programs is warranted Objectives : Cytisine ( Tabex ) has been licensed in Eastern Europe as an aid to smoking cessation for 40 years . Cytisine is a partial agonist with high affinity binding to the α4β2 nicotinic acetylcholine receptor believed to be central to the rewarding effect of nicotine . There is insufficient information on effectiveness to warrant licensing by modern st and ards . To assess whether full-scale controlled trials are warranted , this study sought to obtain an estimate of the 12-month continuous abstinence rates of smokers using cytisine with minimal behavioural support . Design : An uncontrolled , open-label trial . Setting : A smokers ’ clinic in an oncology centre in Warsaw , Pol and . Subjects : 436 consecutive attendees of the smokers ’ clinic of whom 191 were male . The mean dependence score ( Fagerstrom Test for Nicotine Dependence ) was 6.1 . Intervention : The st and ard regimen of Tabex ( cytisine ) was used , involving 25 days of treatment with minimal behavioural support . Main outcome measure : Self-reported continuous abstinence for 12 months ; with abstinence verified by carbon monoxide at the final follow up ( after 12 months ) . Results : 60 participants ( 13.8 % of the total sample ) were abstinent for 12 months . Of the 315 subjects , who had taken the drug , 49 ( 15.5 % ) stopped cytisine because of adverse effects ( mostly gastric disturbances and nausea ) , although they were not serious . The frequency of the minor adverse effects , primarily gastric disturbance , was similar to that observed in previous studies with the drug . Conclusions : The long-term abstinence rates were similar to those observed in smokers receiving nicotine replacement therapy . Full-scale r and omised trials of cytisine ( Tabex ) , conducted to the st and ards required by regulatory authorities , are warranted OBJECTIVE We assessed the safety of long-term varenicline administration for smoking cessation . METHODS In this r and omized , double-blind , multicenter trial , eligible adult smokers ( 18 - 75 years ) who smoked an average of > or = 10 cigarettes/day were r and omized to either varenicline 1 mg twice daily ( BID ) or placebo for 52 weeks . Subjects made weekly clinic visits until week 8 , and then every 4 weeks until week 52 , with a follow-up visit at week 53 . The target quit date was the morning of the week 1 clinic visit . Brief counseling was provided at each visit , and vital signs , adverse events ( AEs ) , and smoking status were documented . Other laboratory measures were collected at specified visits . RESULTS A total of 251 subjects were r and omized to varenicline and 126 to placebo . Approximately half of the subjects in each arm completed the study ( 53.8 % varenicline ; 46.8 % placebo ) . Treatment-emergent AEs were observed in 96.4 % of varenicline- and 82.5 % of placebo-treated subjects during the study . Common varenicline-associated AEs were nausea ( 40.2 % ) , abnormal dreams ( 22.7 % ) , and insomnia ( 19.1 % ) . Most AEs were considered mild or moderate in intensity . AEs leading to discontinuation of varenicline treatment included nausea ( 7.6 % ) , insomnia ( 3.2 % ) , and abnormal dreams ( 2.4 % ) . A single varenicline-related serious AE , bilateral subcapsular cataracts , was observed . At week 52 , 7-day point prevalence abstinence rates were 36.7 % ( varenicline ) and 7.9 % ( placebo ) . CONCLUSIONS Varenicline 1 mg BID can be safely administered for up to 1 year . Varenicline was also a more effective smoking cessation aid than placebo throughout the study , supporting both its short- ( 12-week ) and long-term ( 52-week ) efficacy Background — Less than one-third of smokers hospitalized with an acute coronary syndrome ( ACS ) remain abstinent following discharge . We assessed whether varenicline , begun in-hospital , is efficacious for smoking cessation following ACS . Methods and Results — We conducted a multi-center , double-blind , r and omized , placebo-controlled trial in which smokers hospitalized with an ACS were r and omized to varenicline or placebo for 12 weeks . All patients received low-intensity counseling . The primary end point was point-prevalence smoking abstinence assessed at 24 weeks by 7-day recall and biochemical validation using expired carbon monoxide . A total of 302 patients were r and omized ( mean age 55±9 years ; 75 % male ; 56 % ST-segment elevation myocardial infa rct ion ; 38 % non-ST-segment elevation myocardial infa rct ion ; 6 % unstable angina ) . Patients smoked a mean of 21±11 cigarettes/d at the time of hospitalization and had been smoking for a mean of 36±12 years . At 24 weeks , patients r and omized to varenicline had significantly higher rates of smoking abstinence and reduction than patients r and omized to placebo . Point-prevalence abstinence rates were 47.3 % in the varenicline group and 32.5 % in the placebo group ( P=0.012 ; number needed to treat=6.8 ) . Continuous abstinence rates were 35.8 % and 25.8 % , respectively ( P=0.081 ; number needed to treat=10.0 ) , and rates of reduction ≥50 % in daily cigarette consumption were 67.4 % and 55.6 % , respectively ( P=0.05 ; number needed to treat=8.5 ) . Adverse event rates within 30 days of study drug discontinuation were similar between groups ( serious adverse events : varenicline 11.9 % , placebo 11.3 % ; major adverse cardiovascular events : varenicline 4.0 % , placebo 4.6 % ) . Conclusions — Varenicline , initiated in-hospital following ACS , is efficacious for smoking cessation . Future studies are needed to establish safety in these patients . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00794573 BACKGROUND AND OBJECTIVE Varenicline tartrate , a novel , selective , nicotinic acetylcholine receptor partial agonist , has been developed specifically as a smoking cessation drug . This study evaluated the efficacy of a st and ard regimen of varenicline compared with placebo for smoking cessation in 333 subjects in China , Singapore and Thail and . METHODS This 24-week , r and omized , double-blind , placebo-controlled trial of varenicline , 1 mg bd , consisted of a 12-week treatment period followed by a 12-week non-treatment follow-up period . The primary study end-point was the 4-week continuous abstinence rate defined as the proportion of subjects who reported total abstinence from smoking and other nicotine products from weeks 9 - 12 . A key secondary end-point was the continuous abstinence rate from weeks 9 - 24 , defined as the proportion of subjects who achieved the primary end-point as well as total abstinence from all tobacco products from weeks 13 - 24 . RESULTS Both end-points were achieved by a significantly higher proportion of subjects in the varenicline group than in the placebo group . The 4-week continuous abstinence end-point was achieved by 50.3 % and 31.6 % in the varenicline and placebo groups , respectively ( P = 0.0003 ) , while continuous abstinence from weeks 9 - 24 was achieved by 38.2 % and 25.0 % of subjects , respectively ( P = 0.0080 ) . The treatment effect was generalizable by treatment centre and country . Varenicline was safe and appeared to be well tolerated by most subjects . CONCLUSION Varenicline was significantly more efficacious for smoking cessation than placebo over a 12-week treatment period and a further 12-week non-treatment follow-up period in smokers from China , Singapore and Thail and . No significant side-effects were noted BACKGROUND AND AIMS Nicotine vaccination has been proposed as a possible treatment to aid smoking cessation . First efficacy results of the nicotine vaccine 3'-AmNic-rEPA ( NicVAX ) showed that only a subgroup of the top 30 % antibody responders achieved higher abstinence rates than placebo . The present study examined the efficacy of adding NicVAX versus placebo to varenicline and behavioural support as an aid in smoking cessation and relapse prevention . DESIGN R and omized placebo-controlled trial . SETTING Two research centres ( Maastricht University Medical Centre and Slotervaart Hospital ) in the Netherl and s. PARTICIPANTS A total of 558 smokers were assigned r and omly to six injections with NicVAX ( n = 278 ) or placebo ( n = 280 ) both co-administered with open label varenicline and behavioural support . MEASURES Outcomes were prolonged carbon monoxide-vali date d abstinence from weeks 9 to 52 ( primary ) and weeks 37 to 52 ( secondary ) . We also performed a pre-planned subgroup analysis in the top 30 % antibody responders . FINDINGS There was no difference in abstinence rates between NicVAX and placebo from weeks 9 to 52 [ 27.7 versus 30.0 % , odds ratio ( OR ) = 0.89 , 95 % confidence interval ( CI ) = 0.62 - 1.29 ] or weeks 37 to 52 ( 33.8 versus 33.2 % , OR = 1.03 , 95 % CI = 0.73 - 1.46 ) . The top 30 % antibody responders , compared to the placebo group , showed a non-significant tendency towards higher abstinence rates from weeks 37 to 52 ( 42.2 versus 33.2 % , OR = 1.47 , 95 % CI = 0.89 - 2.42 ) . CONCLUSION The nicotine vaccine , NicVAX , does not appear to improve the chances of stopping smoking when given in addition to varenicline and behavioural support Objectives : To assess the efficacy and safety of varenicline ( Chantix ) for the treatment of alcohol dependence . Varenicline is a partial & agr;4&bgr;2 nicotinic acetylcholine agonist approved by the Food and Drug Administration for smoking cessation . It has reduced drinking in animal studies and in small studies of humans who were both heavy drinkers and smokers . This is the first multisite clinical trial of varenicline in a population of smokers and nonsmokers with alcohol dependence . Methods : Men and women ( n = 200 ) meeting the criteria for alcohol dependence were recruited across 5 clinical sites . Patients received double-blind varenicline or placebo and a computerized behavioral intervention . Varenicline was titrated during the first week to 2 mg/d , which was maintained during weeks 2 to 13 . Results : The varenicline group had significantly lower weekly percent heavy drinking days ( primary outcome ) ( adjusted mean difference = 10.4 ) , drinks per day , drinks per drinking day , and alcohol craving compared with the placebo group ( P < 0.05 ) . The average treatment effect on alcohol use was similar for smokers and nonsmokers . Varenicline was well-tolerated ; adverse events were expected and mild . Conclusions : Varenicline significantly reduced alcohol consumption and craving , making it a potentially viable option for the treatment of alcohol dependence INTRODUCTION Varenicline and bupropion sustained release ( SR ) are both safe and effective for the treatment of tobacco dependence and have different mechanisms of action . Combination pharmacotherapy with these agents may increase long-term smoking abstinence rates above what is observed with single-agent therapy . METHODS We enrolled cigarettes smokers in an open-label , one-arm , Phase II clinical trial to obtain preliminary data on the potential effectiveness and safety of combination therapy with varenicline and bupropion SR for the treatment of tobacco dependence . Eligible subjects received varenicline titrated to 1.0 mg by mouth twice daily and bupropion SR titrated to 150 mg by mouth twice daily for a total of 12 weeks along with behavioral therapy . Self-reported smoking abstinence was biochemically confirmed with expired carbon monoxide . A total of 38 smokers with a mean age of 49.1 years ( SD = 12.4 ) who smoked an average of 19.9 cigarettes/day ( SD = 7.8 ) for 30 years ( SD = 12.3 ) were enrolled . RESULTS Seven-day point-prevalent smoking abstinence rates were 71 % ( 95 % CI = 54%-85 % ) at 3 months and 58 % ( 95 % CI = 41%-74 % ) at 6 months . Mean weight change during the medication phase among smoking-abstinent subjects was 1.6 kg ( SD = 2.4 ) . For both medications , 74 % of subjects took at least 90 % of the prescribed doses . The most common side effects were sleep disturbance ( 26 % ) and nausea ( 24 % ) . No increase in depressive symptoms was observed , and no subjects reported suicidal ideation . DISCUSSION Combination therapy with varenicline and bupropion SR may be effective for increasing smoking abstinence rates above that observed with monotherapy INTRODUCTION The prevalence of smoking is high among the human immunodeficiency virus (HIV)-infected population , yet there are few studies of tobacco dependence treatment in this population . This paper reports the safety of varenicline versus nicotine replacement therapy ( NRT ) and describes preliminary results about the effectiveness of varenicline versus NRT in HIV-infected smokers . METHODS Participants completed 12 weeks of telephone counseling and either varenicline or NRT . Varenicline was encouraged as the preferred intervention ; NRT was used for those unable/unwilling to take varenicline . Adverse events ( AEs ) , related to pharmacotherapy , were monitored . Biochemically confirmed abstinence at 3 months was examined . Inverse probability of treatment weighted logistic regression models was fit to compare participants on varenicline to those on NRT . RESULTS Among participants on varenicline ( n = 118 ) , the most common AEs were nausea , sleep problems , and mood disturbances . One person reported suicidal ideation ; there were no cardiovascular complications . There were no differences in the varenicline AE profile between participants on combination antiretroviral therapy ( ART ) and those not on ART . The percentages of confirmed abstainers were 11.8 % in the NRT group and 25.6 % in the varenicline group . The odds of being abstinent were 2.54 times as great in the varenicline group compared with the NRT group in the propensity weighted model ( 95 % CI 1.43 - 4.49 ) . CONCLUSIONS In this preliminary study , the safety profile of varenicline among HIV-infected smokers resembles findings among smokers without HIV . In addition , varenicline may be more effective at promoting abstinence in this population . Future r and omized clinical trials are warranted INTRODUCTION Patient adherence to smoking cessation medications can impact their effectiveness . It is important to underst and the extent to which prescribed medications are actually taken by smokers , how this influences smoking cessation outcomes , and what factors may influence adherence . METHODS Smokers recruited from a large health plan were r and omized to receive different modes of cessation counseling in combination with varenicline ( Swan , G. E. , McClure , J. B. , Jack , L. M. , Zbikowski , S. M. , Javitz , H. S. , Catz , S. L. , et al. 2010.Behavioral counseling and varenicline treatment for smoking cessation . American Journal of Preventive Medicine , 38 , 482 - 490 ) . One thous and one hundred and sixty-one participants were mailed a 28-day varenicline supply when they set a quit date and were able to request up to two refills from the health plan pharmacy at no cost . Pharmacy fill records were obtained and telephone surveys completed at baseline , 21 days , 12 weeks , and 6 months post target quit date . RESULTS Good adherence to varenicline ( ≥80 % of days taken ) was associated with a twofold increase in 6-month quit rates compared with poor adherence ( 52 % vs. 25 % ) . Smokers were more likely than nonsmokers to stop varenicline early . Purpose ful nonadherence was associated with smoking at 12 weeks and was predicted in multivariate analyses by age , gender , adherence self-efficacy , and initial medication side effect severity . CONCLUSIONS Innovative methods for increasing adherence to smoking cessation medications are needed , particularly early in the quit process . Simple metrics of adherence such as number of days cessation medication is taken can and should be routinely incorporated in effectiveness trials and reported to advance future attempts to underst and and reduce nonadherence OBJECTIVES To evaluate varenicline 's efficacy for smoking cessation versus bupropion SR and placebo and to explore whether factors typically predictive of abstinence influence varenicline 's efficacy versus placebo , as measured by the week 9 - 12 continuous abstinence rate ( CAR9 - 12 ) . METHODS Smokers in 2 r and omized , placebo-controlled trials received varenicline 1 mg BID ( n=696 ) , bupropion SR 150 mg BID ( n=671 ) , or placebo ( n=685 ) for 12 weeks . Nontreatment followup lasted 40 weeks . RESULTS CAR(9 - 12 ) was greater for varenicline ( 44.0 % ) versus bupropion SR ( 29.7 % ; P<0.0001 ) and placebo ( 17.7 % ; P<0.0001 ) . CAR(9 - 12 ) for varenicline versus placebo was not affected by age , gender , or nicotine dependence level . CONCLUSIONS Varenicline was more efficacious than bupropion SR or placebo . Varenicline 's efficacy versus placebo was not influenced by factors predictive of abstinence In this double-blind , placebo-controlled trial , we compared varenicline ( 2 mg ) to placebo for treatment for cocaine and tobacco dependence in 31 methadone-maintained subjects . Subjects received weekly counseling during the 12-week study participation . Our results indicate that varenicline is safe to give to this subject population , as there were no adverse events related to medication during this study . Varenicline was no more effective than placebo for abstinence from cocaine . Treatment with varenicline was associated with a reduced number of cigarettes smoked per day , even though subjects received only a brief education for smoking cessation . The self-report reduction in smoking was corroborated by CO levels and the Fagerström Test of Nicotine Dependence . However , self-ratings of positive mood on the Positive Affect Negative Affect Schedule did significantly decrease in the varenicline group as compared to the placebo group , although this appears to be due to r and omization differences related to lifetime depression diagnosis . These preliminary findings may point to potential therapeutic value of varenicline for smoking cessation in cocaine users maintained on methadone INTRODUCTION Detailed analysis of adherence to tobacco cessation medications and predictors of adherence is sparse in published literature . In this analysis , we assessed adherence to tobacco dependence treatment , association of adherence with abstinence , and predictors of adherence . METHODS We analyzed pooled results from 2 r and omized controlled trials . Adult smokers ( N = 2,045 ) who were r and omly assigned to 12 weeks of treatment and took at least 1 dose of the assigned medication ( varenicline [ 692 ] , bupropion sustained release [ 669 ] , or placebo [ 684 ] ) were included . Treatment adherence was defined as any subject who took > or=1 dose of study drug for > or=80 % days during the 12-week treatment period ( " completers " ) . Smoking abstinence was assessed using carbon monoxide-confirmed 4-week continuous abstinence rate at end of treatment ( Weeks 9 - 12 ) . RESULTS Adherence rates for completers who received varenicline , bupropion , and placebo groups , respectively , were 99.3 % , 98.8 % , and 99.2 % . There was a positive correlation between adherence to treatment and tobacco abstinence in all treatment groups . Treatment effect sizes ( odds ratios ) for active therapy compared with placebo were similar whether considering all subjects or only the completer subset . Age , cigarettes per day , and Week-2 abstinence were significant predictors of adherence for all treatment groups ( all p < .05 ) , with Week-2 abstinence the strongest predictor . DISCUSSION Adherence to pharmacotherapy for smoking cessation is highly correlated with improved tobacco abstinence . Early abstinence experience is a strong driver of adherence INTRODUCTION Inpatient medical setting s offer an opportunistic environment for initiating smoking cessation interventions to patients reflecting on their health . Current evidence has shown the superior efficacy of varenicline tartrate ( VT ) for smoking cessation compared with other tobacco cessation therapies ; however , recent evidence also has highlighted concerns about the safety and tolerability of VT . Given these apprehensions , we aim ed to evaluate the safety and effectiveness of VT plus quitline-counseling compared to quitline-counseling alone in the inpatient medical setting . METHODS Adult patients ( n = 392 , 20 - 75 years ) admitted with a smoking-related illnesses to 3 hospitals were r and omized to receive either 12 weeks of varenicline tartrate ( titrated from 0.5 mg daily to 1 mg twice daily ) plus quitline-counseling ( VT+C ) , ( n = 196 ) or quitline-counseling alone ( n = 196 ) . RESULTS VT was well tolerated in the inpatient setting among subjects admitted with acute smoking-related illnesses ( mean age 52.8±2.89 and 53.7±2.77 years in the VT+C and counseling alone groups , respectively ) . The most common self-reported adverse event during the 12-week treatment phase was nausea ( 16.3 % in the VT+C group compared with 1.5 % in the counseling alone group ) . Thirteen deaths occurred during the study period ( n = 6 were in the VT+C arm compared with n = 7 in the counseling alone arm ) . All of these subjects had known comorbidities or developed underlying comorbidities . CONCLUSIONS VT appears to be a safe and well-tolerated opportunistic treatment for inpatient smokers who have related chronic disease . Based on the proven efficacy of varenicline from outpatient studies and our recent inpatient evidence , we suggest it be considered as part of st and ard care in the hospital setting Abstract Objectives : To conduct a cost-utility analysis of two 12-week smoking-cessation interventions in Japan : smoking-cessation counselling by a physician compared with use of varenicline , an oral smoking-cessation drug , in addition to counselling . Methods : A Markov model was constructed to analyse lifetimemedical costs and QALYs from the perspective of the healthcare payer . The cycle length was 5 years . Both costs and QALYs were discounted at 3 % annually . The cohort of smokers was classified by sex and age , and we assumed that smokers started smoking at the age of 20 years and received smoking-cessation therapy at the ages of 30 , 40 , 50 , 60 or 70 years ( five separate models were run ) . The healthcare costs and QALYs were calculated throughout the term until the age of 90 years . In the base-case analysis , success rates of varenicline plus counselling and counselling alone were assumed to be 37.9 % and 25.5 % , respectively , in male smokers , and 22.2 % and 16.1 % , respectively , in female smokers , based on a r and omized controlled trial conducted in Japan . Both univariate and probabilistic sensitivity analyses were conducted . Results : Prescribed varenicline was shown to be more effective and less costly than smoking-cessation counselling alone . Varenicline would save direct medical costs of Japanese Yen (¥)43 846 ( $ US381 ; $ US1= ¥ 115 ; Oct 2007 ) and generate an increase of 0.094 QALYs in male smokers . In females the incremental costeffectiveness ratio was ¥ 346 143 per QALY gained . Varenicline is estimated to save ¥ 23.7 billion ( $ US206 million ) of the medical costs for tobacco-associated diseases for the whole population . Overall savings are ¥ 9.5 billion . Sensitivity analyses suggested the robustness of the results . Conclusion : As with any data of this nature , there is some uncertainty in the results and further research is warranted . However , based on the results of this pharmacoeconomic evaluation , varenicline , the first non-nicotine , oral treatment developed for smoking cessation , appears to be cost effective and may contribute to future medical cost savings in Japan Light smoking is particularly prevalent among Latino smokers . Nicotine replacement ( NRT ) and varenicline are effective medications for smoking cessation for moderate-heavy smokers but have not been tested in light smokers , and thus , there are no treatment guidelines for use with light smokers . This pilot trial tested the efficacy of NRT and varenicline in increasing smoking abstinence among Latino light smokers . A 3-group ( NRT , varenicline , and varenicline-placebo ) r and omized design was used , and Latino light smokers ( ≤10 cigarettes per day ) received 12 weeks of treatment , which included a culturally informed behavioral health session and ongoing medication management visits . At follow-up , there were no abstinent participants in the placebo and NRT groups . However , 30 % of participants in the varenicline group were abstinent at the 3- , 4- , and 6-month follow-up . This study represents the only investigation that specifically targets Latino light smokers using these treatments and characterizing their treatment adherence BACKGROUND Varenicline , a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist , has been developed specifically for smoking cessation . In Japan , 39.3 % of men smoke and this is a major public health concern . OBJECTIVE The primary objective of this study was to evaluate the efficacy and dose-response relationship of varenicline in Japanese smokers . METHODS In this double-blind , placebo-controlled , r and omized , parallel-group study , subjects were r and omized to receive varenicline at 0.25 mg BID , 0.5 mg BID , 1 mg BID , or placebo for 12 weeks followed by a 40-week , nontreatment follow-up phase . The primary efficacy variable was the continuous abstinence rate ( CAR ) , defined as no reported smoking ( not even a puff ) or other nicotine use and confirmed by end-expiratory carbon monoxide level < or=10 ppm , during the last 4 weeks of treatment ( weeks 9 - 12 ) . Secondary end points included CARs for weeks 9 - 24 and 9 - 52 . Craving , withdrawal , and smoking satisfaction were determined by the Minnesota Nicotine Withdrawal Scale , the Brief Question naire on Smoking Urges , and the modified Cigarette Evaluation Question naire . The tolerability of varenicline was also evaluated . RESULTS Of 618 subjects who received treatment , 515 ( 83.3 % ) were classified as nicotine dependent ( scoring > or=5 on the Tobacco Dependence Screener ) , and constituted the primary analysis group . Of these , 385 ( 74.8 % ) subjects were male , and the mean age was within the range of 39.0 to 40.2 years . Across treatment groups , subjects cl aim ed to have smoked a mean of 23.1 to 24.9 cigarettes per day in the preceding 30 days , and the mean score on the Fagerström Test for Nicotine Dependence was within the range from 5.4 to 5.7 . The CAR for weeks 9 - 12 was significantly higher for all doses of varenicline compared with placebo ( 39.5 % [ 51/129 ] ) . The highest CAR of 65.4 % ( 85/130 ) was achieved with varenicline 1 mg BID ( odds ratio [ OR ] [ 95 % CI ] = 2.98 [ 1.78 - 4.99 ] ; P < 0.001 ) . The CAR for weeks 9 - 52 was significantly greater for varenicline 1 mg BID than placebo ( 34.6 % [ 45/130 ] vs 23.3 % [ 30/129 ] ; OR [ 95 % CI ] = 1.81 [ 1.04 - 3.17 ] ; P = 0.036 ) . The CARs for weeks 9 - 24 at 0.25 , 0.5 , and 1 mg BID were 33.6 % ( 43/128 ) , 35.2 % ( 45/128 ) , 37.7 % ( 49/130 ) , and for weeks 9 - 52 at 0.25 and 0.5 mg BID were 27.3 % ( 35/128 ) and 28.9 % ( 37/128 ) but failed to reach significance versus the placebo ( 29.5 % [ 38/129 ] for weeks 9 - 24 and 23.3 % [ 30/129 ] for weeks 9 - 52 ) . Treatment-emergent adverse events ( AEs ) were more prevalent among varenicline-treated subjects ( 79.1 % [ 121/153 ] at 0.25 mg BID , 80.6 % [ 125/155 ] at 0.5 mg BID , and 80.1 % [ 125/156 ] at 1 mg BID ) than placebo subjects ( 71.4 % [ 110/154 ] ) . The 3 most prevalent AEs at varenicline 1 mg BID were nasopharyngitis ( 35.9 % [ 56/156 ] ) , nausea ( 24.4 % [ 38/156 ] ) , and headache ( 10.3 % [ 16/156 ] ) , all of which were of mild or moderate intensity . Nausea was the only AE that appeared dose related ( 7.2 % [ 11/153 ] at 0.25 mg BID , 9.7 % [ 15/155 ] at 0.5 mg BID , and 24.4 % [ 38/156 ] at 1 mg BID ) versus placebo ( 7.8 % [ 12/154 ] ) . CONCLUSIONS Varenicline was associated with dose-dependent improvement in smoking abstinence rates during the last 4 weeks of treatment and in the longer term over 40 weeks of nontreatment follow-up . The dose associated with the highest efficacy was varenicline 1 mg BID Abstract Background : The smoking cessation medicine varenicline has been associated with an increased risk of cardiovascular adverse events compared with placebo in clinical trials . Cases of cardiovascular events , including myocardial infa rct ion ( MI ) and cardiac dysrhythmias , have been noted from spontaneous reporting systems . Objective : The aim of this study was to summarize and describe cardiovascular adverse reactions identified in a general population during intensive postmarketing surveillance of varenicline in New Zeal and . Methods : Observational prospect i ve cohort study using prescription event monitoring methods . The patient cohort was established from pharmacy dispensing data sent directly to the Intensive Medicines Monitoring Programme ( IMMP ) for all New Zeal and patients prescribed varenicline . Adverse cardiovascular events were identified from follow-up question naires completed by doctors , spontaneous reports and by record linkage to national data sets . Cardiovascular events were organized into clinical groupings for further clinical assessment , and key cases were identified . Results : All New Zeal and patients dispensed a prescription for varenicline from 1 April 2007 to 30 November 2010 were included in this study . At 31 January 2011 , the IMMP varenicline events data set included a total of 172 adverse events in the IMMP circulatory System Organ Class . There were 48 reports of myocardial ischaemia , including 12 reports of MI and 8 reports of angina . Two key cases of myocardial ischaemia suggested that this may have been induced by coronary artery spasm secondary to varenicline treatment . There were 50 reports of hypotensive events , with two key cases having documented hypotension associated with chest pain/tightness , and a further 27 reports of dysrhythmia events , including two unexplained sudden deaths . Conclusions : This paper presents a series of cases of cardiovascular events in patients taking varenicline . Whilst there were multiple confounding factors in some patients , key cases were identified that suggested a possible mechanism of dysregulation of blood pressure leading to vasospasm or hypotension OBJECTIVE The hospital can be an important opportunity for smoking cessation interventions . This is the first r and omized , double-blinded , placebo-controlled pilot trial utilizing varenicline and post-discharge , in-person behavioral treatment for hospitalized smokers . METHOD Seventy-nine smokers admitted to a university-based hospital with various diagnoses were enrolled from 2007 to 2009 . The primary outcome was biochemically confirmed abstinence at 24 weeks following discharge . Secondary outcomes included withdrawal symptoms , motivation , utilization of treatment , and medical events . RESULTS Overall abstinence at 24 weeks was 27 % with no difference between varenicline and placebo treatment groups ( 23 % vs. 31 % ) . There were no significant differences in motivation to stop smoking or withdrawal symptoms . Over 40 % of all subjects utilized post-discharge behavioral treatment with significantly higher abstinence rates compared with those who did not ( 53.1 % vs. 8.5 % , p<0.01 ) . Overall adverse events were similar in both treatment groups with the only significant difference being more nausea in the varenicline group ( 25 % vs. 5 % ; p<0.01 ) . Twenty-three subjects were re-hospitalized with no significant differences between treatment groups ( 13 varenicline vs. 10 placebo ) . CONCLUSION This pilot trial of varenicline in hospitalized smokers demonstrated feasibility of implementation , produced some hypothesis-generating findings , and suggested the potential benefit of face-to-face treatment following discharge INTRODUCTION Quit rates for smoking cessation attempts are maximized by using counseling with medication . Internet-based counseling might be a suitable replacement for in-person counseling . METHODS Patients in a military medical system in the active phase of quitting presented for study intake . They were r and omized to in-person counseling ( n = 44 ) or Internet counseling ( n = 173 ) . In-person counseling consisted of four 1.5 hour classes based on the American Cancer Society 's Freshstart program . Internet counseling consisted of daily e-mails with recommended activities through Pfizer 's GetQuit program . Both groups were concomitantly treated with st and ard dose varenicline . The primary outcome was the quit rate at 12 weeks , defined as abstinence and an exhaled carbon monoxide level < 10 ppm at the 12-week visit . All those lost to follow-up were considered persistent smokers . RESULTS 217 smokers were r and omized , of which 43 % returned for the 12-week follow-up visit . Quit rates between the two groups were similar ( Internet group : 21 % , n = 36/173 ; in-person group : 18 % , n = 8/44 , p = 0.7 ) . CONCLUSIONS Internet-based counseling might be equivalent to in-person counseling for smoking cessation in patients taking varenicline . Additional studies with more complete and longer-term ( ≥1 year ) follow-up are needed to confirm these findings Introduction : Although most smokers diagnosed with lung cancer report that they want to quit smoking , many do not succeed . Smokers who quit when lung cancer is diagnosed have improved treatment efficacy , quality of life , and survival . Effective smoking cessation interventions targeted to thoracic oncology patients are needed . Methods : This pilot study examined the feasibility and potential efficacy of a 12-week program that combined smoking cessation counseling with varenicline . Seven-day point prevalence tobacco abstinence rates at the end of treatment were compared with a usual care control group . From January 2008 to August 2009 , patients with a diagnosed or suspected thoracic malignancy were recruited at their initial visit to a thoracic surgeon or thoracic oncologist at Massachusetts General Hospital . Results : Of 1130 patients screened , 187 ( 17 % ) were current smokers , and an additional 66 ( 6 % ) reported quitting within the past 6 months . One hundred sixteen ( 67 % ) of smokers were eligible , and 49 ( 42 % ) of eligible smokers enrolled ( control group n = 17 , intervention group n = 32 ) . Intervention participants completed a median of nine counseling sessions ; 50 % of intervention participants completed the full varenicline course . At 12-week follow-up , biochemically vali date d 7-day point prevalence tobacco abstinence rates were 34.4 % in the intervention group versus 14.3 % in the control group ( odds ratio = 3.14 , 95 % confidence interval = 0.59–16.62 , p = 0.18 ) . Conclusion : Our findings support the feasibility and acceptability of this program . At the end of treatment , quit rates were higher in the control group . Further testing is indicated to establish the efficacy of this treatment package in a r and omized clinical trial BACKGROUND Smoking is the most important risk factor for COPD and accelerates its progression . Despite the health implication s , a large proportion of patients with COPD continue to smoke , so finding effective smoking cessation interventions for this population is paramount . To our knowledge , this is the first r and omized clinical trial to compare the efficacy and safety of varenicline tartrate vs placebo in smokers with mild to moderate COPD . METHODS In a 27-center , double-blind , multinational study , 504 patients with mild to moderate COPD ( postbronchodilator FEV1/FVC , < 70 % ; FEV1 percent predicted normal value , ≥50 % ) and without known psychiatric disturbances were r and omized to receive varenicline ( n=250 ) or placebo ( n=254 ) for 12 weeks , with a 40-week nontreatment follow-up . The primary end point was carbon monoxide-confirmed continuous abstinence rate ( CAR ) for weeks 9 to 12 . A secondary end point was CAR for weeks 9 to 52 . RESULTS CAR for weeks 9 to 12 was significantly higher for patients in the varenicline group ( 42.3 % ) than for those in the placebo group ( 8.8 % ) ( OR , 8.40 ; 95 % CI , 4.99 - 14.14 ; P<.0001 ) . CAR in the patients treated with varenicline remained significantly higher than in those treated with placebo through weeks 9 to 52 ( 18.6 % vs 5.6 % ) ( OR , 4.04 ; 95 % CI , 2.13 - 7.67 ; P<.0001 ) . Nausea , abnormal dreams , upper-respiratory tract infection , and insomnia were the most commonly reported adverse events ( AEs ) for patients in the varenicline group . Serious AEs were infrequent in both treatment groups . Two patients in the varenicline group and one patient in the placebo group died during the study . Reports of psychiatric AEs were similar for both treatment groups . CONCLUSIONS Varenicline was more efficacious than placebo for smoking cessation in patients with mild to moderate COPD and demonstrated a safety profile consistent with that observed in previous trials . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT00285012 ; URL : www . clinical trials.gov Abstract Background : Psychiatric adverse events , including depression , suicidal ideation and psychotic reactions have been reported in patients taking the smoking cessation medicine varenicline . However , data regarding the frequency of psychiatric adverse reactions in ‘ real-life ’ postmarketing use are limited to date . Objective : The aim of the study was to calculate the occurrence rates of psychiatric adverse reactions in a nationwide general population prescribed varenicline in New Zeal and . Methods : Observational prospect i ve cohort study using Prescription Event Monitoring methods . All New Zeal and patients dispensed a prescription for varenicline from 1 April 2007 to 31 March 2008 were included in this study . Patients were followed up by multiple methods , including linkage to national morbidity and mortality data sets , question naires to patients ’ doctors and assessment of spontaneous reports sent to the Intensive Medicines Monitoring Programme . Main outcome measures were occurrence rates of psychiatric adverse events in the total patient cohort and in the subgroup for whom a follow-up question naire was returned ( the ‘ responder population ’ ) . Results : The cohort for this study included 3415 patients prescribed varenicline during the first year of monitoring in New Zeal and . Follow-up by record linkage was performed for 3353 ( 98 % ) patients , and question naires were returned for 1394 ( 42 % ) of these patients . Of 1394 question naires returned , 1310 were valid and defined as the ‘ responder ’ population . Sleep disorders , including insomnia , sleep disturbance , dreams and nightmares , were the most frequently reported psychiatric events and were experienced by 56 ( 4.3 % ) patients in the responder population . Symptoms of depression were reported by 39 ( 2.98 % ) patients in the responder population ( 24 new-onset depression , 14 worsening of pre-existing depression and 1 report of impaired motivation ) . Withdrawal reactions after stopping varenicline were reported by 6 ( 0.46 % ) patients in the responder population . Serious psychiatric reactions including suicide ( one case ) , suicidal ideation ( two cases ) and psychotic reactions ( three cases ) were also identified . Six self-harm events ( one fatal , five non-fatal ) were identified in the total cohort , giving an occurrence rate of 0.18 % ( 95 % CI 0.06 , 0.38 ) in this population . Conclusions : This intensive postmarketing study of 3415 New Zeal and patients demonstrates that psychiatric adverse events are commonly reported in patients taking varenicline . Approximately 3 % of patients experienced symptoms of depression and the majority of these cases appeared to have a causal association with varenicline . Serious psychiatric reactions including suicide , suicidal ideation and psychotic reactions were also identified , but these were less frequently reported BACKGROUND The use of varenicline tartrate alleviates postquit withdrawal discomfort , but it also seems to reduce the " reward " associated with smoking . The current treatment schedule , which commences 1 week before quitting , relies primarily on the first mechanism . We set out to determine whether increasing the prequit medication period renders cigarettes less satisfying and facilitates quitting . METHODS One hundred one smokers attending a stop-smoking clinic in London , United Kingdom , were r and omly allocated to receive varenicline for 4 weeks before the target quit date ( TQD ) or to receive placebo for 3 weeks before the TQD , followed by varenicline for 1 week before the TQD . In both groups , st and ard varenicline treatment was given for 3 months after the TQD . Measures included smoking satisfaction and smoke intake before quitting , urges to smoke and withdrawal discomfort after quitting , and sustained abstinence from the TQD to 3 months . RESULTS Varenicline preloading reduced prequit enjoyment of smoking ( P = .004 ) and smoke intake ( P < .001 ) , with 36.7 % of participants reducing their cotinine concentrations by more than 50 % ( reducers ) . Varenicline preloading did not affect postquit withdrawal symptoms , but it increased 12-week abstinence rates ( 47.2 % in the varenicline arm vs 20.8 % in the placebo arm , P = .005 ) . The effect was particularly strong among the reducers in the varenicline arm ( 66.7 % in reducers vs 22.6 % in nonreducers , P = .002 ) . Varenicline preloading was well tolerated . CONCLUSIONS Although several issues remain to be clarified , varenicline preloading can generate a substantial reduction in ad lib smoking and enhance 12-week quit rates . Current treatment schedules may lead to suboptimal treatment results . Trials with longer follow-up periods are needed to corroborate these findings . Trial Registration clinical trials.gov Identifier : NCT00789074 Quitting smoking is the single most effective strategy to reduce morbidity and premature mortality in smokers . Research has demonstrated the effectiveness of pharmacotherapy in smoking cessation , but few studies have directly compared varenicline and monotherapy nicotine replacement therapy ( NRT ) and none have examined varenicline and combinations of NRT products . The majority of smoking cessation trials involve carefully circumscribed population s , making their results less generalizable to those with severe medical conditions or psychiatric comorbidities . This paper reports on the rationale , methodology and participant characteristics of a r and omized controlled trial design ed to : ( 1 ) determine which pharmacotherapy - NRT , long term combinations of NRT , or varenicline - is most effective in achieving abstinence ; ( 2 ) investigate the incidence of neuropsychiatric symptoms among participants over the course of their quit attempt ; and ( 3 ) assess whether there is a significant difference in the incidence of neuropsychiatric symptoms in those receiving differing pharmacotherapies , and between those with and without psychiatric illnesses . The primary outcome was carbon monoxide confirmed abstinence from weeks 5 - 52 following a target quit date . Secondary outcomes included neuropsychiatric ( i.e. , depression , suicidal ideation , anxiety , anger ) and withdrawal symptoms . Smokers ( N=737 ) were r and omly assigned to one of three treatment conditions , and were scheduled to attend 8 follow-up appointments over 12 months . All participants received 6 - 15 minute practical counseling sessions with nurse counselors experienced in treating tobacco dependence . We expect that the results will lead to an enhanced underst and ing of the efficacy of these pharmacotherapies , including those with a history of psychiatric illness BACKGROUND Rates of smoking in East Asian men range from > 35 % to > 60 % , and are increasing in women and the young . OBJECTIVE This study evaluated the efficacy and tolerability of 1 mg BID varenicline , a novel alpha4beta2 nicotinic acetylcholine receptor partial agonist , for smoking cessation in smokers in Taiwan and Korea . METHODS A r and omized , double-blind , placebo-controlled , 12-week treatment , 12-week follow-up trial was conducted at 5 sites each in Korea and Taiwan . Eligible subjects , smoking > or=10 cigarettes/d , received brief smoking-cessation counseling and were r and omly assigned in a 1:1 ratio to varenicline 1 mg BID ( titrated during the first week ) or placebo . Smoking status was established by self-report and confirmed at clinic visits by end-expiratory carbon monoxide < or=10 ppm . The primary end point was continuous abstinence rate ( CAR ) during the last 4 weeks of treatment . Secondary end points included CAR from weeks 9 to 24 and 7-day point prevalence ( PP ) of abstinence at weeks 12 and 24 . Craving , withdrawal , and smoking satisfaction were determined by the Minnesota Nicotine Withdrawal Scale , the Brief Question naire of Smoking Urges , and the modified Cigarette Evaluation Question naire . Observed or volunteered adverse-event data were recorded at clinic visits . RESULTS Overall , 126 subjects ( 84.9 % male ) received varenicline , and 124 ( 92.7 % male ) received placebo , Subjects were aged 21 to 73 years ( mean age , 39.7 and 40.9 years for varenicline and placebo groups , respectively ) , and the mean ( range ) body weights were 69.0 ( 44.8 - 110.0 ) kg and 71.4 ( 45.5 - 102.0 ) kg , respectively . Subjects had smoked for 3 to 52 years ( mean , 20.2 and 22.1 years in the varenicline and placebo groups , respectively ) . Subjects had smoked a mean of 23 cigarettes/d over the past month , with 51.6 % ( varenicline ) and 46.0 % ( placebo ) having made 1 or more prior serious quit attempts . Smoking-cessation rates at the end of treatment were 59.5 % with varenicline versus 32.3 % with placebo ( P < 0.001 ) . CARs through 12 weeks post-treatment ( weeks 9 - 24 ) were 46.8 % with varenicline and 21.8 % with placebo ( P < 0.001 ) . The 7-day PP was 67.5 % with varenicline versus 36.3 % with placebo at week 12 , and 57.1 % versus 29.0 % with placebo at week 24 ( both , P < 0.001 ) . Treatment-emergent , all-causality adverse events with an incidence > or= 5 % for varenicline were nausea ( 43.7 % for varenicline vs 11.3 % placebo ) , insomnia ( 15.1 % vs 13.7 % ) , increased appetite ( 7.9 % vs 6.5 % ) , constipation ( 7.1 % vs 2.4 % ) , anxiety ( 5.6 % vs 2.4 % ) , and abnormal dreams ( 5.6 % vs 0.8 % ) . Adverse events result ed in < 10 % treatment discontinuations overall . CONCLUSION Varenicline was an efficacious and well-tolerated pharmacotherapy for smoking cessation in this group of Asian smokers over a 12-week treatment period , and its effects persisted for a further 12-week follow-up period Objective : Varenicline was approved by the FDA in 2006 . In 2009 , based largely on case reports , the FDA issued a warning of possible adverse neuropsychiatric effects including depression and suicidal thoughts and behavior for varenicline and bupropion . Prospect i ve trials of varenicline have not reported increased incidence of psychiatric adverse events other than sleep disturbance , but smokers with major mental illness have been excluded from large prospect i ve trials of varenicline to date . We sought to evaluate the effect of a st and ard open-label 12-week varenicline trial on prospect ively assessed safety and smoking outcomes in adults with stable , treated schizophrenia spectrum disorder and nicotine dependence . Methods : One-hundred twelve stable out patients who smoked 10 or more cigarettes/day participated in a 12-week open-label smoking cessation trial of varenicline and weekly group cognitive behavioral therapy . Participants took varenicline for 4 weeks before attempting cessation . Trained raters collected safety and smoking outcome data weekly . Results : Participants demonstrated improved psychotic symptoms , depressive symptoms , and nicotine withdrawal symptoms from baseline to week 12 or early termination . At the end of 12 weeks ’ open-label treatment , the 14- and 28-day continuous abstinence rates were 47.3 % and 34 % , respectively . Expired carbon monoxide declined significantly during treatment in those who did not achieve abstinence . Conclusions : This prospect i ve study suggests that varenicline may be well tolerated and effective for smoking cessation in combination with group cognitive behavioral therapy in stable out patients with schizophrenia , a group with high rates of smoking and smoking-attributable morbidity and mortality . This clinical trial is registered at www . clinical trials.gov as trial # NCT00621777 BACKGROUND Varenicline is an α4β2 partial nicotinic agonist approved for smoking cessation . There have been spontaneous postmarketing reports of neuropsychiatric adverse events ( NPAEs ) in smokers without a history of psychiatric illness quitting with varenicline . METHODS One hundred ten smokers without history of psychiatric illness ( screened by Structured Clinical Interview for DSM-IV ) were r and omized to 12 weeks of varenicline 1 mg twice daily ( n = 55 ) or placebo . Adverse events were solicited systematic ally . Depressive symptoms , anxiety , aggression , and irritability were measured at baseline and weekly using the Montgomery-Åsberg Depression Rating Scale ( MADRS ) , the Hamilton Anxiety Scale ( HAM-A ) , and the Overt Aggression Scale-Modified ( OAS-M ) . The Profile of Mood States ( POMS ) was administered daily . Mixed-model analysis of repeated measures was conducted to compare mean changes in scores between groups across study periods . RESULTS Participants ' mean baseline characteristics were 33 years of age , 22 cigarettes/day and Fagerström Test for Nicotine Dependence score > 7 . Reported NPAEs were similar between groups . No suicidal events were reported . There were no significant differences between groups for the MADRS ( treatment difference vs. placebo = .03 , 95 % confidence interval [ CI ] -.68-.73 ; NS ) , HAM-A ( treatment difference [ TD ] = .14 , 95 % CI -.62-.90 ; NS ) , OAS-M Aggression subscale ( TD = .5 , 95 % CI -1.18 - 2.18 ; NS ) , OAS-M Irritability subscale ( TD = .08 , 95 % CI -.17-.34 ; NS ) , and the POMS total scores ( TD = .5 , 95 % CI -.52 - 1.53 ; NS ) . CONCLUSIONS There were no significant differences between groups on measures of depressive symptoms , anxiety , or aggression/hostility . Systematic ally solicited NPAEs were similar between the varenicline and placebo groups BACKGROUND The efficacy of the smoking-cessation agent varenicline has been reported in Asian smokers ; however , few studies have investigated factors that contribute to lapse and relapse . OBJECTIVE This post hoc analysis aim ed to identify predictors of smoking lapse and relapse . METHODS This was a post-hoc analysis based on a double-blind , placebo-controlled , r and omized , parallel-group study in which Japanese smokers ( aged 20 - 75 years ) who smoked ≥ 10 cigarettes/day and were motivated to quit were r and omized to receive varenicline ( 0.25 mg twice daily [ BID ] , 0.5 mg BID , 1 mg BID ) or placebo for 12 weeks followed by a 40-week non-treatment follow-up . For inclusion in this analysis , participants must have been nicotine dependent ( Tobacco Dependence Screener score ≥ 5 ) and must have successfully quit smoking continuously for 4 weeks ( weeks 9 - 12 ) . Lapse was defined by answering yes to ≥ 1 question in the Nicotine Use Inventory . Relapse was defined by participants having smoked for ≥ 7 days during follow-up measured by the Nicotine Use Inventory . RESULTS Of the 619 r and omized individuals , 515 had a Tobacco Dependence Screener score of ≥ 5 , and 277 quit smoking continuously from weeks 9 to 12 . Approximately 75 % were male , with a mean ( SD ) BMI of 23.0 ( 3.0 ) kg/m(2 ) . Maximum length of continuous abstinence ( CA ) during treatment and age ( both P < 0.0001 ) were significant predictors of lapse . Maximum CA ( P < 0.0001 ) , age ( P = 0.0002 ) , Minnesota Nicotine Withdrawal Scale ( MNWS ) score for urge to smoke ( P = 0.0019 ) , and having made ≥ 1 serious quit attempt ( P = 0.0063 ) were significant predictors of relapse . For participants with a maximum CA of 4 to 6 weeks versus those with a maximum CA of 10 to 11 weeks , the ORs for lapse and relapse were 4.649 ( 95 % CI , 2.071 - 10.434 ) and 3.337 ( 95 % CI , 1.538 - 7.239 ) , respectively . In participants aged 21 - 34 years versus those aged 47 - 72 years , the ORs for lapse and relapse were 3.453 ( 95 % CI 1.851 , 6.441 ) and 3.442 ( 95 % CI 1.795 , 6.597 ) , respectively . Participants with a MNWS urge to smoke score of 2 to 4 versus 0 had an OR for relapse of 3.175 ( 95 % CI , 1.166 - 8.644 ) . Participants having made ≥ 1 versus no serious quit attempts had an OR for relapse of 2.108 ( 95 % CI , 1.168 - 3.805 ) . CONCLUSION Shorter maximum CA and younger age at quit attempt were associated with increased risk of lapse and relapse . Higher MNWS urge to smoke score and having made ≥ 1 serious quit attempt were associated with increased relapse risk . Clinical Trials.gov identifier : NCT00139750 OBJECTIVES This study examined the relation between smoking and suicide , controlling for various confounders . METHODS More than 50,000 predominantly White , middle-aged and elderly male health professionals were followed up prospect ively with biennial question naires from 1986 through 1994 . The primary end point was suicide . Characteristics controlled for included age , marital status , body mass index , physical activity , alcohol intake , coffee consumption , and history of cancer . RESULTS Eighty-two members of the cohort committed suicide during the 8-year follow-up period . In age-adjusted analyses with never smokers as the comparison group , the relative risk of suicide was 1.4 ( 95 % confidence interval [ CI ] = 0.8 , 2.3 ) among former smokers , 2.6 ( 95 % CI = 0.9 , 7.5 ) for light smokers ( < 15 cigarettes/day ) , and 4.5 ( 95 % CI = 2.3 , 8.8 ) among heavier smokers . After adjustment for potential confounders , the relative risks were 1.4 ( 95 % CI = 0.9 , 2.4 ) , 2.5 ( 95 % CI = 0.9 , 7.3 ) , and 4.3 ( 95 % CI = 2.2 , 8.5 ) , respectively . CONCLUSION We found a positive , dose-related association between smoking and suicide among White men . Although inference about causality is not justified , our findings indicate that the smoking-suicide connection is not entirely due to the greater tendency among smokers to be unmarried , to be sedentary , to drink heavily , or to develop cancers INTRODUCTION Varenicline ( Chantix ® ) is an efficacious first-line medication for smoking cessation . Studies suggest that one mechanism by which varenicline facilitates sustained smoking abstinence is by reducing the likelihood of relapse to smoking when a lapse , or slip , occurs during a quit attempt . The present study extends this line of research by conducting a prospect i ve laboratory study to examine the relapse prevention effects of varenicline following a programmed lapse . METHODS Daily smokers ( N = 47 ) completed a 5-week outpatient study in which they were r and omized to receive varenicline or placebo . The first week was a medication induction period that was immediately followed by a 4-week quit attempt . A programmed lapse ( 2 cigarettes smoked in the laboratory ) occurred on the second day of the quit attempt . RESULTS Participants receiving varenicline were slower to relapse and had greater total abstinence rates following lapse exposure . Participants in the varenicline group rated lapse cigarettes lower on measures of reward and intoxication and showed increased behavioral economic dem and elasticity for cigarettes ( reduced cigarette purchasing at higher prices ) compared with those receiving placebo . CONCLUSIONS These results demonstrate a relapse prevention effect of varenicline following smoking lapse exposure and suggest that an attenuation of reward from smoking and the blunting of subjective effects of smoking may underlie and /or contribute to this effect UNLABELLED Chinese translation BACKGROUND Depression is overrepresented in smokers . OBJECTIVE To evaluate smoking abstinence and changes in mood and anxiety levels in smokers with depression treated with varenicline versus placebo . DESIGN Phase 4 , multicenter , parallel , 1:1 allocation , double-blind , r and omization trial . R and omization , stratified by antidepressant use and depression score at baseline , was blocked in sizes of 4 . ( Clinical Trials.gov : NCT01078298 ) . SETTING 38 centers in 8 countries . PARTICIPANTS 525 adult smokers with stably treated current or past major depression and no recent cardiovascular events . INTERVENTION Varenicline , 1 mg twice daily , or placebo for 12 weeks , with 40-week nontreatment follow-up . MEASUREMENTS Primary outcome was carbon monoxide-confirmed continuous abstinence rate ( CAR ) for weeks 9 to 12 . Other outcomes included CARs assessed during nontreatment follow-up and ratings of mood , anxiety , and suicidal ideation or behavior . RESULTS 68.4 % versus 66.5 % of the varenicline and placebo groups , respectively , completed the study . Varenicline-treated participants had higher CARs versus placebo at weeks 9 to 12 ( 35.9 % vs. 15.6 % ; odds ratio [ OR ] , 3.35 [ 95 % CI , 2.16 to 5.21 ] ; P < 0.001 ) , 9 to 24 ( 25.0 % vs. 12.3 % ; OR , 2.53 [ CI , 1.56 to 4.10 ] ; P < 0.001 ) , and 9 to 52 ( 20.3 % vs. 10.4 % ; OR , 2.36 [ CI , 1.40 to 3.98 ] ; P = 0.001 ) . There were no clinical ly relevant differences between groups in suicidal ideation or behavior and no overall worsening of depression or anxiety in either group . The most frequent adverse event was nausea ( varenicline , 27.0 % ; placebo , 10.4 % ) . Two varenicline-group participants died during the nontreatment phase . LIMITATIONS Some data were missing , and power to detect differences between groups was low in rare events . Smokers with untreated depression , with co-occurring psychiatric conditions , or receiving mood stabilizers and antipsychotics were not included . CONCLUSION Varenicline increased smoking cessation in smokers with stably treated current or past depression without exacerbating depression or anxiety . PRIMARY FUNDING SOURCE Pfizer IMPORTANCE It is estimated that more than half of those with serious mental illness smoke tobacco regularly . St and ard courses of pharmacotherapeutic cessation aids improve short-term abstinence , but most who attain abstinence relapse rapidly after discontinuation of pharmacotherapy . OBJECTIVE To determine whether smokers diagnosed with schizophrenia and bipolar disease have higher rates of prolonged tobacco abstinence with maintenance pharmacotherapy than with st and ard treatment . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled , parallel-group , relapse-prevention clinical trial conducted in 10 community mental-health centers . Of 247 smokers with schizophrenia or bipolar disease recruited from March 2008-April 2012 , 203 received 12-weeks ' open-label varenicline and cognitive behavioral therapy and 87 met abstinence criteria to enter the relapse prevention intervention . INTERVENTIONS Participants who had 2 weeks or more of continuous abstinence at week 12 of open treatment were r and omly assigned to receive cognitive behavioral therapy and double-blind varenicline ( 1 mg , 2 per day ) or placebo from weeks 12 to 52 . Participants then discontinued study treatment and were followed up to week 76 . MAIN OUTCOMES AND MEASURES Seven-day rate of continuous abstinence at study week 52 , the end of the relapse-prevention phase , confirmed by exhaled carbon monoxide . Secondary outcomes were continuous abstinence rates for weeks 12 through 64 based on biochemically verified abstinence and weeks 12 through 76 , based on self-reported smoking behavior . RESULTS Sixty-one participants completed the relapse-prevention phase ; 26 discontinued participation ( 7 varenicline , 19 placebo ) and were considered to have relapsed for the analyses ; 18 of these had relapsed prior to dropout . At week 52 , point-prevalence abstinence rates were 60 % in the varenicline group ( 24 of 40 ) vs 19 % ( 9 of 47 ) in the placebo group ( odds ratio [ OR ] , 6.2 ; 95 % CI , 2.2 - 19.2 ; P < .001 ) . From weeks 12 through 64 , 45 % ( 18 of 40 ) among those in the varenicline group vs 15 % ( 7 of 47 ) in the placebo group were continuously abstinent ( OR , 4.6 ; 95 % CI , 1.5 - 15.7 ; P = .004 ) , and from weeks 12 through 76 , 30 % ( 12 of 40 ) in the varenicline group vs 11 % ( 5 of 47 ) in the placebo group were continuously abstinent ( OR , 3.4 ; 95 % CI , 1.02 - 13.6 ; P = .03 ) . There were no significant treatment effects on psychiatric symptom ratings or psychiatric adverse events . CONCLUSIONS AND RELEVANCE Among smokers with serious mental illness who attained initial abstinence with st and ard treatment , maintenance pharmacotherapy with varenicline and cognitive behavioral therapy improved prolonged tobacco abstinence rates compared with cognitive behavioral therapy alone after 1 year of treatment and at 6 months after treatment discontinuation . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00621777 IMPORTANCE Smoking cessation medications are routinely used in health care ; it is vital to identify medications that most effectively treat this leading cause of preventable mortality . OBJECTIVE To compare the efficacies of varenicline , combination nicotine replacement therapy ( C-NRT ) , and the nicotine patch for 26-week quit rates . DESIGN , SETTING , AND PARTICIPANTS Three-group r and omized intention-to-treat clinical trial occurring from May 2012 to November 2015 among smokers recruited in the Madison , Wisconsin , and Milwaukee , Wisconsin , communities ; 65.5 % of smokers offered the study ( 2687/4102 ) refused participation prior to r and omization . INTERVENTIONS Participants were r and omized to one of three 12-week open-label smoking cessation pharmacotherapy groups : ( 1 ) nicotine patch only ( n = 241 ) ; ( 2 ) varenicline only ( including 1 prequit week ; n = 424 ) ; and ( 3 ) C-NRT ( nicotine patch + nicotine lozenge ; n = 421 ) . Six counseling sessions were offered . MAIN OUTCOMES AND MEASURES The primary outcome was carbon monoxide-confirmed self-reported 7-day point-prevalence abstinence at 26 weeks . Secondary outcomes were carbon monoxide-confirmed self-reported initial abstinence , prolonged abstinence at 26 weeks , and point-prevalence abstinence at weeks 4 , 12 , and 52 . RESULTS Among 1086 smokers r and omized ( 52 % women ; 67 % white ; mean age , 48 years ; mean of 17 cigarettes smoked per day ) , 917 ( 84 % ) provided 12-month follow-up data . Treatments did not differ on any abstinence outcome measure at 26 or 52 weeks , including point-prevalence abstinence at 26 weeks ( nicotine patch , 22.8 % [ 55/241 ] ; varenicline , 23.6 % [ 100/424 ] ; and C-NRT , 26.8 % [ 113/421 ] ) or at 52 weeks ( nicotine patch , 20.8 % [ 50/241 ] ; varenicline , 19.1 % [ 81/424 ] ; and C-NRT , 20.2 % [ 85/421 ] ) . At 26 weeks , the risk differences for abstinence were , for patch vs varenicline , -0.76 % ( 95 % CI , -7.4 % to 5.9 % ) ; for patch vs C-NRT , -4.0 % ( 95 % CI , -10.8 % to 2.8 % ) ; and for varenicline vs C-NRT , -3.3 % ( 95 % CI , -9.1 % to 2.6 % ) . All medications were well tolerated , but varenicline produced more frequent adverse events than did the nicotine patch for vivid dreams , insomnia , nausea , constipation , sleepiness , and indigestion . CONCLUSIONS AND RELEVANCE Among adults motivated to quit smoking , 12 weeks of open-label treatment with nicotine patch , varenicline , or C-NRT produced no significant differences in biochemically confirmed rates of smoking abstinence at 26 weeks . The results raise questions about the relative effectiveness of intense smoking pharmacotherapies . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01553084 BACKGROUND Cytisine , a partial agonist that binds with high affinity to the α(4)β(2 ) nicotinic acetylcholine receptor , is a low-cost treatment that may be effective in aiding smoking cessation . This study assessed the efficacy and safety of cytisine as compared with placebo . METHODS We conducted a single-center , r and omized , double-blind , placebo-controlled trial . Participants were r and omly assigned to receive cytisine or matching placebo for 25 days ; participants in both groups received a minimal amount of counseling during the study . The primary outcome measure was sustained , biochemically verified smoking abstinence for 12 months after the end of treatment . Of 1542 adult smokers screened , 740 were enrolled and 370 were r and omly assigned to each study group . RESULTS The rate of sustained 12-month abstinence was 8.4 % ( 31 participants ) in the cytisine group as compared with 2.4 % ( 9 participants ) in the placebo group ( difference , 6.0 percentage points ; 95 % confidence interval [ CI ] , 2.7 to 9.2 ; P=0.001 ) . The 7-day point prevalence for abstinence at the 12-month follow-up was 13.2 % in the cytisine group versus 7.3 % in the placebo group ( P=0.01 ) . Gastrointestinal adverse events were reported more frequently in the cytisine group ( difference , 5.7 percentage points ; 95 % CI , 1.2 to 10.2 ) . CONCLUSIONS In this single-center study , cytisine was more effective than placebo for smoking cessation . The lower price of cytisine as compared with that of other pharmacotherapies for smoking cessation may make it an affordable treatment to advance smoking cessation globally IMPORTANCE St and ard varenicline tartrate dosing was formulated to avoid adverse effects ( primarily nausea ) , but some patients may be underdosed . To our knowledge , no evidence -based guidance exists for physicians considering increasing varenicline dose if there is no response to the st and ard dosage . OBJECTIVE To determine whether increasing varenicline dose in patients showing no response to the st and ard dosage improves treatment efficacy . DESIGN , SETTING , AND PARTICIPANTS In a double-blind r and omized placebo-controlled trial , 503 smokers attending a stop smoking clinic commenced varenicline use 3 weeks before their target quit date ( TQD ) . Two hundred participants reporting no strong nausea , no clear reduction in smoking enjoyment , and less than 50 % reduction in their baseline smoking on day 12 received additional tablets of varenicline or placebo . INTERVENTIONS All participants began st and ard varenicline tartrate dosing , gradually increasing to 2 mg/d . Dose increases of twice-daily varenicline ( 0.5 mg ) or placebo took place on days 12 , 15 , and 18 ( up to a maximum of 5 mg/d ) . MAIN OUTCOMES AND MEASURES Participants rated their smoking enjoyment during the prequit period and withdrawal symptoms weekly for the first 4 weeks after the TQD . Continuous vali date d abstinence rates were assessed at 1 , 4 , and 12 weeks after the TQD . RESULTS The dose increase reduced smoking enjoyment during the prequit period , with mean ( SD ) ratings of 1.7 ( 0.8 ) for varenicline vs 2.1 ( 0.7 ) for placebo ( P = .001 ) . It had no effect on the mean ( SD ) frequency of urges to smoke at 1 week after the TQD , their strength , or the severity of withdrawal symptoms : these ratings for varenicline vs placebo were 2.7 ( 1.1 ) vs 2.6 ( 0.9 ) ( P = .90 ) , 2.6 ( 1.1 ) vs 2.8 ( 1.0 ) ( P = .36 ) , and 1.5 ( 0.4 ) vs 1.6 ( 0.5 ) ( P = .30 ) , respectively . The dose increase also had no effect on smoking cessation rates for varenicline vs placebo at 1 week ( 37 [ 37.0 % ] vs 48 [ 48.0 % ] , P = .14 ) , 4 weeks ( 51 [ 51.0 % ] vs 59 [ 59.0 % ] , P = .32 ) , and 12 weeks ( 26 [ 26.0 % ] vs 23 [ 23.0 % ] , P = .61 ) after the TQD . There was significantly more nausea ( P < .001 ) and vomiting ( P < .001 ) reported in the varenicline arm than in the placebo arm . CONCLUSIONS AND RELEVANCE Increasing varenicline dose in smokers with low response to the drug had no significant effect on tobacco withdrawal symptoms or smoking cessation . Physicians often consider increasing the medication dose if there is no response to the st and ard dosage . This approach may not work with varenicline . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01206010 AIM While older behavioural and pharmacological approaches to preventing relapse to smoking show little efficacy , a recent r and omized trial of an extended course of varenicline reported positive results . In this secondary analysis , trial data were examined to see whether smokers who manage to achieve abstinence only later in the original course of treatment are more likely to benefit from having the course extended . METHODS A total of 1208 patients abstinent for at least the last week of 12 weeks ' treatment with varenicline were r and omized to 3 months continued varenicline or placebo . Overall , 44 % of the 12-week abstainers were abstinent from the target quit date ( TQD ) , while the rest stopped smoking later . We examined the relationship between quit pattern and the varenicline versus placebo difference in continuous abstinence rates at week 52 and contributions of baseline patient characteristics . RESULTS With increasing delay in initial quitting , 12-month success rates declined . Participants who had their last cigarette at week 11 of open-label treatment had quit rates at 52 weeks of 5.7 % compared with 54.9 % in those who last smoked in week 1 [ odds ratio ( OR ) 20.3 ( 6.3 , 65.9 ) ; P < 0.0001 ] . Patients who failed to initiate abstinence in the first week benefited more from extended treatment than patients continuously abstinent from week 1 [ OR 1.7 ( 1.2 , 2.4 ) ; P = 0.0015 versus OR 1.1 ( 0.8 , 1.5 ) ; P = 0.6995 , respectively ; with the interaction of the quit pattern with treatment effect reaching borderline significance ( P = 0.0494 ) ] . No other patient characteristics were related to treatment effect . CONCLUSIONS Compared with smokers who quit smoking on their TQD , those who have an initial delay in achieving sustained abstinence have increased risk of relapse even several months later , and may be more likely to benefit from extended treatment with varenicline Most treatment guidelines recommend that smokers should set a target quit date ( TQD ) at treatment onset because making a public commitment to quit on a given date should increase motivation . On the other h and , allowing smokers the flexibility to choose when to stop after starting treatment might allow smokers to better tailor their quit date and might improve the acceptability of treatment among smokers not willing to set a TQD . In a recent placebo-controlled study , we found varenicline effective when smokers were not required to set a quit date a priori ; i.e. , with a " flexible quit date " ( FQD ) approach . The current analysis compares the effect sizes and quit rates in this FQD study with those of nine prior varenicline r and omized controlled trials ( RCTs ) that used a TQD approach . The odds ratio for varenicline versus placebo in the FQD study was the 4th highest of the 10 trials and the incidence of continuous abstinence for varenicline was 5th highest . These results suggest that a FQD approach can produce quit rates similar to a TQD approach . Cross- study comparisons can have hidden bias ; thus , a RCT of fixed versus flexible quit date s would provide a more valid test . Also , a study of whether different sub population s of smokers may be more interested in or especially benefit from , one or the other approach to quitting is indicated INTRODUCTION Phone counseling has become st and ard for behavioral smoking cessation treatment . Newer options include Web and integrated phone-Web treatment . No prior research , to our knowledge , has systematic ally compared the effectiveness of these three treatment modalities in a r and omized trial . Underst and ing how utilization varies by mode , the impact of utilization on outcomes , and predictors of utilization across each mode could lead to improved treatments . METHODS One thous and two hundred and two participants were r and omized to phone , Web , or combined phone-Web cessation treatment . Services varied by modality and were tracked using automated systems . All participants received 12 weeks of varenicline , printed guides , an orientation call , and access to a phone supportline . Self-report data were collected at baseline and 6-month follow-up . RESULTS Overall , participants utilized phone services more often than the Web-based services . Among treatment groups with Web access , a significant proportion logged in only once ( 37 % phone-Web , 41 % Web ) , and those in the phone-Web group logged in less often than those in the Web group ( mean = 2.4 vs. 3.7 , p = .0001 ) . Use of the phone also was correlated with increased use of the Web . In multivariate analyses , greater use of the phone- or Web-based services was associated with higher cessation rates . Finally , older age and the belief that certain treatments could improve success were consistent predictors of greater utilization across groups . Other predictors varied by treatment group . CONCLUSIONS Opportunities for enhancing treatment utilization exist , particularly for Web-based programs . Increasing utilization more broadly could result in better overall treatment effectiveness for all intervention modalities INTRODUCTION Nicotine replacement therapy to aid smoking reduction increases the probability of a future quit attempt among smokers not currently planning to quit smoking . We tested whether varenicline , a partial nicotine agonist , would also increase future quit attempts . METHODS This r and omized , placebo-controlled trial recruited 218 smokers who were interested in quitting but had no plans to quit in the next month . Participants used varenicline ( 2 mg/day ) or placebo for 2 - 8 weeks plus received brief counseling on methods to reduce cigarettes/day . The primary measure was the incidence of a quit attempt within 6 months of study entry . Secondary measures were point prevalence abstinence , motivation to stop smoking , and reduction in cigarettes/day . RESULTS Varenicline increased the incidence of a quit attempt more than placebo at the Nebraska site ( 73 % vs. 41 % ; p < .001 ) but not at the Vermont site ( 45 % vs. 51 % ; p = .45 ) . Varenicline increased most other measures of quit attempts , motivation and abstinence , independent of site . The beneficial effects of varenicline in quit attempts appeared to be mediated by greater reductions in cigarettes/day , dependence , craving , and cigarette satisfaction . Varenicline had a greater effect on quit attempts in less-dependent smokers , in minority smokers , and in those who had less prior cessation or reduction activity . Adverse events were minimal . CONCLUSIONS Varenicline increased quit attempts in smokers who are not currently trying to quit at one of the two study sites and improved most all secondary outcomes independent of site . This appeared to be due to decreasing cigarettes/day and level of dependence INTRODUCTION The rate of smokeless tobacco use in India is 20 % ; its use causes serious health problems , and no trial has assessed behavioral or pharmacological treatments for this public health concern . This trial evaluated varenicline for treating smokeless tobacco dependence in India . METHODS This was a double-blind placebo-controlled r and omized trial of varenicline ( 12 weeks , 1 mg , twice per day ) with 237 smokeless tobacco users in India . All participants received behavioral counseling . Outcomes included self-reported and biochemically verified abstinence at the end of treatment ( EOT ) , lapse and recovery events , safety , and medication adherence . RESULTS Self-reported EOT abstinence was significantly greater for varenicline ( 43 % ) versus placebo ( 31 % ; adjusted odds ratio [ AOR ] = 2.6 , 95 % CI = 1.2 - 4.2 , p = .009 ) . Biochemically confirmed EOT abstinence was greater for varenicline versus placebo ( 25.2 % vs. 19.5 % ) , but this was not statistically different ( AOR = 1.6 , 95 % CI = 0.84 - 3.1 , p = .15 ) . Compared with placebo , varenicline did not reduce the risk for a lapse ( hazard ratio [ HR ] = 0.86 , 95 % CI = 0.69 - 1.1 , p = .14 ) , but it did increase the likelihood of recovery to abstinence ( HR = 1.2 , 95 % CI = 1.02 - 1.4 , p = .02 ) . Greater adherence increased EOT cessation rates for varenicline ( 39 % vs. 18 % , p = .003 ) but not for placebo ( 28 % vs. 14 % , p = .06 ) . There were no significant differences between varenicline and placebo in rate of side effects , serious adverse events , hypertension , or stopping or reducing medication . CONCLUSIONS Varenicline is safe for treating smokeless tobacco dependence in India , and further examination of this medication for this important public health problem is warranted |
13,706 | 17,062,633 | Some evidence suggested similar kidney outcomes but better blood pressure outcomes with angioplasty , particularly in patients with bilateral renal disease .
Weak evidence suggested no large differences in mortality or cardiovascular events between medical and revascularization treatments .
No evidence directly compared adverse event rates between treatments . | Context Is medical therapy as effective as revascularization for atherosclerotic renal artery stenosis ?
The Editors Renal artery stenosis is defined as narrowing of the renal artery lumen .
Atherosclerosis , which usually involves the ostium and proximal third of the main renal artery and the perirenal aorta , accounts for 90 % of cases of renal artery stenosis ( 1 ) .
Atherosclerotic renal artery stenosis is increasingly common in aging population s , particularly elderly people with diabetes , hyperlipidemia , aortoiliac occlusive disease , coronary artery disease , or hypertension .
Atherosclerotic renal artery stenosis is a progressive disease that may occur alone or in combination with hypertension and ischemic kidney disease ( 1 ) .
Although the prevalence of atherosclerotic renal artery stenosis is poorly defined , it may vary from 30 % among patients with coronary artery disease identified by angiography ( 2 ) to 50 % among elderly people or those with diffuse atherosclerotic vascular diseases ( 3 ) .
In the United States , 12 % to 14 % of patients in whom dialysis is initiated have been found to have atherosclerotic renal artery stenosis ( 4 ) .
Treatment options include medication alone or revascularization of the stenosed artery or arteries .
Combination therapy with multiple antihypertensive agents , often including angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers , calcium-channel blockers , and -blockers , is frequently prescribed .
Some clinicians also use statins to decrease low-density lipoprotein cholesterol levels and antiplatelet agents , such as aspirin or clopidogrel , to reduce the risk for thrombosis .
The current st and ard for revascularization in most patients is percutaneous transluminal angioplasty with stent placement across the stenosis .
Angioplasty without stent placement is less commonly used .
Revascularization by surgical reconstruction is generally done only in patients with complicated renal artery anatomy or in those who require pararenal aortic reconstructions for aortic aneurysms or severe aortoiliac occlusive disease .
The American College of Cardiology and the American Heart Association recently published guidelines for management of patients with peripheral arterial disease , including renal artery stenosis ( 5 , 6 ) .
To determine which patients , if any , with atherosclerotic renal artery stenosis would most benefit from angioplasty with stent placement , as opposed to continued aggressive medical treatment , the National Institutes of Health has sponsored the large , multicenter Cardiovascular Outcomes in Renal Atherosclerotic Lesions ( CORAL ) trial .
Meanwhile , the Agency for Healthcare Research and Quality , under Section 1013 of the Medicare Modernization Act , commissioned a review asking key questions related to the effectiveness of aggressive medical therapy compared with renal artery angioplasty with stent placement .
However , because no published evidence directly compared angioplasty with stent placement and aggressive medical treatment with currently available drugs , the review covered direct comparisons of revascularization , including angioplasty with or without stent placement and surgery , and various medical regimens and indirect comparisons of angioplasty ( with stent placement ) and surgical interventions , various medical therapies , and natural history ( 8) .
In addition , at this time point , angiotensin-converting enzyme inhibitors began to be used more routinely in the treatment of patients with severe hypertension . | The objective was to identify subgroups of patients with hypertension and atherosclerotic renal artery stenosis who may benefit from immediate intervention . In the DRASTIC study , patients with hypertension , significant atherosclerotic renal artery stenosis , and a normal or mildly impaired renal function were r and omized between immediate balloon angioplasty ( PTRA ; n=56 ) and drug therapy followed by angioplasty after 3 months , if needed ( Med-PTRA ; n=50 ) . In this secondary analysis of the data , changes in the renal function and blood pressure after 1 year were studied by analysis of covariance in the following subgroups : patients with positive captopril – renin challenge test , abnormal captopril renogram , recently developed hypertension , bilateral stenosis , and severe stenosis . We found a benefit of immediate angioplasty only for patients with bilateral stenosis . Their creatinine clearance had decreased ( mean±s.d . : −4.2±13.5 ml/min ) in the Med-PTRA group , whereas it had improved substantially ( + 10.0±15.7 ml/min ) in the PTRA group ( P=0.02 ) . For patients with unilateral stenosis , the change in creatinine clearance did not differ between PTRA and Med-PTRA ( + 4.3±15.5 and + 1.3±12.5 ml/min , respectively ) . The patients with bilateral stenosis also seemed to benefit most from immediate intervention with regard to blood pressure control . None of the other subgroups had a clear benefit of immediate intervention regarding renal function or blood pressure control . In conclusion , intervention should not be postponed in patients with bilateral stenosis , even if renal function is normal . Other hypertensive patients with atherosclerotic renal artery disease could initially well be treated by aggressive multidrug therapy alone unless hypertension persists or renal function deteriorates Renal function and antihypertensive drug efficacy were determined in a prospect i ve , double-blind , multicenter study comparing enalapril plus hydrochlorothiazide with st and ard triple therapy ( hydrochlorothiazide , timolol , and hydralazine ) in 75 patients with documented renovascular hypertension . Both groups had significant mean decreases in systolic and diastolic blood pressures . Effective control of diastolic hypertension occurred in 96 percent of patients receiving enalapril compared with 82 percent of patients receiving the triple-drug regimen . Effective renal plasma flow was significantly increased by enalapril therapy . In contrast , the glomerular filtration rate had a bimodal response . In 80 percent of enalapril-treated patients , there was no significant change in the inulin clearance , although in 20 percent of patients ( 10 ) , there was a 28 percent decrease in the inulin clearance with a concomitant 12 percent increase in renal plasma flow . Seven of the 10 patients had unilateral renal artery stenosis , but in all 10 , it was high- grade stenosis ( more than 80 to 90 percent stenosis ) . Although a significant rise in the serum creatinine level occurred in one patient in association with diuretic therapy , volume repletion reversed this azotemia . No oliguric acute renal failure occurred in the enalapril-treated group . The cause of the decrease in glomerular filtration rate induced by enalapril plus hydrochlorothiazide in a minority of patients with renal artery stenosis appears to be quite complex . Although the abolishment of the autoregulation of glomerular filtration secondary to blockage of angiotensin II appears to be a primary cause , the roles of decreased arterial pressure , renal counterbalance , concurrent diuretic therapy , and other hemodynamic factors that may maintain glomerular ultrafiltration pressure must also be considered . The results of this study show that enalapril plus hydrochlorothiazide is effective in treating renovascular hypertension . Special care is needed for a small group of patients with renovascular hypertension in whom there is a decrease in the glomerular filtration rate with this therapy . This may identify a subset of patients with unilateral or bilateral high- grade renal artery stenosis in whom alternative therapy -- percutaneous angioplasty or surgical intervention -- may be considered ACUTE renal failure occasionally complicates therapy with the oral angiotensin-converting-enzyme inhibitor captopril.1 2 3 4 5 A variety of mechanisms have been postulated to account for captopril- OBJECTIVE The objective of our study was to evaluate the safety of CO(2 ) and gadodiamide angiography for diagnosing and percutaneously treating renal artery stenosis in patients with chronic renal insufficiency and presumed ischemic nephropathy . SUBJECTS AND METHODS One hundred forty-six consecutive patients with chronic renal insufficiency ( serum creatinine > 1.5 mg/dL ) were examined for renal artery stenosis using CO(2 ) and gadodiamide as the angiographic contrast agents . If renal artery stenosis was detected , percutaneous balloon angioplasty with or without stenting was performed . In patients for whom 48-hr creatinine levels were available , we performed an analysis to determine the incidence of contrast-involved nephropathy ( increase in serum creatinine of 0.5 mg/dL at 48 hr without identifiable cause ) . Major complications were reported up to 1 week , and mortality was reported up to 30 days after the procedure . RESULTS Ninety-five patients had serum creatinine levels available at 48 hr . An increase in creatinine of greater than 0.5 mg/dL at 48 hr occurred in three patients ( 3.2 % ) , presumably caused by CO(2 ) , by gadodiamide , or by both . Neither diabetes nor the degree of preexisting chronic renal insufficiency was a predictor of worsening renal function 48 hr after the procedure . The volumes of CO(2 ) and gadodiamide used for diagnostic studies alone versus the volume used for interventional studies was not significantly different ( for CO(2 ) , p = 0.09 ; for gadodiamide , p = 0.30 ) . Eleven major complications occurred in eight patients ( 5.5 % ) . Two deaths ( 1.4 % ) occurred within 30 days . One death was due to cholesterol embolization and the other was not believed to be related to the procedure . CONCLUSION Angiography and percutaneous treatment of renal artery stenosis in patients with chronic renal insufficiency and suspected ischemic nephropathy can be performed relatively safely using CO(2 ) and gadodiamide as angiographic contrast agents without an increased risk of complications . Contrast-induced nephropathy potentially occurred in 3.2 % of patients . Neither the degree of underlying renal insufficiency nor diabetes was a risk factor for predicting a greater likelihood of renal function worsening at 48 hr of follow-up . The volumes of CO(2 ) and gadodiamide used in this study did not result in an increased risk of contrast-involved nephropathy Data for the effects on blood pressure of renal artery balloon angioplasty are mostly from uncontrolled studies . The aim of this study was to document the efficacy and safety of angioplasty for lowering blood pressure in patients with atherosclerotic renal artery stenosis . Patients were r and omly assigned antihypertensive drug treatment ( control group , n = 26 ) or angioplasty ( n = 23 ) . Twenty-four-hour ambulatory blood pressure , the primary end point , was measured at baseline and at termination . Termination took place 6 months after r and omization or earlier in patients who developed refractory hypertension . In those allocated angioplasty , antihypertensive treatment was discontinued after the procedure but was subsequently resumed if hypertension persisted . Secondary end points were the treatment score and the incidence of complications . Two patients in the control group and 6 in the angioplasty group suffered procedural complications ( relative risk , 3.4 ; 95 % confidence interval , 0.8 to 15.1 ) . Early termination was required for refractory hypertension in 7 patients in the control group . Antihypertensive treatment was resumed in 17 patients in the angioplasty group . Mean ambulatory blood pressure at termination did not differ between control ( 141+/-15/84+/-11 mm Hg ) and angioplasty ( 140+/-15/81+/-9 mm Hg ) groups . Angioplasty reduced by 60 % the probability of having a treatment score of 2 or more at termination ( relative risk , 0.4 ; 95 % confidence interval , 0.2 to 0.7 ) . There was 1 case of dissection with segmental renal infa rct ion and 3 of restenosis in the angioplasty group . No patient suffered renal artery thrombosis . In unilateral atherosclerotic renal artery stenosis , angioplasty is a drug-sparing procedure that involves some morbidity . Previous uncontrolled and unblinded assessment s of angioplasty overestimated its potential for lowering blood pressure PURPOSE To compare the results of balloon percutaneous transluminal renal angioplasty ( PTRA ) and stent placement in atherosclerotic ostial , proximal , and isolated truncal stenoses . MATERIAL S AND METHODS Between January 1994 and April 1998 the authors prospect ively followed up 163 consecutive patients with 200 atherosclerotic renal arterial lesions after primary PTRA or primary stent placement . Duplex ultrasonography was performed 1 day and 3 , 6 , and 12 months later . RESULTS The primary 12-month PTRA patency rates were 34 % ( 21 of 33 atherosclerotic lesions ) for ostial stenoses , 65 % ( 20 of 60 ) for proximal stenoses , and 83 % ( five of 30 ) for truncal stenoses ( chi(2 ) value , 15.63 ; P < .001 ) . The corresponding stent patency rates were 80 % ( four of 21 ) , 72 % ( nine of 34 ) , and 66 % ( five of nine ) , respectively ( chi(2 ) value , 4.11 ; not significant ) . Significant stent-related reduction in risk of restenosis was limited to the ostial stenoses ( P = .002 ) . CONCLUSION Renal arterial stent placement considerably improves patency in ostial stenoses , but compared with the technically successful PTRA , it does not significantly improve primary patency in proximal and isolated truncal renal arterial stenoses The purpose s of this study were to determine the prevalence of angiographically significant renal artery stenosis in a patient population referred for diagnostic cardiac catheterization and to develop a model that predicts the highest-risk subset of patients who have significant renal artery narrowing . A prospect i ve validation cohort study was undertaken in a referral-based university hospital . After left ventriculography , abdominal aortography was performed to screen for the presence of renal artery disease . A convenience sample of 1,302 of 1,651 consecutive patients undergoing diagnostic cardiac catheterization were enrolled in the study . Of the 1,302 abdominal aortograms performed , 1,235 ( 95 % ) were deemed of adequate quality for the evaluation of renal artery anatomy . Renal artery disease was identified in 30 % of the patients . Insignificant renal artery stenosis was found in 187 ( 15 % ) and significant ( greater than or equal to 50 % diameter narrowing ) stenosis was found in 188 ( 15 % ) . Significant unilateral disease was present in 11 % , and bilateral disease was present in 4 % . By univariable and multivariable logistic regression analysis , the association of both clinical ly and catheterization-derived variables with renal artery disease was assessed . Multivariable predictors included age , severity of coronary artery disease , congestive heart failure , female gender , and peripheral vascular disease . Hypertension was not an associated variable . These data reveal the previously undetected high prevalence of renal artery disease in patients undergoing cardiac catheterization and provide clinical and angiographic features that assist in predicting its presence Purpose : To determine pretreatment variables that may predict 1-year clinical outcome of stent placement for renal artery stenosis . Methods : In a prospect i ve study , 40 consecutive patients ( 29 men ; mean age 60 ± 9.1 years ) with angiographically proven atherosclerotic renal artery stenosis were treated with stent placement because of drug resistant hypertension ( n=14 ) , renal function impairment ( n=14 ) , or both ( n=12 ) . Clinical success at 1 year was defined as a decrease of diastolic blood pressure ≥10 mmHg or a decrease in serum creatinine ≥20 % , depending on the indication for treatment . Regression analysis was performed using anatomical parameters from angiography and intravascular ultrasound , estimates of renal blood flow from renal scintigraphy , and single-kidney renal function measurements . Results : Patients treated for hypertension had better outcome than those treated for renal function impairment , with clinical success rates of 85 % and 35 % , respectively . Preserved renal function , with low serum creatinine and high 2-kidney glomerular filtration rate at baseline , was associated with clinical success in the entire patient group at follow-up ( p=0.02 and p=0.03 , respectively ) . An elevated vein-to-artery renin ratio on the affected side was borderline predictive ( p=0.06 ) . In patients treated for renal impairment , lateralization to the affected kidney ( affected kidney — to–2-kidney count ratio ≤0.45 ) on the scintigram emerged as a significant predictor for clinical success , with an odds ratio of 15 ( p=0.048 ) . Conclusions : Clinical success of renal artery stent placement is better for the treatment of hypertension than for preserving renal function . In patients with renal function impairment , lateralization to the affected kidney on the scintigram appears to be a predictor of clinical success This prospect i ve multicenter study included 1,205 patients , who were referred for difficult-to-treat hypertension or analysis of possible secondary hypertension . After a st and ardized selection protocol based on sharply defined drug-resistant hypertension or renal function impairment during angiotensin-converting enzyme inhibition , patients underwent renal scintigraphy and a captopril-renin challenge test . A set of clinical characteristics was also recorded . Sensitivity and specificity of renal scintigraphy for diagnosing renal artery stenosis were 0.72 and 0.90 and of the captopril-renin test 0.77 to 0.91 and 0.69 to 0.75 depending on the criterion used . The clinical characteristics were used to construct a clinical prediction rule for renal artery stenosis , which had a sensitivity of 0.68 and a specificity of 0.87 at a cut-off level of 30 % predicted probability . However , with the prediction rule a sensitivity of 0.90 could be reached by performing arteriography only in patients with a predicted probability of stenosis of > or = 10 % , result ing in a considerable reduction of the number of arteriograms to be made . A diagnostic strategy is advocated starting with drug-resistant hypertension and continuing to renal arteriography only in patients with increased probability of stenosis . Patients with atherosclerotic renal artery stenosis were then r and omized to balloon angioplasty ( n = 56 ) versus antihypertensive medication ( n = 50 ) . Three months after r and omization 22 patients from the medication group underwent balloon angioplasty in second instance . In an intention-to-treat analysis , no difference in blood pressure was found between the groups after 3 months , nor after 12 months of follow-up , although there was a small medication-sparing effect of balloon angioplasty . The lack of a beneficial effect of balloon angioplasty compared with medication could not be attributed to the high stenosis recurrence rate after angioplasty , nor to the fact that the inclusion criterion was set at a stenosis level of > or = 50 % so that patients with relatively mild stenosis were also included . Renal function after angioplasty was slightly better in the angioplasty group than in the medication group , and improvement of the renal scintigram occurred more often after angioplasty . Apart from the treatment of patients with specific characteristics , the presented therapeutic approach starts with extending the antihypertensive drug therapy to control blood pressure . Only if blood pressure can not be controlled or if renal function deteriorates , balloon angioplasty ( with stent placement ) is indicated Despite a high procedural success rate , long‐term blood pressure control after successful renal artery stenting of hypertensive patients has been inconsistent . This most likely reflects the absence of clinical guidelines for the selection of patients likely to benefit from renal revascularization . A cohort of 150 consecutive hypertensive patients ( mean age , 66.7 years ; 86 women ) with 180 renal artery lesions ( ≥75 % ) underwent primary Palmaz stent deployment . Mean arterial blood pressure ( MAP ) , serum creatinine , and antihypertensive medication requirements were monitored prospect ively . Specific definitions of blood pressure cure , improvement , or treatment failure were followed . Renal artery duplex Doppler or angiography was performed to assess stent patency at a mean 13 months ( range , 7–15 months ) . Multivariate logistic regression analysis was used to select clinical variables that best related to a beneficial blood pressure control at follow‐up . The procedural success rate was 97.3 % ( 146 patients ) and major in‐laboratory complications were infrequent ( 1.3 % ) . Late MAP values in 127 patients ( 91 % ) fell from 110 ± 13.7 to 97.6 ± 10.6 mm Hg ( P < 0.001 ) ; antihypertensive medication requirements decreased from 2.9 ± 1.2 to 1.9 ± 1.1 ( P < 0.01 ) . The 13‐month stent restenosis rate defined by duplex Doppler or angiography was 12 % . Multivariate logistic regression analysis identified a preprocedure MAP of > 110 mm Hg ( odds ratio , 2.9 ; P = 0.003 ) and bilateral renal stenoses ( odds ratio , 4.6 ; P = 0.009 ) as predictors of a beneficial blood pressure response at follow‐up . This study provides general preprocedure guidelines for the selection of hypertensive patients with atherosclerotic renal lesions likely to benefit from primary Palmaz stenting and confirms a high procedural success and low stent restenosis rate . Cathet . Cardiovasc . Intervent . 47:167–172 , 1999 . © 1999 Wiley‐Liss , ZusammenfassungHintergrundNierenarterienstenosen können sekundären arteriellen Bluthochdruck und Niereninsuffizienz verursachen . Die perkutane transluminale Stentangioplastie ( PTRAS ) ermöglicht eine effektive Beh and lung mit einer hohen technischen Erfolgsrate . Diese Studie beschäftigt sich mit den morphologischen und klinischen Langzeitergebnissen anh and einer Kontrolluntersuchung . Hauptziele waren die Evaluierung der Restenoserate sowie die Überprüfung des arteriellen Blutdruckes und der Nierenfunktion . Material ien und Method en40 Patienten , bei denen eine primär erfolgreiche PTRAS einer Nierenarterie durchgeführt wurde , wurden prospektiv eingeladen . Bei dieser Kontrolluntersuchung wurden eine Risikofaktorenerhebung , die Messung des arteriellen Blutdruckes sowie der Nierenfunktion und eine Multi-detector-Computer-tomographie-Angiographie durchgeführt ( CTA ) . Result ateDie mediane Nachbeobachtungszeit betrug 3,3 Jahre . 67,5 % der Patienten litten an Hyperlipidämie , 35 % rauchten Zigaretten und 15 % hatten Diabetes mellitus . Alle Patienten hatten Bluthochdruck , i m Vergleich zur präinterventionellen Situation war die Blutdrucksituation jedoch noch bei 37,5 % verbessert . Das Serumkreatinin war bei 25 % der patienten erhöht , der mittlere Kreatininspiegel lag bei 1,3±0,4 mg/dl . Eine hämodynamisch relevante Restenose wurde von Untersucher 1 bei 5 Patienten und von Untersucher 2 bei 6 Patienten gefunden , was eine Restenoserate nach der medianen Nachbeobachtungszeit von 12,5 % bzw . 15 % ergibt . Beide Untersucher entdeckten weitere 3 hämodynamisch relevante Stenosen in den kontralateralen Nierenarterien . KonklusionPTRAS führt zu ausgezeichneten morphologischen Langzeitergebnissen , die klinischen Langzeitergebnisse basierend auf den Parametern arterielle Hypertonie und Nierenfunktion sind jedoch nur moderat . stage renal disease . Percutaneous transluminal angioplasty with stent implantation ( PTRAS ) allows effective and consistent treatment with a high technical success rate . The present trial focuses on the morphological and clinical results as assessed at a long-term follow-up ( FU ) visit . The main goals were assessment of the restenosis rate and evaluation of arterial hypertension and renal function . Patients and methods 40 patients who had undergone successful stenting of a main renal artery were prospect ively enrolled . At the FU visit , all patients underwent a risk-factor assessment , evaluation of arterial blood pressure and serum creatinine , and multi-detector computed tomography angiography ( CTA ) . Results Median FU was 3.3 years . Hyperlipidemia was present in 67.5 % of the patients , current cigarette smoking in 35 % and diabetes mellitus in 15 % . All patients still suffered from arterial hypertension but , compared with the pre-interventional situation , arterial hypertension was improved in 37.5 % . Serum creatinine was increased in 25 % of patients , mean creatinine level was 1.3±0.4 mg/dl . Hemodynamically relevant restenosis was detected by observer 1 in five patients and by observer 2 in six patients , giving restenosis rates of 12.5 % and 15 % respectively , after the median FU period . Both observers detected three additional relevant stenoses in the contralateral main renal arteries . Conclusions PTRAS gives excellent morphological long-term results . However , the clinical long-term outcome regarding arterial hypertension and renal function is only moderate Purpose : To report a prospect i ve study evaluating the long-term impact of stent-supported angioplasty on renal function and blood pressure control . Methods : In a 6-year period , 456 hemodynamically significant de novo renal artery stenoses ≥70 % were treated in 340 consecutive hypertensive patients ( 223 men ; mean age 66±10 years , range 44–84 ) with or without impaired renal function . Baseline data on serum creatinine ( sCr ) , intrarenal resistance index , ambulatory 24-hour blood pressure monitoring , and documentation of the number and dose of antihypertensive drugs were compared to values obtained during follow-up . The primary endpoint was a 10 % decrease in sCr ; the glomerular filtration rate and changes in blood pressure control were additional outcome measures . Results : During a mean follow-up of 34±20 months , sCr decreased significantly from 1.45±0.87 to 1.39±0.73 mg/dL ( p=0.048 ) . In 34 % of the patients , sCr decreased > 10 % , 39 % were unchanged , and 27 % had an increase > 10 % . Glomerular filtration rate increased from 59±26 to 62±26 mL/min/1.73 m2 ( p=0.6 ) . Systolic , diastolic , and mean blood pressure measurements significantly improved immediately after the intervention ( 132/72/93 versus 144/79/102 mmHg at baseline , p<0.0001 ) and remained improved during follow-up ( p<0.0001 ) . Blood pressure control was improved in 46 % , unchanged in 43 % , and deteriorated in 11 % . Baseline sCr , bilateral intervention , percent diameter stenosis , and 3-vessel coronary disease were independent predictors of improved renal function during follow-up ; the number of antihypertensive drugs taken before the intervention predicted improved blood pressure control . Conclusions : Stent-supported angioplasty of renal artery stenoses preserves renal function and improves blood pressure control in a broader spectrum of patients than previously thought PURPOSE To evaluate the clinical outcomes of patients undergoing renal artery stenting with intravascular ultrasound ( IVUS ) guidance and compare measurements between IVUS and angiography . METHODS One hundred thirty-one patients ( 71 women ; mean age 71 + /- 8 years ) underwent IVUS-guided Palmaz stent implantation in 153 stenotic renal arteries at a single center . The indications for stenting were uncontrolled hypertension ( 102 , 77.9 % ) , renal insufficiency ( 10 , 7.6 % ) , and both conditions ( 19 , 14.5 % ) . The majority of lesions were ostial ( 114 , 74.5 % ) ; the remainder occupied the proximal renal artery ( 39 , 25.5 % ) . The mean lesion length and diameter stenosis were 6.5 + /- 3.0 mm and 74 % + /- 10 % , respectively , as measured by angiography . Data were recorded in a prespecified data base ; angiographic and IVUS images were analyzed at dedicated core laboratories and compared . RESULTS Angiographic success was achieved in all patients , but IVUS indicated the need for additional intervention in 36 ( 23.5 % ) cases . There was strong correlation between the angiographic and IVUS measurements of lesion length ( r = 0.60 , p < 0.0001 ) and pre-/postprocedural minimal luminal diameter ( r = 0.72 and 0.63 , respectively ; p < 0.0001 ) . The mean contrast volume was 74 + /- 18 mL per case . In-hospital renal failure occurred in 8 ( 6.1 % ) patients ; 2 ( 1.5 % ) required transient hemodialysis . At a mean 15-month follow-up , patients were treated with fewer antihypertensive medications ( p = 0.05 ) , and systolic and diastolic arterial blood pressures had decreased ( p = 0.001 ) ; no significant change was noted in serum creatinine . CONCLUSIONS IVUS-guided stenting facilitates safe renal artery revascularization . IVUS imaging may complement angiography in certain cases , which should be studied further in prospect i ve studies with iodinated or noniodinated contrast agents Delapril , a new angiotensin converting enzyme ( ACE ) inhibitor discovered in the laboratory of Takeda Chemical Industries , Ltd. , is the result of drug design based on the structure-activity relationships of ACE inhibitors . Delapril is an antihypertensive agent with a relatively long duration of action and no SH moiety in its structure . Following administration , it is converted into two active metabolites . Delapril effectively lowered blood pressure in 73 % of 1,008 patients with hypertension during clinical trials in Japan . Efficacy rates were 73 % for essential hypertension , 85 % for renal hypertension , and 80 % for renovascular hypertension . Excellent hypotensive response was observed in all age groups , from young to elderly patients . Side effects during administration of delapril , based on subjective evidence , were reported in 80 out of the 1,008 cases ( 7.9 % ) . The main symptoms included orthostatic dizziness ( 1.7 % ) , dizziness ( 1.3 % ) , and nausea ( 1.1 % ) . Dry cough , which has attracted attention in recent years as a side effect of ACE inhibitors , was reported at a low incidence of 1.1 % . In a double-blind , controlled study in patients with mild to moderate essential hypertension in which captopril served as a positive control , delapril showed superior hypotensive effect and greater safety . Data derived from the Japan Study Group on Delapril indicate that this ACE inhibitor has excellent hypotensive effects and a high level of safety . It is suitable as a first-line drug in both monotherapy and combined therapy BACKGROUND Patients with hypertension and renal-artery stenosis are often treated with percutaneous transluminal renal angioplasty . However , the long-term effects of this procedure on blood pressure are not well understood . METHODS We r and omly assigned 106 patients with hypertension who had atherosclerotic renal-artery stenosis ( defined as a decrease in luminal diameter of 50 percent or more ) and a serum creatinine concentration of 2.3 mg per deciliter ( 200 micromol per liter ) or less to undergo percutaneous transluminal renal angioplasty or to receive drug therapy . To be included , patients also had to have a diastolic blood pressure of 95 mm Hg or higher despite treatment with two antihypertensive drugs or an increase of at least 0.2 mg per deciliter ( 20 micromol per liter ) in the serum creatinine concentration during treatment with an angiotensin-converting-enzyme inhibitor . Blood pressure , doses of antihypertensive drugs , and renal function were assessed at 3 and 12 months , and patency of the renal artery was assessed at 12 months . RESULTS At base line , the mean ( + /-SD ) systolic and diastolic blood pressures were 179+/-25 and 104+/-10 mm Hg , respectively , in the angioplasty group and 180+/-23 and 103+/-8 mm Hg , respectively , in the drug-therapy group . At three months , the blood pressures were similar in the two groups ( 169+/-28 and 99+/-12 mm Hg , respectively , in the 56 patients in the angioplasty group and 176+/-31 and 101+/-14 mm Hg , respectively , in the 50 patients in the drug-therapy group ; P=0.25 for the comparison of systolic pressure and P=0.36 for the comparison of diastolic pressure between the two groups ) ; at the time , patients in the angioplasty group were taking 2.1+/-1.3 defined daily doses of medication and those in the drug-therapy group were taking 3.2+/-1.5 daily doses ( P<0.001 ) . In the drug-therapy group , 22 patients underwent balloon angioplasty after three months because of persistent hypertension despite treatment with three or more drugs or because of a deterioration in renal function . According to intention-to-treat analysis , at 12 months , there were no significant differences between the angioplasty and drug-therapy groups in systolic and diastolic blood pressures , daily drug doses , or renal function . CONCLUSIONS In the treatment of patients with hypertension and renal-artery stenosis , angioplasty has little advantage over antihypertensive-drug therapy We investigated the prevalence of renal artery disease and outcome in a cohort of atherosclerotic patients with renal dysfunction . We studied 44 consecutive patients who were older than 50 years of age , who had renal dysfunction and in whom one or more of the following atherosclerotic diseases was confirmed : cerebral infa rct ion , coronary artery disease or peripheral vascular disease . Renal artery stenosis was assessed by gadolinium-enhanced magnetic-resonance angiography . Patients who were treated medically were prospect ively followed up in our outpatient clinic and the impact of renal artery stenosis on survival was evaluated . Renal artery stenosis was found in 22 ( 50 % ) of the 44 patients . Difference in kidney length and carotid artery stenosis were identified as independent predictors of renal artery stenosis . Among the patients who were treated medically ( n=42 ) , rates of mortality were 4.4 , 12.7 and 18.1 per 100 patient-years in those without renal artery stenosis , those with unilateral renal artery stenosis and those with bilateral renal artery stenosis , respectively . The mortality and renal survival curves were significantly different among these three groups . These findings indicate that renal artery stenosis is common in patients with renal dysfunction and concomitant cardiovascular disease , especially in those with carotid artery stenosis , and that a substantial difference in the length of kidneys may be a predictor of renovascular disease . Patients with renal dysfunction result ing from renal artery stenosis are at risk of death from cardiovascular disease and end-stage renal failure BACKGROUND Atherosclerotic renal artery stenosis is a problem with no consensus on diagnosis or therapy . The consequences of renal ischemia are neuroendocrine activation , hypertension , and renal insufficiency that can potentially result in acceleration of atherosclerosis , further renal dysfunction , myocardial infa rct ion , heart failure , stroke , and death . Whether revascularization improves clinical outcomes when compared with optimum medical therapy is unknown . METHODS CORAL is a r and omized clinical trial contrasting optimum medical therapy alone to stenting with optimum medical therapy on a composite cardiovascular and renal end point : cardiovascular or renal death , myocardial infa rct ion , hospitalization for congestive heart failure , stroke , doubling of serum creatinine , and need for renal replacement therapy . The secondary end points evaluate the effectiveness of revascularization in important subgroups of patients and with respect to all-cause mortality , kidney function , renal artery patency , microvascular renal function , and blood pressure control . We will also correlate stenosis severity with longitudinal renal function and determine the value of stenting from the perspectives of quality of life and cost-effectiveness . The primary entry criteria are ( 1 ) an atherosclerotic renal stenosis of > or = 60 % with a 20 mm Hg systolic pressure gradient or > or = 80 % with no gradient necessary and ( 2 ) systolic hypertension of > or = 155 mm Hg on > or = 2 antihypertensive medications . R and omization will occur in 1080 subjects . The study has 90 % power to detect a 28 % reduction in primary end point hazard rate . CONCLUSIONS CORAL represents a unique opportunity to determine the incremental value of stent revascularization , in addition to optimal medical therapy , for the treatment of atherosclerotic renal artery stenosis BACKGROUND Spiral or helical arterial blood flow patterns have been widely observed in both animals and humans . The absence of spiral flow has been associated with carotid arterial disease . The aim of this study was to detect the presence of aortic spiral flow using magnetic resonance imaging ( MRI ) and to evaluate the relationship of the presence of spiral aortic flow with renal arterial disease and renal function in the follow-up of patients with suspected renal atheromatous disease . METHODS Prospect i ve study of 100 patients with suspected renal arterial disease and 44 patient controls . Using a 1.5 T MRI unit ( Siemens Symphony ) , phase contrast flow quantification and three-dimensional contrast enhanced MR angiography of the abdominal aorta were performed . Renal arterial stenoses ( RAS ) were classified minimal , moderate or severe . Renal function was followed at 3 months before and 6 months after MRI . RESULTS Non-spiral flow was more prevalent in patients with more severe RAS . Renal impairment progressed significantly in severe RAS without spiral flow ( P = 0.0065 ) , but did not progress significantly in severe RAS with spiral flow ( P = 0.12 ) . In minimal or moderate RAS with or without spiral flow there was no significant progression ( P = 0.16 , 0.13 , 0.47 , 0.092 , respectively ) . CONCLUSIONS Aortic spiral blood flow can be assessed with MRI . Lack of aortic spiral blood flow in patients with severe RAS is associated with significant short-term renal function deterioration . Determination of blood flow patterns may be a useful indicator of renal impairment progression in patients with suspected renal artery stenosis BACKGROUND The utility of renal artery stenting ( RS ) in preserving renal function ( RF ) is not well established . Our prospect i ve study aim ed to examine the clinical effects of RS in patients with proximal renal artery stenosis and chronic renal failure ( CRF ) . METHODS Fifty-two patients , with atherosclerotic renal artery stenosis ( ARAS ) and renal impairment underwent successful monolateral ( 33 patients ) or global RS ( 19 patients : six bilateral stenting , two surgical solitary kidney and 11 functional solitary kidney ) . Patients were considered eligible if they had at least a mild renal impairment ( serum creatinine ( Cr ) > 1.5 mg/dL ) . To assess a significant change in RF , we compared the slopes of the regression lines derived from the reciprocal of Cr vs. time , plotted before and after stenting . Patients had a median post-procedure follow-up of 24 months ( range 9 - 54 ) . RESULTS Before stenting all patients exhibited a negative slope , indicating progressive renal failure . After stenting the slopes became positive in eight patients ( 15.5 % ) , indicating a significant improvement in RF ; in 31 patients ( 59.5 % ) the slopes were not significantly different from 0 and were associated with a stable RF , while 13 patients ( 25 % ) presented negative slopes and showed a continuous reduction in RF . Previous serum Cr , initial diameter of the treated kidney , vascular resistive index , and mono vs. global stenting were not significantly associated to post stenting RF . CONCLUSIONS RS appears to be associated with RF stabilization in the majority of patients with CRF The goal of this study was to determine the incidence of and risk factors for renal atrophy among kidneys with atherosclerotic renal artery stenosis ( ARAS ) . Participants with at least one ARAS were followed prospect ively with duplex scans performed every six months . Renal atrophy was defined as a reduction in renal length of greater than 1 cm . A total of 204 kidneys in 122 subjects were followed for a mean of 33 months . The two-year cumulative incidence ( CI ) of renal atrophy was 5.5 % , 11.7 % , and 20.8 % in kidneys with a baseline renal artery disease classification of normal , < 60 % stenosis , and > or = 60 % stenosis , respectively ( P = 0.009 , log rank test ) . Other baseline factors associated with a high risk of renal atrophy included a systolic blood pressure > 180 mm Hg ( 2-year CL = 35 % , P = 0.01 ) , a renal artery peak systolic velocity > 400 cm/second ( 2-year CI = 32 % , P = 0.02 ) , and a renal cortical end diastolic velocity < or = 5 cm/second ( 2-year CI = 29 % , P = 0.046 ) . The number of kidneys demonstrating atrophy per participant was correlated with elevations in the serum creatinine concentration ( P = 0.03 ) . In patients with ARAS , there is a significant risk of renal atrophy among kidneys exposed to elevated systolic blood pressure and among those with high- grade ARAS and low renal cortical blood flow velocity as assessed by renal duplex scanning . The occurrence of renal atrophy is well-correlated with changes in the serum creatinine concentration BACKGROUND Percutaneous transluminal angioplasty ( PTA ) for ostial atherosclerotic renal-artery stenosis has poor results . Angioplasty with stent placement ( PTAS ) may be more effective . We undertook a r and omised prospect i ve study to compare PTA with PTAS in patients with ostial atherosclerotic renal-artery stenosis . METHODS Patients with ostial atherosclerotic renal-artery stenosis were assigned to receive PTA or PTAS . Secondary PTAS was allowed if PTA failed immediately or during 6 months ' follow-up . Analysis was by intention to treat . FINDINGS 42 patients were assigned PTA and 43 were assigned PTAS , but one patient in the PTAS group was excluded from the study . Primary success rate ( < 50 % residual stenosis ) of PTA was 57 % ( 24 patients ) compared with 88 % ( 37 patients ) for PTAS ( difference between groups 31 % [ 95 % CI 12 - 50 ] ) . Complications were similar . At 6 months , the primary patency rate was 29 % ( 12 patients ) for PTA , and 75 % ( 30 patients ) for PTAS ( 46 % [ 24 - 68 ] ) . Restenosis after a successful primary procedure occurred in 48 % of patients for PTA and 14 % for PTAS ( 34 % [ 11 - 58 ] ) . 12 patients underwent secondary stenting for primary or late failure of PTA within the follow-up period : success was similar to that of primary PTAS . Evaluation based on intention to treat showed no difference in clinical results at six months for PTA or PTAS . INTERPRETATION PTAS is a better technique than PTA to achieve vessel patency in ostial atherosclerotic renal-artery stenosis . Primary PTAS and primary PTA plus PTAS as rescue therapy have similar outcomes . However , the burden of reintervention after PTA outweighs the potential saving in stents , so primary PTAS is a better approach to use BACKGROUND Renal artery stenosis ( RAS ) is associated with substantial morbidity and mortality . This relationship is strongest in the presence of renal insufficiency ( RI ) . The goal of this study is to assess the relationship between RI , mortality , and adverse events in the setting of renovascular disease . METHODS Two hundred sixty-one patients with significant RAS treated with endovascular stenting were followed up prospect ively for 21 + /- 18 months ( range , 0 to 85 months ) . Blood pressure ( BP ) , renal function , medication use , and comorbidities were assessed . Death was verified through the Social Security Death Master Index File , and cause of death was derived from death certificates . Medical records of 230 subjects subsequently were review ed to identify adverse cardiovascular and renal events . RESULTS Overall , 37 % of patients experienced at least 1 adverse event postprocedure . Myocardial infa rct ion ( MI ) and congestive heart failure ( CHF ) events increased with degree of baseline RI . Seventy-three deaths ( 28 % ) occurred postprocedure ( range , 13 to 2,457 days ) . Baseline characteristics associated with mortality included advanced age , decreased use of beta-blockers , increased use of diuretics , increased serum creatinine ( Cr ) level , decreased Cr clearance ( CrCl ) , bilateral stenoses or stenosis of a solitary kidney , history of CHF , and history of MI . Follow-up characteristics associated with mortality included lower systolic and diastolic BP , increased serum Cr level , and decreased CrCl . RI at baseline and follow-up remained associated with mortality after adjusting for other clinical ly and statistically significant variables . Patients in whom renal function improved after stenting appeared to show improved survival over those without improved renal function ( 45 % versus 0 % cumulative survival , P < 0.05 ) . CONCLUSION In patients with RAS undergoing stent therapy , baseline RI is associated with an increased incidence of adverse events , as well as decreased survival , independent of other baseline clinical factors . Importantly , improvement in renal function appears to be associated with increased survival Palmaz‐Schatz stent revascularization of renal artery stenosis was successfully performed on 1,058 patients who were entered into a voluntary , multicenter registry . The revascularization procedures were performed because of poorly controlled hypertension , preservation of renal function , and congestive heart failure . All 1,058 patients were eligible for ≥ 6‐month clinical follow‐up , which focused on subsequent renal function , blood pressure , number of antihypertensive medications , and survival . At 4‐year follow‐up , systolic and diastolic blood pressures had significantly decreased ( 168 ± 27 mm Hg to 147 ± 21 mm Hg , and 84 ± 15 to 78 ± 12 mm Hg ; P < 0.05 ) and the blood pressure appeared to be more facilely controlled as indicated by the concomitant decrease in number of antihypertensive medications ( 2.4 ± 1.1 to 2.0 ± 1.0 ; P < 0.05 ) . Serum creatinine had also significantly decreased ( 1.7 ± 1.1 to 1.3 ± 0.8 mg/dl ; P < 0.05 ) . The cumulative probability of survival was 74 % ± 3 % at 4 years . Survival was good for patients with normal ( 85 % ± 3 % ) baseline renal function , fair ( 78 % ± 5 % ) with mildly impaired renal function , and poor ( 49 % ± 5 % ) with severely impaired renal function ( baseline creatinine ≥ 2.0 mg/dl ) . The combination of impaired renal function and bilateral disease adversely effected survival ( unilateral 55 % ± 6 % vs. bilateral 36 % ± 11 % ; P < 0.05 ) . Renal artery stent revascularization , in the presence of normal or mildly impaired renal function , had a beneficial effect on blood pressure control and on renal function ( through stabilization or improvement ) . Survival was adversely effected by renal dysfunction despite adequate revascularization . Perhaps early diagnosis of renal artery stenosis and adequate revascularization prior to the onset of renal dysfunction could beneficially impact blood pressure control , preserve or prevent deterioration of renal function , and improve patient survival . Cathet Cardiovasc Intervent 2002;55:182–188 . © 2002 Wiley‐Liss , BACKGROUND Prospect ively identifying patients whose renal function or blood pressure will improve after the correction of renal-artery stenosis has not been possible . We evaluated whether a high level of resistance to flow in the segmental arteries of both kidneys ( indicated by resistance-index values of at least 80 ) can be used prospect ively to select appropriate patients for treatment . METHODS We evaluated 5950 patients with hypertension for renal-artery stenosis using color Doppler ultrasonography , and we measured the resistance index ( [ 1 - end-diastolic velocity divided by maximal systolic velocity ] x 100 ) . Among 138 patients who had unilateral or bilateral renal-artery stenosis of more than 50 percent of the luminal diameter and who underwent renal angioplasty or surgery , the procedure was technically successful in 131 ( 95 percent ) . Creatinine clearance and 24-hour ambulatory blood pressure were measured before renal-artery stenosis was corrected ; 3 , 6 , and 12 months after the procedure ; and yearly thereafter . The mean ( + /-SD ) duration of follow-up was 32+/-21 months . RESULTS Among the 35 patients ( 27 percent ) who had resistance-index values of at least 80 before revascularization , the mean arterial pressure did not decrease by 10 mm Hg or more after revascularization in 34 ( 97 percent ) . Renal function declined ( defined by a decrease in the creatinine clearance ; of at least 10 percent ) in 28 ( 80 percent ) ; 16 ( 46 percent ) became dependent on dialysis and 10 ( 29 percent ) died during follow-up . Among the 96 patients ( 73 percent ) with a resistance-index value of less than 80 , the mean arterial pressure decreased by at least 10 percent in all but 6 patients ( 6 percent ) after revascularization ; renal function worsened in only 3 ( 3 percent ) , all of whom became dependent on dialysis ; and 3 ( 3 percent ) died ( P<0.001 for the comparison with patients with a resistance-index value of at least 80 ) . CONCLUSIONS A renal resistance-index value of at least 80 reliably identifies patients with renal-artery stenosis in whom angioplasty or surgery will not improve renal function , blood pressure , or kidney survival To study the effect of gender on outcome following renal artery stent placement for renovascular hypertension , we prospect Ively followed 66 patients ( 30 males , 36 females ) who underwent Palmaz stent placement in 89 renal arteries . There was no difference in the incidence of procedure-related complications between males and females . At 6-mo follow-up , the decrease in systolic ( 35 + /- 30 mm Hg and 27 + /- 25 mm Hg ) and diastolic ( 15 + /- 23 mm Hg and 14 + /- 14 mm Hg ) blood pressures was similar in female and male patients , respectIvely . Late follow-up at 19 + /- 11 mo also showed no difference in blood pressure response . In 44 patients who underwent repeat angiography at a mean duration of 9.1 + /- 5.6 mo after stent deployment , the incidence of restenosis was 26 % in females and 24 % in males ( P = 0.85 ) . We conclude that gender has no effect on the incidence of complications , blood pressure response , or angiographic restenosis in patients undergoing renal artery stent placement OBJECTIVES This study sought to define the safety and durability of renal stenting after suboptimal/failed renal artery angioplasty in patients with suspected renovascular hypertension . BACKGROUND Few prospect i ve multicenter studies have detailed the safety , efficacy , and long-term clinical benefits of renal artery stent revascularization in hypertensive patients with aorto-ostial atherosclerotic renal artery lesions . METHODS This non-r and omized study enrolled 208 patients with de novo or restenotic > or = 70 % aorto-ostial renal artery stenoses , who underwent implantation of a balloon-exp and able stent after unsuccessful percutaneous transluminal renal angioplasty ( PTRA ) , which was defined as a > or = 50 % residual stenosis , persistent translesional pressure gradient , or a flow-limiting dissection . The primary end point was the nine-month quantitative angiographic or duplex ultrasonography restenosis rate adjudicated by core laboratory analysis . Secondary end points included renal function , blood pressure , and cumulative incidence of major adverse events and target lesion revascularization at 24 months . RESULTS The stent procedure was immediately successful in 182 of 227 ( 80.2 % ) lesions treated . The nine-month restenosis rate was 17.4 % . Systolic/diastolic blood pressure decreased from 168 + /- 25/82 + /- 13 mm Hg ( mean + /- st and ard deviation ) at baseline to 149 + /- 24/77 + /- 12 mm Hg at 9 months ( p < 0.001 vs. baseline ) , and 149 + /- 25/77 + /- 12 mm Hg at 24 months ( p < 0.001 vs. baseline ) . Mean serum creatinine concentration was unchanged from baseline values at 9 and 24 months . The 24-month cumulative rate of major adverse events was 19.7 % . CONCLUSIONS In hypertensive patients with aorto-ostial atherosclerotic renal artery stenosis in whom PTRA is unsuccessful , Palmaz ( Cordis Corp. , Warren , New Jersey ) balloon-exp and able stents provide a safe and durable revascularization strategy , with a beneficial impact on hypertension OBJECTIVES We assessed the safety and efficacy of stent placement in patients with poorly controlled hypertension and renal artery stenoses , which are difficult to treat with balloon angioplasty alone . BACKGROUND Preliminary experience with stent placement suggests improved results over balloon angioplasty alone in patients with atherosclerotic renal artery stenosis . METHODS Balloon-exp and able stents were placed in 100 consecutive patients ( 133 renal arteries ) with hypertension and renal artery stenosis . Sixty-seven of the patients had unilateral renal artery stenosis treated and 33 had bilateral renal artery stenoses treated with stents placed in both renal arteries . RESULTS Angiographic success , as determined by quantitative angiography , was obtained in 132 ( 99 % ) of 133 lesions . Early clinical success was achieved in 76 % of the patients . Six months after stent placement , the systolic blood pressure was reduced from 173 + /- 25 to 147 + /- 23 mm Hg ( p < 0.001 ) ; the diastolic pressure from 88 + /- 17 to 76 + /- 12 mm Hg ( p < 0.001 ) ; and the mean number of antihypertensive medications per patient from 2.6 + /- 1 to 2.0 + /- 0.9 ( p < 0.001 ) . Angiographic follow-up at a mean of 8.7 + /- 5.0 months in 67 patients revealed restenosis ( > 50 % diameter narrowing ) in 15 ( 19 % ) of 80 stented vessels . CONCLUSIONS Renal artery stenting is an effective treatment for renovascular hypertension , with a low angiographic restenosis rate . Stent placement appears to be a very attractive therapy in patients with lesions difficult to treat with balloon angioplasty such as renal aorto-ostial lesions and restenotic lesions , as well as after a suboptimal balloon angioplasty result |
13,707 | 30,583,914 | Evidence suggests that engaging with gardens , and gardening , can favourably impact the emotional and social health of people with dementia and , an explanatory theoretical model is proposed . | Abstract Engaging with the natural environment contributes to favourable psychosocial health outcomes . | Objective : To assess whether forest therapy is effective for treating depression and anxiety in patients with chronic stroke by using several psychological tests . We measured reactive oxygen metabolite ( d-ROM ) levels and biological antioxidant potentials ( BAPs ) associated with psychological stress . Methods : Fifty-nine patients with chronic stroke were r and omly assigned to either a forest group ( staying at a recreational forest site ) or to an urban group ( staying in an urban hotel ) ; the duration and activities performed by both groups were the same . Scores on the Beck Depression Inventory ( BDI ) , Hamilton Depression Rating Scale ( HAM-D17 ) , Spielberger State-Trait Anxiety Inventory ( STAI ) , d-ROMs and BAPs were evaluated both before and after the treatment programs . Results : In the forest group , BDI , HAM-D17 and STAI scores were significantly lower following treatment , and BAPs were significantly higher than baseline . In the urban group , STAI scores were significantly higher following treatment . Moreover , BDI , HAM-D17 and STAI scores of the forest group were significantly lower , and BAPs were significantly higher following treatment ( ANCOVA , p < 0.05 ) . Conclusion : Forest therapy is beneficial for treating depression and anxiety symptoms in patients with chronic stroke , and may be particularly useful in patients who can not be treated with st and ard pharmacological or electroconvulsive therapies Major depressive disorder ( MDD ) is prevalent after traumatic brain injury ( TBI ) ; however , there is a lack of evidence regarding effective treatment approaches . We conducted a choice-stratified r and omized controlled trial in 100 adults with MDD within 10 years of complicated mild to severe TBI to test the effectiveness of brief cognitive behavioral therapy administered over the telephone ( CBT-T ) ( n = 40 ) or in-person ( CBT-IP ) ( n = 18 ) , compared with usual care ( UC ) ( n = 42 ) . Participants were recruited from clinical and community setting s throughout the United States . The main outcomes were change in depression severity on the clinician-rated 17 item Hamilton Depression Rating Scale ( HAMD-17 ) and the patient-reported Symptom Checklist-20 ( SCL-20 ) over 16 weeks . There was no significant difference between the combined CBT and UC groups over 16 weeks on the HAMD-17 ( treatment effect = 1.2 , 95 % CI : -1.5 - 4.0 ; p = 0.37 ) and a nonsignificant trend favoring CBT on the SCL-20 ( treatment effect = 0.28 , 95 % CI : -0.03 - 0.59 ; p = 0.074 ) . In follow-up comparisons , the CBT-T group had significantly more improvement on the SCL-20 than the UC group ( treatment effect = 0.36 , 95 % CI : 0.01 - 0.70 ; p = 0.043 ) and completers of eight or more CBT sessions had significantly improved SCL-20 scores compared with the UC group ( treatment effect = 0.43 , 95 % CI : 0.10 - 0.76 ; p = 0.011 ) . CBT participants reported significantly more symptom improvement ( p = 0.010 ) and greater satisfaction with depression care ( p < 0.001 ) , than did the UC group . In-person and telephone-administered CBT are acceptable and feasible in persons with TBI . Although further research is warranted , telephone CBT holds particular promise for enhancing access and adherence to effective depression treatment A method for assessing affect states among older people with Alzheimer 's disease was developed for use in a study design ed to evaluate a special care unit for such residents of a nursing home . The 6-item Philadelphia Geriatric Center Affect Rating Scale was design ed for the use of research and other staff in assessing positive affect ( pleasure , interest , contentment ) and negative affect ( sadness , worry/anxiety , and anger ) by direct observation of facial expression , body movement , and other cues that do not depend on self-report , among 253 demented and 43 nondemented residents . Each affect scale was highly reliable , expressed in estimated portions of a 10-minute observation period when the affect expression occurred . Validity estimates were affirmative in showing discriminant correlations between the positive states and various independent measures of social and other outwardly engaged behavior and between negative states and other measures of depression , anger , anxiety , and withdrawal . Limited support for the two-factor dimensionality of the affect ratings was obtained , although positive and negative affect were correlated , rather than independent . Some hope is offered that the preference and aversions of Alzheimer patients may be better understood by observations of their emotional behaviors and that such methods may lead to a better ability to judge institutional quality PURPOSE To assess the effects of horticultural therapy ( HT ) on mood state and heart rate ( HR ) in patients participating in an inpatient cardiac rehabilitation program . METHODS Cardiac rehabilitation in patients ( n = 107 ) participated in the study . The HT group consisted of 59 subjects ( 34 males , 25 females ) . The control group , which participated in patient education classes ( PECs ) , consisted of 48 subjects ( 31 males , 17 females ) . Both HT sessions and PEC are components of the inpatient rehabilitation program . Each group was evaluated before and after a class in their respective modality . Evaluation consisted of the completion of a Profile of Mood States ( POMS ) inventory , and an HR obtained by pulse oximetry . RESULTS Changes in the POMS total mood disturbance ( TMD ) score and HR between preintervention and postintervention were compared between groups . There was no presession difference in either TMD score ( 16 + /- 3.6 and 19.0 + /- 3.2 , PEC and HT , respectively ) or HR ( 73.5 + /- 2.5 and 79 + /- 1.8 , PEC and HT , respectively ) . Immediately following the intervention , the HT TMD was significantly reduced ( post-TMD = 1.6 + /- 3.2 , P < .001 ) , while PEC TMD was not significantly changed ( TMD = 17.0 + /- 28.5 ) . After intervention , HR fell in HT by 4 + /- 9.6 bpm ( P < .001 ) but was unchanged in PEC . CONCLUSION These findings indicate that HT improves mood state , suggesting that it may be a useful tool in reducing stress . Therefore , to the extent that stress contributes to coronary heart disease , these findings support the role of HT as an effective component of cardiac rehabilitation Objective : To evaluate the contribution of social communication abilities and affective/behavioral functioning to socialintegration outcomes for persons with traumatic brain injury ( TBI ) . Design : Prospect i ve cohort study . Participants : A total of 184 adults with TBI ( 72.8 % men ) evaluated at least 6 months postdischarge from acute care orinpatient rehabilitation hospitals and after living at least 3 months in the community postdischarge ( Mean = 7.84 monthspostinjury ) . Measures : La Trobe Communication Question naire ( LCQ ) , Assessment of Interpersonal Problem-Solving Skills(AIPSS ) , Affective Behavioral subscale From the Problem Checklist of the Head Injury Family Interview ( AB-HIFI ) , Craig H and icap Assessment and Reporting Technique – Short Form Social Integration subscale ( CHART-SF-SI ) , Community Integration Question naireSocial Integration subscale ( CIQ-SI ) . Results : Social communication measures ( LCQ , AIPSS ) and self-reported behavioralfunctioning ( AB-HIFI ) contributed significantly to concurrently measured social integration outcomes after controlling for demographic and injury-related variables . Separate hierarchical multiple regression analyses revealed that social communication and behavioralvariables accounted for 11.3 % of variance in CIQ-SI and 16.3 % of variance in CHART-SF-SI . Conclusions : Social communication abilities and affective/behavioral functioning make a substantial contribution to social integration outcomes after TBI . The implication s of such evidence for clinical assessment and intervention are discussed BACKGROUND Severe mitral regurgitation ( MR ) is associated with frequent alteration of psychoemotional status ( PES ) , with anxiety and stress symptoms related to health-related quality of life ( HR-QOL ) . Yet , it is unknown whether surgical correction of MR leads to improvement or deterioration in PES and HR-QOL . METHODS We prospect ively performed comprehensive MR assessment and administered question naires assessing PES and HR-QOL in 131 patients ( aged 60 years ; 75 % men ) before and 6 months after operation for organic MR and compared them to 62 patients who did not undergo operation for mitral disease and 36 normal controls of similar age assessed with the same methods . RESULTS Baseline PES was poorer preoperatively in patients undergoing mitral operation compared with patients who did not undergo mitral operation and normal controls ( anxiety and posttraumatic stress [ PTS ] ; both p < 0.01 ) with poorer physical HR-QOL ( p < 0.01 ) . Six months later , all these psychoemotional variables improved ( all p ≤ 0.02 ) in the patients who underwent mitral operation , whereas no change was observed in the other 2 groups ( all p > 0.1 ) . Improvement after mitral repair result ed in postoperative normalization of emotional and physical well-being , with similar scores among all groups ( all p ≥ 0.4 ) . At 6-month follow-up , no difference in improvement in PES and HR-QOL was noted according to the surgical approach ( robotic versus sternotomy , all p ≥ 0.2 ) . CONCLUSIONS Patients with severe organic MR present with frequent psychoemotional alterations and HR-QOL deterioration , in contrast to patients who do not undergo mitral operation and normal controls . After mitral operation , notable improvement results in normalization of emotional and physical well-being . Quantification of emotional and physical well-being provides important outcome measures in patients with organic MR and uncovers important benefits provided by surgical correction of MR |
13,708 | 27,230,550 | the mortality rate is different in children who are given enteral nutrition alone versus enteral and parenteral combined;4 .
the mortality rate is different in children who are given both enteral feeds and parenteral nutrition versus no nutrition .
No statistically significant differences were observed for mortality , sepsis , ventilator days , length of stay , unexpected adverse events , resting energy expenditure , nitrogen balance , or albumin levels . | BACKGROUND Nutritional support in the critically ill child has not been well investigated and is a controversial topic within paediatric intensive care .
There are no clear guidelines as to the best form or timing of nutrition in critically ill infants and children .
This is an up date of a review that was originally published in 2009 . .
OBJECTIVES The objective of this review was to assess the impact of enteral and parenteral nutrition given in the first week of illness on clinical ly important outcomes in critically ill children .
There were two primary hypotheses:1 .
the mortality rate of critically ill children fed enterally or parenterally is different to that of children who are given no nutrition;2 .
the mortality rate of critically ill children fed enterally is different to that of children fed parenterally . | Objective : To analyze the effect of an immune enhancing ( IE ) diet on infection and metabolic indices in children with severe head injury fed either an IE or a regular formula . Design : R and omized , blinded , controlled study . Setting : Pediatric intensive care unit in a university hospital . Patients : A total of 40 mechanically ventilated children with severe head injury . Interventions : Within 12 hrs of pediatric intensive care unit admission , patients were r and omized to receive a masked formula : either IE or regular formula . Feedings were advanced to a target volume of energy intake equal to 0.50 % , 100 % , 125 % , 150 % , and 150 % of the predicted basal metabolic rate on days 1–5 . Measurements and Main Results : Nutritional and metabolic indices ; interleukins-1β , -6 , and -8 ; tumor necrosis factor-α ; and outcome end points ( survival , length of stay , length of mechanical ventilation ) were compared between the two groups . Only interleukin-8 levels were lower in the IE group compared with the regular formula group by day 5 ( 23.6 ± 1.5 vs. 35.5 ± 4 pg/mL , p < .04 ) . In multivariate regression analysis , interleukin-8 was also independently negatively correlated with immunonutrition ( p < .04 ) . Nitrogen balance became positive in 30.8 % of patients in the regular formula group and in 69.2 % of patients in the IE group by day 5 ( p < .05 ) . Less gastric cultures were positive in the IE group compared with the regular formula group ( 26.7 % vs. 71.4 % , p < .02 ) . Nosocomial infections ( 15 % vs. 25 % ) , length of stay ( 16.7 vs. 12.2 days ) , length of mechanical ventilation ( 11 vs. 8 days ) , and survival ( 80 % vs. 95 % ) did not differ between groups . Conclusions : Although immunonutrition might decrease interleukin-8 and gastric colonization in children with severe head injury , it might not be associated with additional advantage over the one demonstrated by regular early enteral nutrition Introduction During pressure support ventilation ( PSV ) a part of the breathing pattern is controlled by the patient , and synchronization of respiratory muscle action and the result ing chest wall kinematics is a valid indicator of the patient 's adaptation to the ventilator . The aim of the present study was to analyze the effects of different PSV setting s on ventilatory pattern , total and compartmental chest wall kinematics and dynamics , muscle pressures and work of breathing in patients with acute lung injury . Method In nine patients four different levels of PSV ( 5 , 10 , 15 and 25 cmH2O ) were r and omly applied with the same level of positive end-expiratory pressure ( 10 cmH2O ) . Flow , airway opening , and oesophageal and gastric pressures were measured , and volume variations for the entire chest wall , the ribcage and abdominal compartments were recorded by opto-electronic plethysmography . The pressure and the work generated by the diaphragm , rib cage and abdominal muscles were determined using dynamic pressure-volume loops in the various phases of each respiratory cycle : pre-triggering , post-triggering with the patient 's effort combining with the action of the ventilator , pressurization and expiration . The complete breathing pattern was measured and correlated with chest wall kinematics and dynamics . Results At the various levels of pressure support applied , minute ventilation was constant , with large variations in breathing frequency/ tidal volume ratio . At pressure support levels below 15 cmH2O the following increased : the pressure developed by the inspiratory muscles , the contribution of the rib cage compartment to the total tidal volume , the phase shift between rib cage and abdominal compartments , the post-inspiratory action of the inspiratory rib cage muscles , and the expiratory muscle activity . Conclusion During PSV , the ventilatory pattern is very different at different levels of pressure support ; in patients with acute lung injury pressure support greater than 10 cmH2O permits homogeneous recruitment of respiratory muscles , with result ing synchronous thoraco-abdominal expansion BACKGROUND Multiple organ dysfunction syndrome ( MODS ) is a major cause of mortality in intensive care units . A breakdown in gut barrier function and immune dysfunction are associated with the onset of MODS . Probiotic bacteria have been shown to modulate intestinal barrier and immune function . OBJECTIVE This study assessed the efficacy of a probiotic compound in a viable and nonviable formulation in modulating intestinal permeability and immune function and preventing the onset of MODS in patients in the intensive care unit . DESIGN A double-blind , r and omized controlled trial was conducted in the intensive care unit of a tertiary care teaching hospital . Twenty-eight critically ill patients admitted to the intensive care unit were r and omly assigned to receive 1 of 3 treatments daily for 7 d : 1 ) placebo , 2 ) viable probiotics , or 3 ) equivalent probiotic sonicates . MODS scores and systemic concentrations of immunoglobulin ( Ig ) A and IgG were measured on days -1 , 4 , and 7 , and intestinal permeability measurements were taken daily . RESULTS The patients responded to viable probiotics with a significantly larger increase in systemic IgA and IgG concentrations than in the patients who received placebo or sonicates ( P < 0.05 ) . MODS scores were not significantly affected by probiotic treatment . Over the study period , intestinal permeability decreased in most patients . CONCLUSION Patients receiving viable probiotics show a greater enhancement in immune activity than do patients receiving either placebo or probiotic bacterial sonicates Objective : To assess the effect of isocaloric isonitrogenous parenteral glutamine supplementation on intestinal permeability and nitrogen loss in newborns and infants after major digestive-tract surgery . Summary Background Data : Glutamine supplementation in critically ill and surgical adults may normalize intestinal permeability , attenuate nitrogen loss , improve survival , and lower the incidence of nosocomial infections . Previous studies in critically ill children were limited to very-low-birthweight infants and had equivocal results . Methods : Eighty newborns and infants were included in a double-blind , r and omized trial comparing st and ard parenteral nutrition ( sPN ; n = 39 ) to glutamine-supplemented parenteral nutrition ( GlnPN ; glutamine target intake , 0.4 g kg−1 day−1 ; n = 41 ) , starting on day 2 after major digestive-tract surgery . Primary endpoints were intestinal permeability , as assessed by the urinary excretion ratio of lactulose and rhamnose ( weeks 1 through 4 ) ; nitrogen balance ( days 4 through 6 ) , and urinary 3-methylhistidine excretion ( day 5 ) . Secondary endpoints were mortality , length of stay in the ICU and the hospital , number of septic episodes , and usage of antibiotics and ICU re sources . Results : Glutamine intake plateaued at 90 % of the target on day 4 . No differences were found between patients assigned sPN and patients assigned GlnPN regarding any of the endpoints . Glutamine supplementation was not associated with adverse effects . Conclusions : In newborns and infants after major digestive-tract surgery , we did not identify beneficial effects of isonitrogenous , isocaloric glutamine supplementation of parenteral nutrition . Glutamine supplementation in these patients therefore is not warranted until further research proves otherwise The aim of the study was to analyse the effects of early enteral feeding on the prevention of enterogenic infection in severely burned patients . A total of 22 patients with severe burns were r and omly divided into an early enteral feeding group ( EF ) and a delayed enteral feeding group ( DF ) . The levels of serum endotoxin and TNF-alpha were dynamically detected in the members of both groups , and two unmetabolized sugars ( lactulose and mannitol ) were orally administered to these patients 1 , 3 and 5 days postburn . Intestinal permeability was evaluated by detecting the concentrations of lactulose and mannitol in the urine and the lactulose-mannitol ratio ( L/M ) ratio . The levels of serum endotoxin and TNF-alpha in severely burned patients were significantly higher than in normal subjects ( P<0.01 ) . The endotoxin level was positively related to the TNF-alpha level ( rEF=0.93 , P<0.01 ; rDF=0.80 , P<0.05 ) . The urinary lactulose levels in both groups were significantly higher than in normal ( P<0.01 ) , the urinary mannitol levels showed no obvious changes ( P>0.05 ) . The urinary L/M ratios in both groups were significantly higher than in normal subjects ( P<0.01 ) . The urinary L/M ratio was positively related to the serum endotoxin level ( r=0.95 , P<0.01 ) . The urinary lactulose levels and the urinary L/M ratios in the EF group were significantly lower than in the DF group ( P<0.01 ) . The levels of serum endotoxin and TNF-alpha in the EF group were significantly lower than in the DF group ( P<0.01 ) . It is suggested that intestinal permeability was markedly higher after burns than normal , and was positively related to the gut-derived endotoxemia . Early enteral feeding may decrease intestinal permeability , preserve the intestinal mucosal barrier and have a beneficial effect on the reduction of enterogenic infection BACKGROUND / PURPOSE Nutritional support of surgical patients has improved in recent years because of the possibility of modulating catabolism and anabolism , thus enhancing the immune response and repair processes . The objective of this study was to evaluate metabolic effects of early parenteral nutrition ( PN ) after major surgery . METHODS The authors studied 63 children aged 4 to 14 years with diffuse peritonitis caused by perforated-suppurative appendicitis . They were assigned r and omly to a study group ( SG , n = 31 ) , which received PN for 5 days , starting 24 to 48 hours after surgery or to a control group ( CG , n = 32 ) , that received st and ard treatment ( fluids ) . Weight , C-reactive protein ( CRP ) , albumin , prealbumin , glycemia , nitrogen balance ( NB ) , and insulinlike growth factor ( IGF-I ) , were evaluated on postoperative days 1 , 4 , and 6 . RESULTS Early nutritional support was associated with a significant improvement in NB and IGF-I ( Repeat measures analysis of variance IGF-I , P<.001 and NB P<.01 ) . CONCLUSIONS The authors conclude that early parenteral nutrition has a positive effect on the anabolic response as shown by improved NB and higher IGF-I levels in pediatric patients after major surgery Objective To compare the effect of early enteral feeding using immune-enhancing ( IE ) vs. non-immune-enhancing ( NIE ) formulas on cytokines in children with septic shock . Design and setting A single-center , r and omized , blinded controlled trial in a pediatric intensive care unit of a university hospital . Patients We r and omized 38 patients with septic shock to either IE or NIE . Feedings were advanced to a target volume of energy intake equal to 1/2 , 1 , 5/4 , 6/4 , and 6/4 of the predicted basal metabolic rate on days 1–5 , respectively . Measurements and results Interleukins ( IL ) 1β , 6 , and 8 , tumor necrosis factor α , C-reactive protein , Pediatric Risk of Mortality ( PRISM ) score , survival , secondary infections , length of stay , and mechanical ventilation were compared within and between the two groups . Actual mean energy and protein intakes did not differ between the two groups and the caloric-protein balance was not correlated to cytokine levels . On day 5 IL-6 levels were significantly lower ( 11.8±2.4 vs. 38.3±3.6 ) and IL-8 significantly higher in the IE than in the NIE group ( 65.4±17 vs. 21±2.5 ) . After 5 days of nutritional support a significant decrease in IL-6 levels was recorded only in group IE ( mean of paired differences 39.4±3 pg/ml ) . In multivariate regression analysis the variation in cytokines was independently correlated only to PRISM ( R2=−0.50 ) , but pediatric intensive care unit outcome endpoints did not differ between the two groups . Conclusions Early IE nutrition may modulate cytokines in children with septic shock , but there is no evidence that this immunomodulation has any impact on short-term outcome Objectives : To measure energy expenditure in critically ill children and compare it with the energy expenditure predicted by recommended formulas , and relate the measured energy expenditure to nutritional and clinical indices . Design : A prospect i ve , clinical study . Setting : Tertiary care pediatric intensive care unit in a university children 's hospital . Patients : A total of 37 patients with critical illness who were mechanically ventilated for ≥24 hrs were studied . Interventions : None . Measurements and Main Results : Chronic protein‐energy malnutrition ( CPEM ) and acute protein‐energy malnutrition were defined by the Waterlow 's stages and fat and protein stores were classified as defined by Frisancho , Ryan , and Martinez . Severity of illness was assessed by the Pediatric Risk of Mortality Score , the Therapeutic Intervention Scoring System , and indices of organ failure . Oxygen consumption , carbon dioxide production , and the respiratory quotient were measured by indirect calorimetry , and energy expenditure ( MEE ) was calculated using the modified Weir formula . Resting energy expenditure ( PBMR ) , predicted energy expenditure , and caloric intake were calculated using recommended formulas . A total of 77 measurements were made in 37 children . MEE was significantly lower than PBMR as estimated by all equations except the Talbot equations . MEE was significantly lower than predicted energy expenditure and the recommended daily allowances . On the first day , the MEE/PBMR ratio was < 0.9 in 56.8 % , 0.9‐1.1 in 21.6 % , and > 1.1 in 21.6 % of patients . MEE did not differ significantly among disease groups or between medical and surgical patients . There was no difference in MEE with or without neuromuscular blockade . MEE was lower in the presence of multiple organ system failure ( MOSF ) ( 1019 + 166 kcal/m2 without MOSF vs. 862 + 241 with MOSF ; p = .025 ) . A total of 21 % had CPEM and 8.1 % had acute protein‐energy malnutrition . Multivariate stepwise regression analysis showed that the protein intake , midarm muscle area , midarm fat area , the use of vasoactive agents , and sedation correlated with MEE ( p < .05 ) . With CPEM , MEE was correlated to the severity of illness ( p < .05 ) . Patients at risk for protein stores depletion ( midarm muscle areas 1 and 2 ) had a higher incidence of MOSF compared with nutritionally normal children ( p < .05 ) , whereas patients with fat stores depletion ( midarm fat area 2 ) had a higher probability of death ( 50 % vs. 6 % , respectively ) . Conclusions : Recommended daily allowances and energy expenditure predicted by using a stress‐related correction to the resting energy expenditure grossly overestimate MEE . MEE is close to PBMR and in many patients , it is lower than PBMR . MEE that is lower than PBMR is associated with a higher morbidity . Nutritional repletion should thus be based on MEE to avoid the problems of over‐ or underfeeding STUDY OBJECTIVES To determine the effect of feeding tube position ( gastric vs small bowel ) on adequacy of nutrient delivery and feeding complications , including microaspiration , in critically ill children . DESIGN R and omized controlled trial . SETTING Pediatric ICU in a university teaching hospital . PATIENTS Seventy-four critically ill patients < 18 years of age receiving mechanical ventilation were r and omized to receive gastric or small-bowel feeding . INTERVENTIONS All feeding tubes were inserted at the bedside . Color , pH , and bilirubin concentration of the feeding tube aspirates were used to guide placement . Final tube position was confirmed radiographically . Continuous feedings were advanced to achieve a caloric goal based on age and body weight . Tracheal secretions were collected daily and tested for gastric pepsin by immunoassay . MEASUREMENTS AND RESULTS Thirty-two patients were r and omized to the gastric group , and 42 patients were r and omized to the small-bowel group . Twelve patients exited the study because a small-bowel tube could not be placed at the bedside , leaving 30 patients in the small-bowel group . Gastric and small-bowel groups were similar at baseline in age , sex , percentage of ideal body weight , serum prealbumin concentration , and pediatric risk of mortality score . The percentage of daily caloric goal achieved was less in the gastric group compared to the small-bowel group ( 30 + /- 23 % vs 47 + /- 22 % , p < 0.01 ) . No difference was found in the proportion of tracheal aspirates positive for pepsin between the gastric and small-bowel groups ( 50 of 146 aspirates vs 50 of 172 aspirates , respectively ; p = 0.3 ) . No differences were found in the frequency of feeding tube displacement , abdominal distension , vomiting , or diarrhea between groups . CONCLUSIONS Small-bowel feeds allow a greater amount of nutrition to be successfully delivered to critically ill children . Small-bowel feeds do not prevent aspiration of gastric contents The use of total parenteral nutrition ( TPN ) , in the critically ill , may be associated with the translocation of bacteria and their products from the lumen of the gastrointestinal tract ( GIT ) to the systemic circulation . We report a study comparing the effects of TPN and enteral nutrition ( EN ) on GIT function . Twenty-four critically ill patients were r and omly allocated to receive TPN or EN . GIT absorption was measured by urinary recovery of D-xylose and 3-O-methyl-D-glucose ( 3O MG ) after enteral administration . The ratio between urinary recovery of lactulose and L-rhamnose ( L/R ) was used to measure GIT mucosal permeability . Results are expressed as the percentage of enterally administered saccharide recovered . Measurements were performed at entry to the study and on every subsequent third day . Baseline recovery of D-xylose ( 5.95 + /- 1.61 % , EN ; 6.56 + /- 3.38 % , TPN ) and 3O MG ( 12.35 + /- 4.06 % , EN ; 7.96 + /- 4.19 % , TPN ) was significantly lower than for the controls ( 35.03 + /- 1.40 % for D-xylose , p < 0.05 compared to both study groups ; 49.20 + /- 1.98 % for 3O MG , p < 0.05 compared to both study groups ) . Baseline L/R ratio was increased ( 0.292 + /- 0.072 % , EN ; 0.463 + /- 0.118 % , TPN ) compared with the controls ( 0.038 + /- 0.006 % , p < 0.05 compared to both study groups ) . In the EN group , the L/R ratio displayed a progressive , significant fall . In the TPN group , no significant change in the L/R ratio occurred . This study demonstrates that GIT dysfunction is evident in critically ill patients and suggests that loss of GIT mucosal integrity is reversed by the institution of EN OBJECTIVE To determine the impact of rapid advancement to more concentrated formula on weight gain and duration of hospitalization for infants after cardiac surgery . STUDY DESIGN We performed a double-blinded , r and omized trial of rapid advancement to higher achieved formula concentration for postoperative infants younger than 1 year of age . After transfer to the inpatient ward from the critical care unit , infants were r and omly assigned to rapid advancement to a higher achieved formula concentration ( 2-day transition ) or usual care ( 5-day transition , lower concentration target ) . RESULTS The adequacy of energy intake ( expressed as the median percentage of the estimated energy requirement ) before discharge from the hospital was 98 % in the intervention versus 78 % in the usual care group ( P = .01 ) . Before discharge , the median rate of weight gain was greater in the rapid advancement ( 20 g/d ) versus the usual care group ( loss of 35 g/d , P < .03 ) . The median postoperative duration of stay on the cardiology inpatient unit was 5 days for the intervention versus 6 days for the usual care group ( P < .05 ) . CONCLUSIONS Rapid advancement to higher achieved formula concentration significantly improved energy intake and weight gain and decreased duration of postoperative hospital stay in infants after cardiac surgery Fifty-one brain-injured patients with peak 24-hour admission Glasgow Coma Scale ( GCS ) scores of 4 to 10 were prospect ively r and omly assigned to receive total parenteral ( TPN ) or enteral ( EN ) nutrition . Patients were studied from hospital admission to 18 days postinjury . Outcome was assessed by the Glasgow Outcome Scale at 3 months , 6 months , and 1 year postinjury . The TPN group received a significantly higher cumulative mean intake of protein than the EN group ( mean + /- st and ard error of the mean : 1.35 + /- 0.12 vs. 0.91 + /- 0.9 gm/kg/day ; p = 0.004 ) . Mean cumulative caloric balance was also significantly higher in the TPN than in the EN group ( 75.6 % + /- 5.13 % vs. 59 % + /- 4.26 % ; p = 0.02 ) . Nitrogen balance was significantly more negative in the EN group during the 1st week postinjury ( p = 0.002 ) . The incidence of pneumonia , urinary tract infections , septic shock , and infections was not significantly different between groups . Classic nutritional assessment parameters such as anergy screens , total lymphocyte counts , and albumin levels were not significantly different between groups . The 11 patients in the EN group who did not tolerate tube feedings for 1 week postinjury had a significantly higher incidence of septic shock ( p = 0.008 ) . The change over time in GCS scores between groups was significantly different , with the TPN group showing a mean four-point increase in GCS score compared with a three-point increase in the EN group ( p = 0.02 ) . At 3 months the TPN group had a significantly higher percentage of favorable outcomes ( 43.5 % vs. 17.9 % , respectively ; p = 0.05 ) . At 6 months , 43.5 % of the TPN group had a favorable outcome while 32.1 % of the EN group had a favorable outcome ( p = 0.29 ) . By 1 year , 47.8 % of the TPN group and 32.1 % of the EN group had a favorable outcome ( p = 0.20 ) . In conclusion , more calories and protein usually can be administered to acute brain injury patients via the TPN route than by EN feedings via nasogastric or nasoduodenal routes . Traditional parameters for nutritional assessment are not useful in study ing the efficacy of nutritional support during the first 2 weeks after head injury . Neurological recovery from head injury occurs more rapidly in patients with better early nutritional support A comparative nutritional study in brain-injured patients ( BIP ) was performed to assess the influence of a combined enteral-parenteral nutrition ( CN ) and a total parenteral nutrition ( TPN ) on protein catabolism in the early posttraumatic period . 20 male BIP ( Glasgow coma scale 5–7 ) were r and omized to one of the two feeding regimes . Nutritional support was based on 150–175 % basic energy expenditure . Amino acid intake was 1.4 g/kg/day in the TPN and 2.4 g/kg/day in the CN group . Negative nitrogen balance ( NNB ) averaged x ( SEM=3.06 g/m2/day ) in the TPN group and x ( SEM=2.33 g/m2/day ) in the CN group . Between both feeding regimes not statistically significant differences could be observed concerning mortality , N-balance , creatinine and 3-methylhistidine excretions . Protein concentration of the regurgitated gastric fluid was significantly higher in the CN than in the TPN study group . Data imply that both alimentary regimes are of similar value , but BIP with imparired gastric function , such as high tube reflux , are better treated by TPN BACKGROUND Provision of enteral nutrition via the gastric route is a common nursing procedure in pediatric intensive care units . Little research , however , has focused on children 's tolerance of different types of gastric feeding regimens . OBJECTIVES To examine the relationship between 2 gastric feeding regimens , continuous and intermittent , and children 's tolerance as measured by the number of stools and prevalences of diarrhea and vomiting . METHODS A r and omized controlled trial was conducted in an Australian pediatric intensive care unit ; 45 children were r and omly assigned to either the continuous or the intermittent gastric feeding groups . Participants remained in the assigned feeding group for the duration of the study , and values of variables used to monitor patients ' tolerance were recorded . RESULTS Both feeding groups were similar with respect to Pediatric Index Mortality score , age , weight , sex , diagnosis , and use of pharmacological agents known to affect the gastrointestinal tract . Additionally , the 2 groups did not differ in study duration or the daily volume of administered enteral formula per kilogram of body weight . The number of stools per day and the prevalences of diarrhea and vomiting did not differ significantly between the 2 groups . DISCUSSION Continuous and intermittent gastric feeding regimens have similar outcomes with respect to the number of stools per day and the prevalence of diarrhea and vomiting in pediatric intensive care patients . Further gastric feeding studies and the development of enteral feeding guidelines for critically ill children are needed Seriously ill infants often display protein-calorie malnutrition due to the metabolic dem and s of sepsis and respiratory failure . Glutamine has been classified as a conditionally essential amino acid , with special usefulness in critical patients . Immunomodulation , gut protection , and prevention of protein depletion are mentioned among its positive effects in such circumstances . With the intent of evaluating the tolerance and clinical impact of a glutamine supplement in seriously ill infants , a prospect i ve r and omized study was done with nine patients . Anthropometric and biochemical determinations were made , and length of stay in the intensive care unit ( ICU ) , in the hospital , and under artificial ventilation , and septic morbidity and mortality were tabulated . Infants in the treatment group ( n = 5 ) were enterally administered 0.3 g/kg of glutamine , whereas controls received 0.3 g/kg of casein during a st and ard period of five days . Septic complications occurred in 75 % of the controls ( 3/4 ) versus 20 % of the glutamine-treated group ( 1/5 , p < or = 0.10 ) , and two patients in the control group died of bacterial infections ( 50 % vs. 0 % , p < or = 0.10 ) . Days in the ICU , in the hospital , and with ventilation numerically favored glutamine therapy , although without statistical significance . The supplements were usually well tolerated , and no patient required discontinuation of the program . The conclusion was that glutamine supplementation was safe and tended to be associated with less infectious morbidity and mortality in this high-risk population Objective The purpose of this study was to evaluate current methods of predicting energy requirements and to develop and vali date new equations derived from energy expenditure measurements of ventilated , critically ill children . Design Prospect i ve , observational , sequential study . Setting Pediatric intensive care unit . Patients A total of 100 ventilated , critically ill children who fit the criteria of energy expenditure measurement . Additional patients ( n = 25 ) were included in the validation study . Intervention An indirect calorimeter was used to measure energy expenditure for a period of 30 mins . Measurements and Main Results The mean measured energy expenditure was 185 ± 51 kJ/kg per day . Predicted energy expenditure from st and ard equations was compared with measured energy expenditure by using the Bl and and Altman “ methods comparison procedure , ” and poor precision and accuracy were observed . Patient variables were collected at the time of measurement , and multiple regression analysis was performed to determine the independent contribution of each variable to measure energy expenditure . New predictive equations were formulated and vali date d with additional energy expenditure measurements . Patient variables that did not correlate significantly with energy expenditure were gender , Pediatric Risk of Mortality score , and commencement of nutritional support . An equation was derived from patient variables ( age , weight , weight for age Z score , body temperature , number of days after intensive care admission , and primary reason for admission ) that correlated significantly ( r2 = .898 ) with measured energy expenditure . A second , simplified equation ( energy expenditure kJ/day = { 17 × age [ months ] } + { 48 × weight [ kg ] } + { 292 × body temperature ° C } − 9677 ) was produced ( r2 = .867 ) . Validation found no significant difference between measured and predicted energy expenditure by the new equations ; however , the equations did not predict accurately for patients < 2 months of age . Conclusion The new equations provide a more accurate alternative to current predictive methods in assessing energy requirements of ventilated , critically ill children Twenty-one infants who were c and i date s for TPN because of respiratory disease were r and omized into experimental ( TPN ) and control ( glucose-electrolyte ) groups . Serum GOT , GPT , GGTP , 5 ' nucleotidase , total , direct , and conjugated ( ethyl anthranilate-reactive ) bilirubin , and bile salt concentrations were determined at entry into the study and at one week . One week of TPN caused significant elevations of GGTP , 5'-N and EA bilirubin values , whereas SGOT , SGPT , SBS , and total and direct bilirubin were unaffected . Addition of a lipid infusion to TPN did not alter these differences . These data are interpreted as showing : ( 1 ) amino acid infusion has an early effect on hepatic function which is independent of the many diseases for which this therapy is used and of the concomitant use of lipid ; ( 2 ) the initial effect appears to be on the canalicular membrane ; and ( 3 ) the sinusoidal membrane is apparently unaffected by one week of TPN UNLABELLED Burns increase the metabolic dem and s of the body and can lead to severe weight loss and increased risk of death . Early enteral support is believed to improve gastrointestinal , immunological , nutritional and metabolic responses to critical injury ; however , this premise is in need of further substantiation by definitive data . This research aim ed to examine the effectiveness and safety of early enteral feeding in paediatric patients suffering from burns . MATERIAL S AND METHODS This clinical trial was carried out with a total number of 688 children with burns hospitalised in the Burn Department across a 2-year period ( September 2002-September 2004 ) . The subjects were r and omised into two groups . A total of 322 patients received only intravenous resuscitation , in accordance with current treatment protocol s , in the first 48 h and were considered as the late enteral nutrition group ( LEN group ) ; 366 patients were nourished early enteral nutrition group ( EEN group ) , such that both groups received similar amounts of fluid in the first 48 h. Initiation of enteral nutrition commenced between 3 and 6 h following the burn . The patients were kept in the unit until they were discharged . Wound management did not vary between groups . RESULTS In our study , the mean age was 5±3 years in the LEN group and 5±3.5 years in the EEN group . Hot liquids were the most common cause of burns in both groups . The mean percentage of burn was reported as 20±13 in the LEN group and 22±15 in the EEN group . Mean duration of hospitalisation was 16.4±3.7 days in the LEN group and 12.6±1.3 in the EEN group for cured patients ( P<0.05 ) . A total of 40 patients ( 12 % ) in the LEN group and 31 patients ( 8.5 % ) in the EEN group expired ( P<0.05 ) . CONCLUSION Our research showed that EEN decreases duration of hospitalisation and mortality in children with burns The author studied the clinical and laboratory effects of early parenteral nutrition ( EPN ) in patients who were comatose as a result of acute drug poisoning . All patients were unconscious at the time of admission and entry into the study and received our usual conservative therapy for the first 24 hours . Alternate patients received an EPN solution containing amino acids and glucose . Volume , composition , and caloric content of the EPN solution were calculated separately for each patient according to weight and height nomograms . It was found that the group receiving EPN ( n = 46 ) normalized their nitrogen balance sooner and demonstrated a consistent decrease in their creatine phosphokinase level . Serum amino acid values in patients treated with EPN did not change significantly during the treatment trial . The control group ( n = 40 ) demonstrated a significantly lower serum amino acid concentration on the third day of treatment ( p < .001 ) , had significantly more pneumonias ( p < .05 ) , and their hospitalization time was significantly longer ( .01 < p < .05 ) than the EPN group . There were significantly fewer instances of disseminated intravascular coagulation in the group receiving EPN ( p < .05 ) OBJECTIVES In a blinded , prospect i ve , r and omized , controlled clinical trial , we compared nitrogen balance ( NB ) , nutritional indices , antioxidant catalysts , and outcome in critically ill children given an immune-enhancing formula ( I ) or conventional early enteral nutrition ( C ) . METHODS Fifty patients , 103 + /- 7 months old , with disorders prompting admission to the pediatric intensive care unit , including sepsis , respiratory failure , and severe head injury , were enrolled in the study . Within 12 h of admission , patients were r and omized to receive I ( n=25 ) or C ( n=25 ) . Caloric intake was aim ed at meeting patient 's predicted basal metabolic rate by day 2 and predicted energy expenditure by day 4 , irrespective of group assignment . Outcome endpoints and complications were recorded ; NB , transthyretin , retinol-binding protein , transferrin , zinc , copper , and metabolic indices were measured on days 1 and 5 and compared with clinical and nutritional characteristics within and between groups . RESULTS Both diets achieved their initial targets of covering predicted basal metabolic rate by day 2 and predicted energy expenditure by day 4 . Twenty four-hour NB became positive in 40 % of patients in group C and occurred in 64 % of patients in group I by day 5 . Only in group I did the mean NB become positive by day 5 ( 0.07+/-0.07 g/kg versus -0.24+/-0.03 g/kg on day 1 , P<0.001 ) compared with group C in which the mean NB remained negative ( -0.06+/-0.04 g/kg versus -0.25+/-0.06 g/kg on day 1 , P<0.001 ) . By day 5 , nutritional indices and antioxidant catalysts showed a higher increasing trend in group I compared with group C and higher osmolality ( P<0.02 ) , sodium ( P<0.03 ) , and urea ( P<0.04 ) . Diarrhea for group I ( P<0.02 ) and gastric distention for group C ( P<0.04 ) were the most frequently recorded complications . Mortality or length of stay did not differ between groups , but there was a trend for less gastric gram plus isolates ( P<0.05 ) or for C and ida species ( P<0.04 ) and nosocomial infections in group I compared with group C. CONCLUSIONS Although less well tolerated , immunonutrition is a feasible method of early enteral nutrition in the pediatric intensive care unit . It has a favorable effect on nutritional indices and antioxidant catalysts , but not on outcome hard endpoints . Although it poses a higher metabolic burden to the patient , it shows a trend to improve colonization and infection rates . Appropriate modifications for specific age population s might improve its tolerability and benefits among critically ill children A modular tube feeding recipe ( MTF ) was design ed to meet the unique nutritional needs of burn patients , applying principles previously documented in our burned guinea pig model . MTF , a high-protein , low-fat , linoleic acid-restricted formulation is enriched with omega-3 fatty acids , arginine , cysteine , histidine , vitamin A , zinc , and ascorbic acid . Fifty patients , 3 to 76 years of age with burns ranging from 10 to 89 % total body surface area were prospect ively r and omized into three groups which blindly compared MTF to two enteral regimens widely utilized in the nutritional support of burns . Age , percent total and third-degree burn , resting energy expenditure , and calorie and protein intake were similar in all groups . Data analysis demonstrated significant superiority of MTF in the reduction of wound infection ( p less than 0.03 ) and length of stay/percent burn ( p less than 0.02 ) . MTF was also associated with a decreased incidence of diarrhea , improved glucose tolerance , lower serum triglycerides , reduced total number of infectious episodes and trends toward improved preservation of muscle mass , although statistical significance was not achieved . Seventy percent of deaths occurred in the group supported with an inherently large dose of fat and linoleic acid . Combining these observations , it is believed that MTF is effective in modulating an improved response to burn injury STUDY OBJECTIVES To assess the consistency of caloric intake with American College of Chest Physicians ( ACCP ) recommendations for critically ill patients and to evaluate the relationship of caloric intake with clinical outcomes . DESIGN Prospect i ve cohort study . SETTING Adult ICUs at two teaching hospitals . PARTICIPANTS Patients with an ICU length of stay of at least 96 h. MEASUREMENTS AND RESULTS On ICU admission , severity of illness ( ie , simplified acute physiology score II ) and markers of nutritional status ( ie , serum albumin level and body mass index ) were recorded . The route of feeding ( ie , enteral or parenteral ) , actual caloric intake ( ie , percentage of ACCP recommendations : 0 to 32 % [ tertile I ] ; 33 to 65 % [ tertile II ] ; > /== " BORDER="0 " > 66 % [ tertile III ] ) , and evidence of GI intolerance ( ie , gastric aspirate levels , > /== " BORDER="0 " > 100 mL ) were recorded daily . The following outcomes were assessed : status on hospital discharge ( alive vs dead ) ; spontaneous ventilation before ICU discharge ( yes vs no ) ; and ICU discharge without developing nosocomial sepsis ( yes vs no ) . The average caloric intake among 187 participants was 50.6 % of the ACCP targets and was similar in both hospitals . Caloric intake was inversely related to the mean number of gastric aspirates > /== " BORDER="0 " > 100 mL/d ( Spearman rho = -0.04 ; p = 0.06 ) , but not to severity of illness , nutritional status , or route of feeding . After accounting for the number of gastric aspirates > /== " BORDER="0 " > 100 mL , severity of illness , nutritional status , and route of feeding , tertile II of caloric intake ( vs tertile I ) was associated with a significantly greater likelihood of achieving spontaneous ventilation prior to ICU discharge . Tertile III of caloric intake ( vs tertile I ) was associated with a significantly lower likelihood of both hospital discharge alive and spontaneous ventilation prior to ICU discharge . CONCLUSIONS Study participants were underfed relative to ACCP targets . These targets , however , may overestimate needs , since moderate caloric intake ( ie , 33 to 65 % of ACCP targets ; approximately 9 to 18 kcal/kg per day ) was associated with better outcomes than higher levels of caloric intake Objective Compare the energy expenditure , predicted by anthropometric equations , with that measured by continuous on-line indirect calorimetry in ventilated , critically ill children during the early postinjury period . Design Prospect i ve , clinical study . Setting Pediatric intensive care unit of a pediatric university hospital . Patients A total of 43 ventilated , critically ill children during the first 6 hrs after injury . Interventions An indirect calorimeter was used to continuously measure the energy expenditure for 24 hrs . Measurements and Main Results Clinical data collected were age , gender , actual and ideal weight , height , and body surface . Nutritional status was assessed by Waterlow and Shukla Index . Severity of illness was determined by Pediatric Risk of Mortality , Physiologic Stability Index , and Therapeutic Intervention Scoring System . Energy expenditure was measured ( MEE ) by continuous on-line indirect calorimetry for 24 hrs . Predicted Energy Expenditure ( PEE ) was calculated using the Harris-Benedict , Caldwell-Kennedy , Schofield , Food and Agriculture/World Health Organization/United Nation Union , Maffeis , Fleisch , Kleiber , Dreyer , and Hunter equations , using the actual and ideal weight . MEE and PEE were compared using paired Student ’s t-test , linear correlation ( r ) , intraclass correlation coefficient ( pI ) , and the Bl and -Altman method . Mean MEE result ed in 674 ± 384 kcal/day . Most of the predictive equations overestimated MEE in ventilated , critically ill children during the early postinjury period . MEE and PEE differed significantly ( p < .05 ) except when the Caldwell-Kennedy and the Fleisch equations were used . r2 ranged from 0.78 to 0.81 ( p < .05 ) , and pI was excellent ( > .75 ) for the Caldwell-Kennedy , Schofield , Food and Agriculture/World Health Organization/United Nation Union , Fleisch , and Kleiber equations . The Bl and -Altman method showed poor accuracy ; the Caldwell-Kennedy equation was the best predictor of energy expenditure ( bias , 38 kcal/day ; precision , ±179 kcal/day ) . The accuracy in the medical group was higher ( pI range , .71–.94 ) than in surgical patients ( pI range , .18–.75 ) . Conclusions Predictive equations do not accurately predict energy expenditure in ventilated , critically ill children during the early postinjury period ; if available , indirect calorimetry must be performed Early enteral support is believed to improve gastrointestinal , immunological , nutritional , and metabolic responses to critical injury ; however , this premise is in need of further substantiation by definitive data . The purpose of this prospect i ve study was to examine the effectiveness and safety of early enteral feeding in pediatric patients who had burns in excess of 25 % total body surface area . Seventy-seven patients with a mean percent total body surface area burn of 52.5 + /- 2.3 ( range 26 - 91 ) , percent full thickness injury of 44.7 + /- 2.8 ( range 0 - 90 ) , and age ranging from 3.1 to 18.4 ( mean 9.3 + /- 0.5 ) were r and omized to two groups : early ( feeding within 24 hours of injury ) vs control ( feeding delayed at least 48 hours postburn ) . Nutrient intake was measured daily , indirect calorimetry was performed biweekly , and blood and urine sample s were obtained for the assay of cortisol , glucagon , insulin , gastrin , epinephrine , norepinephrine , dopamine , triiodothyronine , tetraiodothyronine , albumin , transferrin , prealbumin , retinol-binding protein , glucose , nitrogen balance , and 3-methylhistidine throughout the study period . Three protocol violations occurred , and two patients were transferred to another hospital ; these patients were excluded from the study . No patient in either group experienced tube feeding aspiration . No differences were evident in infection , diarrhea , hospital length of stay , or mortality outcomes . A higher incidence of reportable adverse events coincided with early feeding ( 22 vs 8 % ) , but this was not statistically significant . The delayed feeding group demonstrated a significant caloric deficit during postburn week ( PBW ) 1 ( P < .0001 ) and PBW2 ( P = .0022 ) . Serum insulin ( P = .0004 ) and triiodothyronine ( P = .0162 ) were higher in the early fed group during PBW1 . A decrease in 3-methylhistidine output ( suggesting a decrease in protein breakdown ) was also evident during PBW1 ( P = .0138 ) . No other significant trends in study outcome variables were noted . In conclusion , provision of enteral nutrients shortly after burn injury reduces caloric deficits and may stimulate insulin secretion and protein retention during the early phase postburn . These data , however , do not necessarily reaffirm the safety of early enteral feeding , nor do they associate earlier feeding with a direct improvement in endocrine status or a reduction in morbidity , mortality , hypermetabolism , or hospital stay . Future studies are needed to establish precise feeding implementation times that maximize clinical benefit while minimizing morbidity in the critically injured burn patient OBJECTIVE This study was conducted to develop evidence -based clinical practice guidelines for nutrition support ( ie , enteral and parenteral nutrition ) in mechanically ventilated critically ill adults . OPTIONS The following interventions were systematic ally review ed for inclusion in the guidelines : enteral nutrition ( EN ) versus parenteral nutrition ( PN ) , early versus late EN , dose of EN , composition of EN ( protein , carbohydrates , lipids , immune-enhancing additives ) , strategies to optimize delivery of EN and minimize risks ( ie , rate of advancement , checking residuals , use of bedside algorithms , motility agents , small bowel versus gastric feedings , elevation of the head of the bed , closed delivery systems , probiotics , bolus administration ) , enteral nutrition in combination with supplemental PN , use of PN versus st and ard care in patients with an intact gastrointestinal tract , dose of PN and composition of PN ( protein , carbohydrates , IV lipids , additives , vitamins , trace elements , immune enhancing substances ) , and the use of intensive insulin therapy . OUTCOMES The outcomes considered were mortality ( intensive care unit [ ICU ] , hospital , and long-term ) , length of stay ( ICU and hospital ) , quality of life , and specific complications . EVIDENCE We systematic ally search ed MEDLINE and CINAHL ( cumulative index to nursing and allied health ) , EMBASE , and the Cochrane Library for r and omized controlled trials and meta-analyses of r and omized controlled trials that evaluated any form of nutrition support in critically ill adults . We also search ed reference lists and personal files , considering all articles published or unpublished available by August 2002 . Each included study was critically appraised in duplicate using a st and ard scoring system . VALUES For each intervention , we considered the validity of the r and omized trials or meta-analyses , the effect size and its associated confidence intervals , the homogeneity of trial results , safety , feasibility , and the economic consequences . The context for discussion was mechanically ventilated patients in Canadian ICUs . BENEFITS , HARMS , AND COSTS The major potential benefit from implementing these guidelines is improved clinical outcomes of critically ill patients ( reduced mortality and ICU stay ) . Potential harms of implementing these guidelines include increased complications and costs related to the suggested interventions . SUMMARIES OF EVIDENCE AND RECOMMENDATIONS : When considering nutrition support in critically ill patients , we strongly recommend that EN be used in preference to PN . We recommend the use of a st and ard , polymeric enteral formula that is initiated within 24 to 48 hours after admission to ICU , that patients be cared for in the semirecumbent position , and that arginine-containing enteral products not be used . Strategies to optimize delivery of EN ( starting at the target rate , use of a feeding protocol using a higher threshold of gastric residuals volumes , use of motility agents , and use of small bowel feeding ) and minimize the risks of EN ( elevation of the head of the bed ) should be considered . Use of products with fish oils , borage oils , and antioxidants should be considered for patients with acute respiratory distress syndrome . A glutamine-enriched formula should be considered for patients with severe burns and trauma . When initiating EN , we strongly recommend that PN not be used in combination with EN . When PN is used , we recommend that it be supplemented with glutamine , where available . Strategies that maximize the benefit and minimize the risks of PN ( hypocaloric dose , withholding lipids , and the use of intensive insulin therapy to achieve tight glycemic control ) should be considered . There are insufficient data to generate recommendations in the following areas : use of indirect calorimetry ; optimal pH of EN ; supplementation with trace elements , antioxidants , or fiber ; optimal mix of fats and carbohydrates ; use of closed feeding systems ; continuous versus bolus feedings ; use of probiotics ; type of lipids ; and mode of lipid delivery . VALIDATION This guideline was peer- review ed and endorsed by official representatives of the Canadian Critical Care Society , Canadian Critical Care Trials Group , Dietitians of Canada , Canadian Association of Critical Care Nurses , and the Canadian Society for Clinical Nutrition . SPONSORS This guideline is a joint venture of the Canadian Critical Care Society , the Canadian Critical Trials Group , the Canadian Society for Clinical Nutrition , and Dietitians of Canada . The Canadian Critical Care Society and the Institute of Nutrition , Metabolism , and Diabetes of the Canadian Institutes of Health Research provided funding for development of this guideline BACKGROUND / PURPOSE Protein catabolism appears to be markedly elevated among neonates on extracorporeal membrane oxygenation ( ECMO ) . The aim of this study was to determine the effect of dietary caloric intake on protein catabolism in neonates on ECMO to help construct therapies that may promote anabolism . METHODS Twelve total parenteral nutrition (TPN)-fed ( 88.1 + /- 5.0 [ SE ] kcal/kg/d ; range , 60 to 113 kcal/kg/d ; 2.3 + /- 0.2 g/kg/d protein ) neonates were studied on ECMO at day of life 7.2 + /- 0.8 d. Protein kinetics were determined using infusions of NaH13CO3 and 1-[13C]leucine . RESULTS As expected , C-reactive protein levels were significantly elevated compared with normal controls ( 44.0 + /- 7.6 mg/L v 1.9 + /- 1.1 mg/L ; P < .001 ) . Negative protein balance ( -2.3 + /- 0.6 g/kg/d ; range , 1 to -6.4 g/kg/d ) highly correlated ( r = -0.88 , P < .001 ) with total protein turnover . Increased dietary caloric intake correlated with increased amino acid oxidation ( r = 0.85 , P < .001 ) , increased total protein turnover ( r = 0.73 , P < .01 ) , continued negative protein balance ( r = 0.72 , P < .01 ) , increased whole-body protein breakdown ( r = 0.66 , P < .05 ) , and increased CO2 production rate ( r = 0.73 , P < .01 ) . CONCLUSIONS A surplus of dietary caloric intake does not improve protein catabolism and merely increases CO2 production in these highly stressed neonates . Thus , judicious caloric supplementation is warranted Forty-five acute head trauma patients were r and omized into a neurotrauma nutritional study to compare the efficacy of two forms of st and ard nutritional supplementation ; namely total parenteral nutrition ( TPN ) versus enteral nutrition ( NG ) . Forty patients were male , 5 were female , with a median age of 28 years . The mean admitting Glasgow coma scale score was 5.8 . Patients were given high calorie and nitrogen feedings for the 14 days of the study period in an attempt to achieve positive calorie and nitrogen balance . TPN patients had significantly higher mean daily nitrogen intakes ( P less than 0.01 ) and mean daily nitrogen losses ( P less than 0.001 ) than the NG fed patients ; however , no significant differences were discovered with respect to maintenance of serum albumin levels , weight loss , the incidence of infection , nitrogen balance , and final outcome . The exaggerated nitrogen excretion experienced by patients fed large nitrogen loads illustrates a problem in achieving nitrogen equilibrium in acute head injured patients The effect of overfeeding on survival from peritoneal infection as well as changes in protein metabolism was evaluated . Rats were r and omly divided into two groups and given for 6 days different quantities of a liquid diet containing 18 % of the energy supplied as protein and 82 % as carbohydrate and lipid via an implanted gastric tube . The control group received 301 + /- 4 kcal/kg/day which was equivalent to their mean voluntary intake and the overfeeding group received 528 + /- 8 kcal/kg/day ( P less than 0.001 ) . Following 6 days of enteral feeding , all rats received a jugular vein cannulation and cecal ligation with enterotomies . The overfeeding group showed a significantly ( P less than 0.05 ) higher mortality rate to experimental peritonitis , a 24 % lower leucine incorporation into whole body protein ( P less than 0.05 ) , and a 28 % lower fractional synthetic rate of serum albumin ( P less than 0.05 ) . Although overfeeding in the rat increased body weight gain and was associated with significantly ( P less than 0.001 ) greater nitrogen balance before infection , it can be concluded that such diets increase mortality to peritonitis and reduce whole body protein and serum albumin synthesis in response to such infections Forty-six patients with surgical sepsis were studied prospect ively until death or survival to evaluate the effect of exogenous metabolic support on the observed plasma substrate levels and on the differential endogenous utilization of branch chain amino acids . There were no effects of administered glucose or colloid load . The administered amino acid load had little effect on substrate levels in patients who died ; but significantly effected the observed levels of glycine , isoleucinc , and methionine in patients who survived . Evidence is presented which suggests that fatal sepsis is associated with an increased release of endogenous valine and isoleucine into plasma , as well as increased plasma levels of tyrosine , proline , and methionine . These abnormalities are highly correlated with the increased levels of plasma alanine and occur at a time when the nonsurviving septic patient manifests a tendency toward reduced oxygen consumption and abnormal vascular tone relations — the septic B state . These data are consistent with the hypothesis that increased muscle protein catabolism is occurring with a differential utilization of branch chain amino acids and increased use of leucine and isoleucine and reduced use of valine . This autocannibalism of muscle mass appears to be the source of the increased plasma alanine and is little influenced by administered amino acid support in the absence of control of the septic process We conducted a prospect i ve , observational cohort study design ed to compare intestinal permeability ( IP ) and development of multiple organ dysfunction syndrome ( MODS ) in a subset of critically ill patients in an intensive care unit ( ICU ) . All patients with an expected ICU stay of 72 h or more were entered into the study , and IP was determined on a daily basis whenever possible from the urinary fractional excretion of orally administered lactulose and mannitol ( LMR ) . Forty-seven consecutive patients were studied , and 28 developed MODS either at the time of admission or during their ICU course . These patients , as a group , had significantly worse IP at admission than did a non-MODS cohort ( LnLMR : -2.10 + /- 1.10 versus -3.26 + /- 0.83 ) . Those patients who developed MODS following admission also had a significantly greater admission IP than did the non-MODS group ( -2.51 + /- 0.85 ) . Differences in IP between cohorts could not be explained by differences in the incidence of systemic inflammatory response syndrome (SIRS)/sepsis or shock . With multivariate regression analysis , the only parameter present on admission that was predictive of subsequent MODS was IP . Differences in IP and the severity of organ dysfunction were also present ( MODS severity mild : -3.01 + /- 0.72 ; moderate : -1.97 + /- 0.69 ; and severe : -1.12 + /- 0.96 ) . Patients who developed MODS had a persistently abnormal IP during their ICU stay , and a significantly delayed improvement in their IP compared with the non-MODS cohort . We conclude that the development of MODS is associated with an abnormal and severe derangement of IP that is detectable prior to the onset of the syndrome . This observation lends credence to the premise that gastrointestinal ( GI ) dysfunction may be causally associated with the development of MODS in the critically ill patient A large r and omized trial is needed to evaluate the safety and efficacy of glutamine ( GLN ) and antioxidant ( AOX ) supplements . However , high doses of such nutrients via enteral and parenteral routes early in the course of critical illness is often interrupted by high illness acuity and other treatment priorities . The purpose of this pilot trial was to evaluate the feasibility of delivering high-dose GLN and AOX supplements early on in the course of critical illness , and to estimate recruitment for the larger REDOXS study |
13,709 | 18,843,720 | Results of trials conducted by more experienced practitioners appeared to yield greater effects in pain reduction .
Touch therapies may have a modest effect in pain relief . | BACKGROUND Pain is a global public health problem affecting the lives of large numbers of patients and their families .
Touch therapies ( Healing Touch ( HT ) , Therapeutic Touch ( TT ) and Reiki ) have been found to relieve pain , but some review s have suggested there is insufficient evidence to support their use .
OBJECTIVES To evaluate the effectiveness of touch therapies ( including HT , TT , and Reiki ) on relieving both acute and chronic pain ; to determine any adverse effect of touch therapies . | To comprehend the results of a r and omised controlled trial ( RCT ) , readers must underst and its design , conduct , analysis , and interpretation . That goal can be achieved only through total transparency from authors . Despite several decades of educational efforts , the reporting of RCTs needs improvement . Investigators and editors developed the original CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to help authors improve reporting by use of a checklist and flow diagram . The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement . The checklist items pertain to the content of the Title , Abstract , Introduction , Methods , Results , and Discussion . The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect , or because the information is essential to judge the reliability or relevance of the findings . We intended the flow diagram to depict the passage of participants through an RCT . The revised flow diagram depicts information from four stages of a trial ( enrolment , intervention allocation , follow- up , and analysis ) . The diagram explicitly shows the number of participants , for each intervention group , included in the primary data analysis . Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis . In sum , the CONSORT statement is intended to improve the reporting of an RCT , enabling readers to underst and a trial 's conduct and to assess the validity of its results A pilot study was conducted to investigate the effects of Healing Touch ( HT ) on agitation in persons with dementia . Because of the restricted availability of patients , the main purpose of the study was to investigate the effectiveness of HT on dementia patients who demonstrated similar high levels of agitation as measured by the Cohen-Mansfield Agitation Inventory . Results indicated that agitation levels were significantly lowered and that HT is worthy of further study & NA ; Pain intensity is frequently measured on an 11‐point pain intensity numerical rating scale ( PI‐NRS ) , where 0=no pain and 10=worst possible pain . However , it is difficult to interpret the clinical importance of changes from baseline on this scale ( such as a 1‐ or 2‐point change ) . To date , there are no data driven estimates for clinical ly important differences in pain intensity scales used for chronic pain studies . We have estimated a clinical ly important difference on this scale by relating it to global assessment s of change in multiple studies of chronic pain . Data on 2724 subjects from 10 recently completed placebo‐controlled clinical trials of pregabalin in diabetic neuropathy , postherpetic neuralgia , chronic low back pain , fibromyalgia , and osteoarthritis were used . The studies had similar design s and measurement instruments , including the PI‐NRS , collected in a daily diary , and the st and ard seven‐point patient global impression of change ( PGIC ) , collected at the endpoint . The changes in the PI‐NRS from baseline to the endpoint were compared to the PGIC for each subject . Categories of ‘ much improved ’ and ‘ very much improved ’ were used as determinants of a clinical ly important difference and the relationship to the PI‐NRS was explored using graphs , box plots , and sensitivity/specificity analyses . A consistent relationship between the change in PI‐NRS and the PGIC was demonstrated regardless of study , disease type , age , sex , study result , or treatment group . On average , a reduction of approximately two points or a reduction of approximately 30 % in the PI‐NRS represented a clinical ly important difference . The relationship between percent change and the PGIC was also consistent regardless of baseline pain , while higher baseline scores required larger raw changes to represent a clinical ly important difference . The application of these results to future studies may provide a st and ard definition of clinical ly important improvement in clinical trials of chronic pain therapies . Use of a st and ard outcome across chronic pain studies would greatly enhance the comparability , validity , and clinical applicability of these studies Pain , swelling , loss of function , and hyperthermia are acute postoperative sequelae of inflammation due to tissue injury during surgical procedures . Pharmacologic strategies for minimizing the clinical manifestations of surgical trauma are often directed toward blocking the formation or inhibiting the effects of the biochemical mediators of acute inflammation . This study compared two nonsteroidal anti-inflammatory drugs ( NSAIDs ) , flurbiprofen and ibuprofen , with a prototype glucocorticoid , methylprednisolone , in two replicate placebo-controlled studies for suppression of inflammation due to the surgical removal of impacted third molars . The results indicate that NSAIDs produce greater initial analgesia than do steroids , whereas steroids result in greater suppression of swelling and less loss of function . Examination of the pooled data from the two studies indicates that NSAID pretreatment results in a modest suppression of swelling in comparison with placebo . These data suggest that the acute analgesic effects of NSAIDs in the oral surgery model are due to suppression of a nociceptive process , presumably prostagl and in formation , rather than a generalized anti-inflammatory effect Reiki is one type of alternative therapy that is increasing in popularity . It is advocated by its practitioners as a precise method for connecting universal life energy with the body 's innate process of healing through h and s-on techniques . The cl aim of Reiki practitioners is that Reiki reduces a variety of physical problems and improves psychospiritual well-being . There are abundant anecdotal records that support the previous cl aim , and a few pioneer scientific studies are starting to emerge . Although the Reiki research in totality supports the anecdotal records , the absence of r and omized and placebo-controlled trials precludes the interpretation of the outcomes as result ing from specific effects as opposed to placebo effects plus natural history . Authorities in the field indicate that research ers interested in placebo-controlled studies should have the placebo treatment look exactly like the real intervention in every respect . Because no studies could be found in the literature that tested st and ardization procedures for real and placebo Reiki , the decision was made to conduct one . The purpose of this study was to test the st and ardization procedures developed by our research team for placebo Reiki , before going ahead and conducting our planned full-scale r and omized and placebo-controlled Reiki efficacy study . This study used a 4-round , crossover experimental design in which 20 blinded subjects ( 12 students , 4 breast cancer survivors , and 4 observers ) were exposed to a combination of 2 interventions ( Reiki plus Reiki , or placebo plus placebo , or Reiki plus placebo , or placebo plus Reiki ) ; and were then asked to evaluate the interventions using a self-administered question naire . The blinded observers were used in round number 4 . Two real Reiki practitioners in the Usui system were chosen first , then 2 placebo practitioners who closely resembled them were recruited . The placebo practitioners were trained in Reiki by the study Reiki Master and the principal investigator , but were not initiated . The belief in Reiki is that only practitioners that are initiated could give Reiki , thus making it possible to have a placebo arm in efficacy studies . The findings of the study indicate that the developed st and ardization procedures were successful because none of the final participants in round 4 ( 4 breast cancer patients and 4 observers ) could differentiate between the identity of placebo and Reiki practitioners . The qualitative comments expressed by the participants further con-firmed the quantitative data . It was concluded based on these findings that it is safe to go ahead and conduct the planned r and omized 3-arm Reiki efficacy clinical trial . It is recommended that scholars interested in Reiki research could incorporate our techniques to strengthen their design s by adding a placebo arm |
13,710 | 27,750,068 | In a Scottish CRC cohort and up date d meta- analysis there was some evidence that statin use was associated with improved survival .
However , these associations were weak in magnitude and , particularly for post-diagnosis use , varied markedly between studies | BACKGROUND The aim of this study was to investigate the association between statin use and survival in a population -based colorectal cancer ( CRC ) cohort and perform an up date d meta- analysis to quantify the magnitude of any association . | Use of statins is hypothesized to reduce colorectal cancer risk but the evidence remains inconsistent . This may be partly explained by differential associations according to tumor location or molecular subtypes of colorectal cancer . We examined the association between statin use and colorectal cancer risk according to tumor location , KRAS mutation status , microsatellite instability ( MSI ) status , PTGS2 ( COX-2 ) expression , or CpG isl and methylator phenotype ( CIMP ) status in two large prospect i ve cohort studies , the Nurses ' Health Study and Health Professionals Follow-up Study . We applied Cox regression to a competing risks analysis . We identified 1,818 colorectal cancers during 1990 to 2006 . Compared with nonusers , current statin use was not associated with colorectal cancer [ relative risk ( RR ) = 0.99 , 95 % CI = 0.86–1.14 ] or colon cancer ( RR = 1.10 , 95 % CI = 0.94–1.29 ) but was inversely associated with rectal cancer ( RR = 0.59 , 95 % CI = 0.41–0.84 , Pheterogeneity < 0.001 ) . When we examined the association within strata of KRAS mutation status , we found no association with KRAS-mutated cancers ( RR = 1.20 , 95 % CI = 0.87–1.67 ) but did observe a possible inverse association among KRAS wild-type cancers ( RR = 0.80 , 95 % CI = 0.60–1.06 , Pheterogeneity = 0.06 ) . The association did not substantially differ by PTGS2 expression , MSI status , or CIMP status . Current statin use was not associated with risk of overall colorectal cancer . The possibility that statin use may be associated with lower risk of rectal cancer or KRAS wild-type colorectal cancer requires further confirmation . Cancer Prev Res ; 4(11 ) ; 1808–15 . © 2011 AACR The authors compared five methods of study ing survival bias associated with time-to-treatment initiation in a drug effectiveness study using medical administrative data bases ( 1996 - 2002 ) from Quebec , Canada . The first two methods illustrated how survival bias could be introduced . Three additional methods were considered to control for this bias . Methods were compared in the context of evaluating statins for secondary prevention in elderly patients post-acute myocardial infa rct ion who initiated statins within 90 days after discharge and those who did not . Method 1 that classified patients into users and nonusers at discharge result ed in an overestimation of the benefit ( 38 % relative risk reduction at 1 year ) . In method 2 , following users from the time of the first prescription and nonusers from a r and omly selected time between 0 and 90 days attenuated the effect toward the null ( 10 % relative risk reduction ) . Method 3 controlled for survival bias by following patients from the end of the 90-day time window ; however , it suffered a major loss of statistical efficiency and precision . Method 4 matched prescription time distribution between users and nonusers at cohort entry . Method 5 used a time-dependent variable for treatment initiation . Methods 4 and 5 better controlled for survival bias and yielded similar results , suggesting a 20 % risk reduction of recurrent myocardial infa rct ion or death events Epidemiologists are aware that the estimated effect of an exposure can be biased if the investigator fails to adjust for confounding factors when analyzing either a prospect i ve or retrospective etiologic study . St and ard texts warn , however , that intervening factors are an exception : one should not adjust for any factor which is intermediate on the causal pathway between the exposure and the disease . Other factors which are not on the causal pathway but are caused in part by the exposure are often adjusted for in epidemiologic studies . This paper illustrates that bias can result when adjustment is made for any factor which is caused in part by the exposure under study and is also correlated with the outcome under study . Intervening variables are only one example of this phenomenon . The misleading effects of this practice are illustrated with examples Background An association between tumor-specific HMG-CoA reductase ( HMGCR ) expression and good prognosis has previously been demonstrated in breast and ovarian cancer . In this study , the expression , clinicopathological correlates and prognostic value of HMGCR expression in colorectal cancer was examined . Findings Immunohistochemical expression of HMGCR was assessed in tissue microarrays with primary tumours from 557 incident cases of colorectal cancer in the Malmö Diet and Cancer Study . Pearson ’s Chi Square test was applied to explore the associations between HMGCR expression and clinicopathological factors and other investigative biomarkers . Kaplan Meier analysis and Cox proportional hazards modeling were used to assess the relationship between HMGCR expression and cancer-specific survival ( CSS ) according to negative vs positive HMGCR expression . A total number of 535 ( 96.0 % ) tumours were suitable for analysis , of which 61 ( 11.4 % ) were HMGCR negative . Positive cytoplasmic HMGCR expression was associated with distant metastasis-free disease at diagnosis ( p = 0.002 ) , lack of vascular invasion ( p = 0.043 ) , microsatellite-instability ( p = 0.033 ) , expression of cyclin D1 ( p = < 0.001 ) and p21 ( p = < 0.001 ) . Positive HMGCR expression was significantly associated with a prolonged CSS in unadjusted Cox regression analysis in the entire cohort ( HR = 1.79 ; 95 % CI 1.20 - 2.66 ) and in Stage III-IV disease ( HR = 1.71 ; 95 % CI 1.09 - 2.68 ) , but not after adjustment for established clinicopathological parameters . Conclusions Findings from this prospect i ve cohort study demonstrate that HMGCR is differentially expressed in colorectal cancer and that positive expression is associated with favourable tumour characteristics and a prolonged survival in unadjusted analysis . The utility of HMGCR as a predictor of response to neoadjuvant or adjuvant statin treatment in colorectal cancer merits further study .Virtual slidesThe virtual slides for this article can be found here : http://www.diagnosticpathology.diagnomx.eu/vs/2115647072103464 BACKGROUND The st and ard adjuvant treatment of colon cancer is fluorouracil plus leucovorin ( FL ) . Oxaliplatin improves the efficacy of this combination in patients with metastatic colorectal cancer . We evaluated the efficacy of treatment with FL plus oxaliplatin in the postoperative adjuvant setting . METHODS We r and omly assigned 2246 patients who had undergone curative resection for stage II or III colon cancer to receive FL alone or with oxaliplatin for six months . The primary end point was disease-free survival . RESULTS A total of 1123 patients were r and omly assigned to each group . After a median follow-up of 37.9 months , 237 patients in the group given FL plus oxaliplatin had had a cancer-related event , as compared with 293 patients in the FL group ( 21.1 percent vs. 26.1 percent ; hazard ratio for recurrence , 0.77 ; P=0.002 ) . The rate of disease-free survival at three years was 78.2 percent ( 95 percent confidence interval , 75.6 to 80.7 ) in the group given FL plus oxaliplatin and 72.9 percent ( 95 percent confidence interval , 70.2 to 75.7 ) in the FL group ( P=0.002 by the stratified log-rank test ) . In the group given FL plus oxaliplatin , the incidence of febrile neutropenia was 1.8 percent , the incidence of gastrointestinal adverse effects was low , and the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment , decreasing to 1.1 percent at one year of follow-up . Six patients in each group died during treatment ( death rate , 0.5 percent ) . CONCLUSIONS Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer PURPOSE Aspirin and other nonsteroidal anti-inflammatory drugs ( NSAIDs ) protect against colorectal cancer ( CRC ) and are associated with reduced disease recurrence and improved outcome after primary treatment . However , toxicities of NSAIDs have limited their use as antineoplastic therapy . Recent data have suggested that the benefit of aspirin after CRC diagnosis is limited to patients with PIK3CA-mutant cancers . We sought to determine the predictive utility of PIK3CA mutation for benefit from both cyclooxygenase-2 inhibition and aspirin . METHODS We performed molecular analysis of tumors from 896 participants in the Vioxx in Colorectal Cancer Therapy : Definition of Optimal Regime ( VICTOR ) trial , a large r and omized trial comparing rofecoxib with placebo after primary CRC resection . We compared relapse-free survival and overall survival between rofecoxib therapy and placebo and between the use and nonuse of low-dose aspirin , according to tumor PIK3CA mutation status . RESULTS We found no evidence of a greater benefit from rofecoxib treatment compared with placebo in patients whose tumors had PIK3CA mutations ( multivariate adjusted hazard ratio [ HR ] , 1.2 ; 95 % CI , 0.53 to 2.72 ; P = .66 ; (P)INTERACTION = .47 ) compared with patients with PIK3CA wild-type cancers ( HR , 0.87 ; 95 % CI , 0.64 to 1.16 ; P = .34 ) . In contrast , regular aspirin use after CRC diagnosis was associated with a reduced rate of CRC recurrence in patients with PIK3CA-mutant cancers ( HR , 0.11 ; 95 % CI , 0.001 to 0.832 ; P = .027 ; (P)INTERACTION = .024 ) but not in patients lacking tumor PIK3CA mutation ( HR , 0.92 ; 95 % CI , 0.60 to 1.42 ; P = .71 ) . CONCLUSION Although tumor PIK3CA mutation does not predict benefit from rofecoxib treatment , it merits further evaluation as a predictive biomarker for aspirin therapy . Our findings are concordant with recent data and support the prospect i ve investigation of adjuvant aspirin in PIK3CA-mutant CRC BACKGROUND Although pre clinical and epidemiological data suggest that statins may have antineoplastic properties , the impact of statin use on patient survival after a curative resection of stage III colon cancer is unknown . METHODS We conducted a prospect i ve observational study of 842 patients with stage III colon cancer enrolled in a r and omized adjuvant chemotherapy trial from April 1999 to May 2001 to investigate the relationship between statin use and survival . Disease-free survival ( DFS ) , recurrence-free survival ( RFS ) , and overall survival ( OS ) were investigated by Kaplan-Meier curves and log-rank tests in the overall study population and in a subset of patients stratified by KRAS mutation status ( n = 394 ) , and Cox proportional hazards regression was used to assess the simultaneous impact of confounding variables . All statistical tests were two-sided . RESULTS Among 842 patients , 134 ( 15.9 % ) reported statin use after completing adjuvant chemotherapy . DFS among statin users and nonusers was similar ( hazard ratio [ HR ] of cancer recurrence or death = 1.04 , 95 % confidence interval [ CI ] = 0.73 to 1.49 ) . RFS and OS were also similar between statin users and nonusers ( adjusted HR of cancer recurrence = 1.14 , 95 % CI = 0.77 to 1.69 ; adjusted HR of death = 1.15 , 95 % CI = 0.77 to 1.71 ) . Survival outcomes were similar regardless of increasing duration of statin use before cancer diagnosis ( P(trend ) = .63 , .63 , and .59 for DFS , RFS , and OS , respectively ) . The impact of statin use did not differ by tumor KRAS mutation status , with similar DFS , RFS , and OS for statin use among mutant and wild-type subgroups ( P(interaction ) = .84 , .67 , and .98 for DFS , RFS , and OS , respectively ) . CONCLUSION Statin use during and after adjuvant chemotherapy was not associated with improved DFS , RFS , or OS in patients with stage III colon cancer , regardless of KRAS mutation status BACKGROUND : Achieving a pathologic complete response to neoadjuvant chemoradiation improves prognosis in rectal cancer . Statin therapy has been shown to enhance the impact of treatment in several malignancies , but little is known regarding the impact on rectal cancer response to neoadjuvant chemoradiation . OBJECTIVE : The purpose of this study was to determine whether statin use during neoadjuvant chemoradiation improves pathologic response in rectal cancer . DESIGN : This was a retrospective cohort study based on data from a prospect ively maintained colorectal cancer data base . The 2 cohorts were defined by statin use during neoadjuvant chemoradiation . SETTING : This study was performed at a single tertiary referral center . PATIENTS : Four hundred seven patients with primary rectal adenocarcinoma who underwent neoadjuvant therapy then proctectomy between 2000 and 2012 were included . Ninety-nine patients ( 24.3 % ) took a statin throughout the entire course of neoadjuvant therapy . MAIN OUTCOME MEASURES : The primary outcome measure was pathologic response to neoadjuvant chemoradiotherapy as defined by the American Joint Committee on Cancer tumor regression grading system , grade s 0 to 3 . RESULTS : Patients in the statin cohort had a lower median regression grade ( 1 vs 2 , p = 0.01 ) and were more likely to have a better response ( grade s 0–1 vs 2–3 ) than those not taking a statin ( 65.7 % vs 48.7 % , p = 0.004 ) . Statin use remained a significant predictor of an American Joint Committee on Cancer grade 0 to 1 ( OR , 2.25 ; 95 % CI , 1.33–3.82 ) in multivariate analyses . Although statin use itself did not significantly improve oncologic outcomes , an American Joint Committee on Cancer grade 0 to 1 response was associated with statistically significant improvements in overall survival , disease-free survival , cancer-specific mortality , and local recurrence . LIMITATIONS : This was a retrospective study and subject to nonr and omization of patients and incorporated patients on variable statin agents and doses . CONCLUSIONS : Statin therapy is associated with an improved response of rectal cancer to neoadjuvant chemoradiation . These data provide the foundation for a prospect i ve clinical trial |
13,711 | 19,810,776 | Systematic assessment led to higher rates than less systematic assessment .
Conclusion : Adverse effect profiles reported in clinical trials are strongly influenced by expectations from investigators and patients .
This difference can not be attributed to ascertainment methods .
Adverse effect patterns of the drug group are closely related to adverse effects of the placebo group .
These results question the validity of the assumption that adverse effects in placebo groups reflect the ‘ drug-unspecific effects ’ | Background : Biases in adverse effect reporting in r and omized controlled trials ( RCTs ) [ e.g. due to investigator expectations or assessment quality ] can be quantified by study ing the rates of adverse events reported in the placebo arms of such trials .
Objective : We compared the rates of adverse effects reported in the placebo arms of tricyclic antidepressant ( TCA ) trials and placebo arms of selective serotonin reuptake inhibitor ( SSRI ) trials . | CONTEXT The generalized type of social phobia ( social anxiety disorder ) is a severe and often disabling form of social anxiety that affects approximately 5 % of the general population . Earlier research has shown monoamine oxidase inhibitors or benzodiazepines to be effective in treating this condition , but neither has achieved widespread use . OBJECTIVE To compare the efficacy of paroxetine , a selective serotonin reuptake inhibitor , with placebo in adults with generalized social phobia . DESIGN Twelve-week , multicenter , r and omized , double-blind trial . SETTING Thirteen centers across the United States and 1 in Canada . PARTICIPANTS Between April 13 , 1995 , and February 28 , 1996 , 187 persons meeting Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition criteria for generalized social phobia were r and omized ( and 183 returned for at least 1 efficacy assessment ) to treatment . INTERVENTION After a 1-week , single-blind , placebo , run-in period , patients received a double-blind , 11-week course of either paroxetine or matching-image placebo . The initial daily dosage of paroxetine ( or placebo ) was 20 mg with increases of 10 mg/d weekly ( flexible dosing to a maximum of 50 mg/d ) permitted after the second week of treatment . MAIN OUTCOME MEASURES Number of responders based on the Clinical Global Impression Global Improvement Item ( " much improved " or " very much improved " ) ; mean change from baseline on the Liebowitz Social Anxiety Scale total score . RESULTS Fifty ( 55.0 % ) of 91 persons taking paroxetine and 22 ( 23.9 % ) of 92 persons taking placebo were much improved or very much improved at the end of treatment ( odds ratio [ OR ] , 3.88 ; 95 % confidence interval [ CI ] , 2.81 - 5.36 ) . Mean Liebowitz Social Anxiety Scale total scores were reduced by 39.1 % ( the mean baseline score of 78.0 declined by a mean of 30.5 points at follow-up ) in the paroxetine group compared with 17.4 % ( the mean baseline score of 83.5 declined 14.5 points at follow-up ) in the placebo group , a difference of 21.7 % ( 95 % CI , 8.7%-34.7 % ) favoring paroxetine . CONCLUSIONS Paroxetine is an effective treatment for patients with generalized social phobia . Short-term ( ie , 11-week ) treatment results in substantial and clinical ly meaningful reductions in symptoms and disability . Future research should test whether these may be further reduced by extended treatment or supplementation with specific educational-cognitive-behavioral techniques Rationale Seasonal affective disorder ( SAD ) is a relatively common cyclical depressive illness characterized by seasonal depressions during winter . The disorder is commonly responsive to light therapy , but antidepressant drug efficacy has not been definitely established . Serotonin selective re-uptake inhibitors are potentially efficacious treatments for SAD . Objectives The objective of this study was to evaluate the efficacy , tolerability and safety of sertraline treatment for SAD . Methods One hundred and eighty seven out patients with seasonal pattern recurrent winter depression ( DSM-III-R defined ) and a minimum 29-item Hamilton depression scale ( SIGH-SAD version ) score of 22 were r and omized to 8 weeks treatment with either sertraline or placebo in a double-blind , multi-country , multi-center , parallel-group , flexible dose ( 50–200 mg once daily ) study . Efficacy was investigated using physician and patient-rated scales measuring depression , anxiety and symptoms characteristic of seasonal affective disorder . Results Sertraline produced a significantly greater response than placebo at endpoint as measured by changes in the 29-item and 21-item Hamilton depression scales , the clinical global impression ( CGI ) severity scale , the Hamilton anxiety scale , and the hospital anxiety and depression scale . The proportion of sertraline-treated subjects achieving a response on the CGI improvement rating ( ratings of 1 or 2 ) at endpoint ( last observation carried forward ) was significantly greater than that of the placebo group . Overall sertraline was well tolerated with the most frequent placebo adjusted adverse events , being nausea , diarrhea , insomnia and dry mouth . Adverse events were mostly mild to moderate and transient . Conclusions Sertraline pharmacotherapy has been demonstrated to be an effective and well-tolerated therapy for out patients with SAD . As such , sertraline offers an important pharmacological option in the clinical management of this condition The efficacy of paroxetine in the treatment of obsessive-compulsive disorder in Western population s is well established . The present study compares the efficacy and safety of paroxetine with placebo in the treatment of obsessive-compulsive disorder in Japanese patients . Patients aged 16 years or older who met Diagnostic and Statistical Manual of Mental Disorders ( 4th edn ; DSM-IV ) criteria for obsessive-compulsive disorder and had a Yale-Brown Obsessive-Compulsive Scale ( Y-BOCS ) score of > /=16 were r and omized to receive 12 weeks ' therapy in a double-blind manner . Paroxetine 20 - 50 mg/day or placebo was administered following a 1 week , placebo run-in phase . One hundred and ninety-one patients were r and omized to either paroxetine or placebo , 188 patients were assessed as the full analysis set ( FAS ) and 144 patients completed the 12 week study . After adjustment for the Y-BOCS total score at baseline , reductions in obsessive-compulsive total score at week 6 and at the end of therapy were significantly greater in the paroxetine group than the placebo group . Most of the adverse events that occurred during the study were of mild to moderate intensity . Paroxetine is effective and well tolerated in Japanese adult patients with obsessive-compulsive disorder The safety and efficacy of sertraline versus placebo were examined in a group of nondepressed out patients with obsessive-compulsive disorder ( OCD ) . Patients with moderate-to-severe OCD were recruited at 10 sites . After a 1-week placebo lead-in , patients were treated in a double-blind fashion for 12 weeks with sertraline or placebo . Sertraline was administered at a starting dose of 50 mg/day , with flexible titration up to 200 mg/day . The efficacy measures were the Yale-Brown Obsessive Compulsive Scale ( Y-BOCS ) , the National Institute of Mental Health Global Obsessive Compulsive Scale ( NIMH ) , and the Clinical Global Impression Scale ( CGI ) Severity of Illness and Improvement subscales . One hundred sixty-seven patients were r and omly assigned and received at least one dose of double-blind medication : 86 received sertraline and 81 received placebo . All efficacy measures showed significantly greater improvement in the sertraline group from the end of week 8 until the end of week 12 . Significantly greater improvement ( p < 0.05 ) in the sertraline group first became apparent by the end of week 3 on the Y-BOCS and the CGI Improvement scale , and by the end of weeks 6 and 8 , respectively , on the NIMH and CGI Severity scale . Sertraline was well tolerated , without serious adverse effects . In conclusion , sertraline was safe and effective in the treatment of patients with OCD One hundred and sixty patients with a primary diagnosis of obsessive compulsive disorder were enrolled in a multicentre , r and omized , double-blind , placebo-controlled study of fluvoxamine . After a placebo washout phase , patients were r and omized to treatment with placebo or fluvoxamine ( 100–300 mg/day ) for 10 weeks . Seventy-eight patients in each group were evaluable for efficacy . Fluvoxamine was significantly more effective than placebo as assessed by the Yale Brown Obsessive-Compulsive Scale ( Y-BOCS ) , the National Institute of Mental Health Obsessive Compulsive ( NIMH-OC ) scale and ( be Global Improvement item of the Clinical Global Impression ( CGI ) scale . The percentage of patients classified as “ responders ” ( much or very much improved according to the Global Improvement item ) was also significantly higher in the fluvoxamine group from Week 6 onwards , with 33.3 % of fluvoxamine-treated patients and 9.0 % of those given placebo classified as “ responders ” at : endpoint . The “ responders ” to fluvoxamine experienced a substantial clinical benefit as reflected in decreases in their Y-BOCS and NIMH-OC scores . Fluvoxamine was well tolerated with the majority of adverse events considered mild or moderate Selective serotonin reuptake inhibitors are the pharmacological treatment of choice for the treatment of social anxiety disorder ( SAD ) . The efficacy and tolerability of fixed doses of escitalopram were compared to those of placebo in the long‐term treatment of generalised SAD , using paroxetine as an active reference . Patients with a DSM‐IV diagnosis of SAD between 18–65 years of age were r and omised to 24 weeks of double‐blind treatment with placebo ( n = 166 ) , 5 mg escitalopram ( n = 167 ) , 10 mg escitalopram ( n = 167 ) , 20 mg escitalopram ( n = 170 ) , or 20 mg paroxetine ( n = 169 ) . Based on the primary efficacy parameter , Liebowitz Social Anxiety Scale ( LSAS ) total score at Week 12 ( LOCF ) , a significantly superior therapeutic effect compared to placebo was seen for 5 and 20 mg escitalopram and for all doses for the OC analyses . Further improvement in LSAS scores was seen at Week 24 ( OC and LOCF ) , with significant superiority over placebo for all doses of escitalopram , and 20 mg escitalopram was significantly superior to 20 mg paroxetine . Response to treatment ( assessed by a Clinical Global Impression‐Improvement score ≤2 ) was significantly higher for all active treatments than for placebo at Week 12 . Clinical relevance was supported by a significant decrease in all the Sheehan disability scores , and the good tolerability of escitalopram treatment . It is concluded that doses of 5–20 mg escitalopram are effective and well tolerated in the short‐ and long‐term treatment of generalised SAD . Depression and Anxiety 00:000–000 , 2004 . © 2004 Wiley‐Liss , BACKGROUND The serotonin selective reuptake inhibitors are increasingly being used for the treatment of panic disorder . We examined the efficacy and safety of the serotonin selective reuptake inhibitor sertraline hydrochloride in patients with panic disorder . METHODS One hundred seventy-six nondepressed out patients with panic disorder , with or without agoraphobia , from 10 sites followed identical protocol s that used a flexible-dose design . After 2 weeks of single-blind placebo , patients were r and omly assigned to 10 weeks of double-blind , flexible-dose treatment with either sertraline hydrochloride ( 50 - 200 mg/d ) or placebo . RESULTS Sertraline-treated patients exhibited significantly greater improvement ( P=.01 ) at end point than did patients treated with placebo for the primary outcome variable , panic attack frequency . Significant differences between groups were also evident for clinician and patient assessment s of improvement as measured by the Clinical Global Impression Improvement ( P=.01 ) and Severity ( P=.009 ) Scales , Panic Disorder Severity Scale ratings ( P=.03 ) , high end-state function assessment ( P=.03 ) , Patient Global Evaluation rating ( P=.01 ) , and quality of life scores ( P=.003 ) . Adverse events , generally characterized as either mild or moderate , were not significantly different in overall incidence between the sertraline and placebo groups . CONCLUSION Results support the safety and efficacy of sertraline for the short-term treatment of patients with panic disorder Background : Generalized social anxiety disorder is a highly prevalent anxiety disorder with deleterious effects on social and family relationships , as well as work performance . We report the results of a multicenter , r and omized , placebo-controlled trial comparing the efficacy , safety , and tolerability of fluvoxamine controlled release ( CR ) to placebo in patients with generalized social anxiety disorder . Methods : A total of 279 adult patients meeting all inclusion /exclusion criteria was recruited at 23 United States sites and r and omly assigned to receive either fluvoxamine CR ( 100 - 200 mg/d ) or placebo for 12 weeks . The dose could be increased , based on efficacy and tolerability , in increments of 50 mg/d at weekly intervals . The dosage remained constant during weeks 6 to 12 . Results : Treatment with fluvoxamine CR result ed in statistically and clinical ly significant improvements in symptoms associated with generalized social anxiety disorder as early as week 4 on the Liebowitz Social Anxiety Scale and the Clinical Global Impression Scale Global Improvement , and at week 6 on the Sheehan Disability Scale , Clinical Global Impression Scale Severity of Illness and the Patient Global Impression of Improvement Scale . The most frequent adverse events reported by patients on fluvoxamine CR were headache , nausea , somnolence , and insomnia . No weight gain was observed for either treatment group , and at end point , there were no differences between treatments on overall sexual function , as measured by the Arizona Sexual Experience Scale . Conclusions : Both physician and patient-rated scales indicate that fluvoxamine CR is effective and safe for the treatment of generalized social anxiety disorder Several reports suggest that selective serotonin reuptake blockers are helpful in the treatment of panic disorder . The aim of the study was to compare fluvoxamine with placebo in 50 panic disorder patients by using an 8-week , double-blind , parallel-groups design . Weekly assessment included a panic attack diary ( frequency and severity ) , the Montgomery-Asberg Depression Scale , the Clinical Anxiety Scale , and the Sheehan Disability Scale . Although both groups improved on all measures , the fluvoxamine group experienced significantly less frequent major panic attacks from the third week on and significantly lower ratings on anxiety , depression , and disability from the sixth week on . Mean ratings of the severity of major and the severity and frequency of minor attacks were not affected differently by fluvoxamine and placebo . At the end of the study , significantly more patients on fluvoxamine were free of major and minor panic attacks . The results indicate that : ( 1 ) the administration of fluvoxamine , as compared with placebo , led to a significant reduction in the number of panic attacks . ( 2 ) The severity of panic attacks was not affected by fluvoxamine . ( 3 ) The effect of fluvoxamine on anxiety , depressive mood , and disability differed from placebo only after 6 weeks of treatment , after which the placebo group showed either no further improvement or a reversal of symptoms . ( 4 ) Participation in a drug study , even without additional psychotherapy , led to significant improvement in all patients BACKGROUND Escitalopram , the therapeutically active isomer of the racemic selective serotonin reuptake inhibitor antidepressant citalopram , has shown significant anxiolytic effects in placebo-controlled clinical trials of social anxiety disorder , generalized anxiety disorder , and anxiety symptoms associated with major depression . This study evaluated the safety and efficacy of escitalopram in out patients diagnosed with panic disorder . METHOD Male and female out patients between 18 and 80 years of age meeting DSM-IV criteria for panic disorder , with or without agoraphobia , were r and omly assigned to 10 weeks of double-blind treatment with escitalopram , citalopram , or placebo in a study conducted from September 1999 to July 2001 . The primary measure of efficacy was panic attack frequency at week 10 relative to baseline , as assessed by the Modified Sheehan Panic and Anticipatory Anxiety Scale . RESULTS A total of 366 subjects ( 128 escitalopram patients , 119 citalopram patients , and 119 placebo patients ) received at least 1 dose of double-blind treatment . The frequency of panic attacks was statistically significantly improved ( p = .04 ) , and the increase in percentage of patients with zero panic attacks reached borderline significance ( p = .051 ) , in the escitalopram-treated group relative to the placebo-treated group . Both escitalopram and citalopram statistically significantly reduced panic disorder symptoms and severity versus placebo at endpoint ( p < /=.05 ) , as measured by the Panic and Agoraphobia Scale total score , the Clinical Global Impressions scale , the Patient Global Evaluation , and the Quality of Life Enjoyment and Satisfaction Question naire . Treatment with escitalopram was safe and well tolerated , with a similar incidence of the most common adverse events for the escitalopram and placebo groups . The rate of discontinuation for adverse events was 6.3 % for escitalopram , 8.4 % for citalopram , and 7.6 % for placebo . CONCLUSION Escitalopram is efficacious , safe , and well tolerated in the treatment of panic disorder BACKGROUND It is uncertain whether higher doses of selective serotonin reuptake inhibitors have greater efficacy in generalised anxiety disorder . AIMS To assess the efficacy of different doses of escitalopram in generalised anxiety disorder . METHOD R and omised , double-blind , placebo-controlled , fixed-dose , parallel-group , 12-week study , with 681 patients : placebo ( n=139 ) ; escitalopram , 5 mg/day , ( n=134 ) ; 10 mg/day ( n=136 ) ; 20 mg/day ( n=133 ) ; paroxetine , 20 mg/day ( n=139 ) . RESULTS Mean change in the primary efficacy measure was greater with escitalopram 10 and 20 mg than with placebo ; 10 mg was more efficacious than paroxetine . Paroxetine was superior to placebo on some secondary measures , at some time points . Compared with placebo , more patients withdrew because of adverse events with escitalopram 20 mg and paroxetine . CONCLUSIONS Escitalopram was efficacious in generalised anxiety disorder , 20 was not significantly superior to 10 mg/day . Escitalopram 10 mg was more efficacious than paroxetine BACKGROUND Generalized social phobia is common , persistent , and disabling and is often treated with selective serotonin reuptake inhibitor drugs or cognitive behavioral therapy . OBJECTIVE We compared fluoxetine ( FLU ) , comprehensive cognitive behavioral group therapy ( CCBT ) , placebo ( PBO ) , and the combinations of CCBT/FLU and CCBT/PBO . DESIGN R and omized , double-blind , placebo-controlled trial . SETTING Two academic outpatient psychiatric centers . PATIENTS Subjects meeting a primary diagnosis of generalized social phobia were recruited via advertisement . Seven hundred twenty-two were screened , and 295 were r and omized and available for inclusion in an intention-to-treat efficacy analysis ; 156 ( 52.9 % ) were male , 226 ( 76.3 % ) were white , and mean age was 37.1 years . INTERVENTIONS Treatment lasted for 14 weeks . Fluoxetine and PBO were administered at doses from 10 mg/d to 60 mg/d ( or equivalent ) . Group comprehensive cognitive behavioral therapy was administered weekly for 14 sessions . MAIN OUTCOME MEASURES An independent blinded evaluator assessed response with the Brief Social Phobia Scale and Clinical Global Impressions scales as primary outcomes . A videotaped behavioral assessment served as a secondary outcome , using the Subjective Units of Distress Scale . Adverse effects were measured by self-rating . Each treatment was compared by means of chi2 tests and piecewise linear mixed-effects models . RESULTS Clinical Global Impressions scales response rates in the intention-to-treat sample were 29 ( 50.9 % ) ( FLU ) , 31 ( 51.7 % ) ( CCBT ) , 32 ( 54.2 % ) ( CCBT/FLU ) , 30 ( 50.8 % ) ( CCBT/PBO ) , and 19 ( 31.7 % ) ( PBO ) , with all treatments being significantly better than PBO . On the Brief Social Phobia Scale , all active treatments were superior to PBO . In the linear mixed-effects models analysis , FLU was more effective than CCBT/FLU , CCBT/PBO , and PBO at week 4 ; CCBT was also more effective than CCBT/FLU and CCBT/PBO . By the final visit , all active treatments were superior to PBO but did not differ from each other . Site effects were found for the Subjective Units of Distress Scale assessment , with FLU and CCBT/FLU superior to PBO at Duke University Medical Center , Durham , NC . Treatments were well tolerated . CONCLUSIONS All active treatments were superior to PBO on primary outcomes . Combined treatment did not yield any further advantage . Notwithst and ing the benefits of treatment , many patients remained symptomatic after 14 weeks OBJECTIVE To examine the efficacy of fluoxetine in the treatment of depression in patients with probable Alzheimer 's disease ( AD ) . METHODS This double-blind , parallel- design study included a consecutive series of 41 AD subjects meeting DSM-IV criteria for major or minor depression who were r and omized to receive fluoxetine ( up to 40 mg/day ) or identical-appearing placebo . All patients received biweekly evaluations consisting of the Hamilton Depression Scale ( HAM-D ) and the Clinical Global Impression as primary efficacy measures , and the Mini-Mental State Exam , Hamilton Rating Scale for Anxiety , and the Functional Independence Measure as secondary efficacy measures . RESULTS Complete remission of depression was found in 47 % of subjects treated with fluoxetine and in 33 % of subjects treated with placebo . Both the fluoxetine and the placebo groups showed a significant decline in HAM-D scores over time , but the magnitude of mood improvement was similar for both groups . Fluoxetine was well tolerated , and most side effects were mild . CONCLUSION Fluoxetine treatment for depression in AD did not differ significantly from treatment with placebo . Our study also confirms the presence of a placebo effect in the treatment of depression in AD BACKGROUND The use of placebo in clinical trials has been vigorously debated . Placebo control may be useful in disease states , such as stage 1 and stage 2 hypertension as defined by the Sixth Report of the Joint National Committee on Detection , Evaluation and Treatment of High Blood Pressure ( JNC VI ) , in which response rates for placebo are high or close to response rates for effective therapies , or when established interventions have significant adverse effects . OBJECTIVE To compare rates for the control of blood pressure and adverse effects of placebo vs active treatment in patients with stage 1 and stage 2 hypertension . METHODS This study is a r and omized controlled trial evaluating the blood pressure response and adverse effects of placebo vs 6 active treatments administered in 15 Veterans Affairs hypertension centers . The 1292 subjects of the Veterans Affairs Cooperative Study receiving single-drug therapy for hypertension were r and omly allocated to receive treatment with 1 of 6 active drugs ( n= 1105 ) or placebo ( n=187 ) . Treatment success was defined as maintaining a diastolic blood pressure of less than 95 mm Hg for at least 1 year . We compared treatment success rates for the control of blood pressure and adverse effects of placebo vs active treatment . Using the Kaplan-Meier method , we also compared rates of discontinuation from placebo vs active drug treatment over time as a result of adverse drug effects and blood pressure exceeding safety limits . RESULTS At the end of the titration phase , 58 patients who were treated with placebo ( 31 % ) achieved a goal diastolic blood pressure lower than 90 mm Hg and 57 ( 30 % ) achieved success at 1 year . Older white patients who received placebo had a success rate of 38 % vs 23 % to 27 % for the other age-race subgroups . The rates of discontinuation as a result of adverse drug effects were 13 % for patients receiving placebo vs 12 % for patients receiving active treatment ( P=.40 ) . The rates of discontinuation for blood pressure being too high were 14 % for patients receiving placebo vs 7 % for patients receiving active treatment ( P=.01 ) . CONCLUSIONS Placebo control provides an important benchmark for both efficacy and adverse effects . It continues to have an appropriate place in certain therapeutic trials , particularly those involving the treatment of stage 1 and stage 2 hypertension OBJECTIVE Sertraline 's efficacy and tolerability in treating generalized anxiety disorder were evaluated . METHOD Adult out patients with DSM-IV generalized anxiety disorder and a total score of 18 or higher on the Hamilton Anxiety Rating Scale were eligible . After a 1-week single-blind placebo lead-in , patients were r and omly assigned to 12 weeks of double-blind treatment with placebo ( N=188 , mean baseline anxiety score=25 ) or flexible doses ( 50 - 150 mg/day ) of sertraline ( N=182 , mean anxiety score=25 ) . The primary outcome measure was baseline-to-endpoint change in the Hamilton anxiety scale total score . A secondary efficacy measure was the Clinical Global Impression ( CGI ) improvement score ; response was defined as a score of 2 or less . RESULTS Sertraline patients had significantly greater improvement than placebo patients on all efficacy measures at week 4 . Analysis of covariance of the intent-to-treat group at endpoint ( with the last observation carried forward ) showed a significant difference in the decrease from baseline of the least-square mean total score on the Hamilton anxiety scale between sertraline ( mean=11.7 ) and placebo ( mean=8.0 ) . Significantly greater endpoint improvement with sertraline than placebo was obtained for mean scores on the Hamilton anxiety scale psychic factor ( 6.7 versus 4.1 ) and somatic factor ( 5.0 versus 3.9 ) . The rate of responders , based on CGI improvement and last observation carried forward , was significantly higher for sertraline ( 63 % ) than placebo ( 37 % ) . Sertraline was well tolerated ; 8 % of patients versus 10 % for placebo dropped out because of adverse events . CONCLUSIONS Sertraline appears to be efficacious and well tolerated in the treatment of generalized anxiety disorder Selective serotonin reuptake inhibitors may be less efficacious than tricyclic antidepressants in the treatment of severe depression in older patients . The authors compared the 12-week clinical outcome of older depressed patients treated with nortriptyline or paroxetine in a double-blind r and omized comparison in 116 psychiatric in patients and out patients ( mean age : 72+/-8 years ) who presented with a major depressive episode or melancholic depression . Discontinuation and response rates were compared in patients who began or who completed treatment . The discontinuation rate due to side effects was significantly higher with nortriptyline than with paroxetine ( 33 % vs. 16 % ) . There were no significant differences between the rates of response in the Intent-to-Treat analysis ( nortriptyline : 57 % vs. paroxetine : 55 % ) , or the Completer analysis ( nortriptyline : 78 % vs. paroxetine : 84 % ) . Although paroxetine appears to be better tolerated than nortriptyline , the efficacy of these two drugs does not appear to differ in the acute treatment of older depressed patients , including hospitalized patients and those with melancholic features OBJECTIVE This study determined the efficacy and safety of sertraline in the treatment of patients with panic disorder . METHOD The study was a r and omized , double-blind , parallel-group , flexible-dose comparison of sertraline and placebo in out patients with a DSM-III-R diagnosis of panic disorder with or without agoraphobia . After a 2-week single-blind placebo lead-in , 168 patients entered a 10-week double-blind phase in which they were r and omly assigned to treatment with either sertraline or placebo . RESULTS Sertraline was significantly more effective than placebo in decreasing the number of full and limited-symptom panic attacks . Among patients who completed the study , the mean number of panic attacks per week dropped by 88 % in the sertraline-treated patients and 53 % in the placebo-treated patients . Sertraline-treated patients also had significantly more improvement than placebo-treated patients in scores on the Quality of Life Enjoyment and Satisfaction Question naire , patient global evaluation , and Clinical Global Impression severity of illness and global improvement scales . Overall , patients tolerated sertraline well , and only 9 % terminated treatment because of side effects . CONCLUSIONS Sertraline is an effective and well-tolerated treatment for patients with panic disorder OBJECTIVE This study assessed the efficacy and safety of sertraline in the treatment of generalized anxiety disorder ( GAD ) . METHOD The study was conducted from April 2000 to May 2002 . Out patients with DSM-IV GAD ( N = 326 ) who satisfied inclusion /exclusion criteria and completed a 1-week screening phase were r and omly assigned to 10-week double-blind treatment with flexible dosing of sertraline ( 50 - 200 mg/day ) or placebo . The primary efficacy measure was change from baseline in Hamilton Rating Scale for Anxiety ( HAM-A ) total score . Response was defined as a 50 % or greater decrease in HAM-A total score at endpoint . RESULTS Sertraline produced a statistically significant reduction in anxiety symptoms , as measured by HAM-A total change scores ( p = .032 ) , HAM-A psychic anxiety subscale ( p = .011 ) , and Hospital Anxiety and Depression Scale-anxiety subscale ( p = .001 ) . Response rates were significantly higher ( p = .05 ) for the sertraline group ( 59.2 % ) compared to the placebo group ( 48.2 % ) . Sertraline was well tolerated , with only sexual side effects reported significantly more often by subjects receiving sertraline than those receiving placebo . CONCLUSION Despite the relatively small between-group differences , study findings suggest a role for sertraline in the acute treatment of GAD BACKGROUND AND PURPOSE Early poststroke depression ( PSD ) is a frequent and specific entity that impairs the rehabilitation and functional recovery of hemiplegic patients . This trial was design ed to study the efficacy and tolerance of fluoxetine ( FLX ) in the treatment of early PSD . METHODS This was a multicenter , double-blind , placebo-controlled study . Recent hemiplegic patients ( <3 months ) suffering from major depressive disorder ( determined by International Classification of Diseases , 10th Revision , and Montgomery-Asberg Depression Rating Scale [ MADRS ] > 19 ) were r and omized to receive either 20 mg/d fluoxetine ( FLX ) or placebo for 6 weeks . Patients were evaluated by use of the Motricity Index , Mini-Mental State Examination , Functional Independence Measure , and MADRS . Statistical analysis was performed by using an intent-to-treat approach comparing the 2 groups at day 0 ( baseline ) and days 15 , 30 , and 45 ( end point ) . RESULTS Of 121 patients screened , 31 were included in the study , 16 in the FLX group and 15 in the placebo group . There were no significant differences in baseline characteristics among the 2 groups . The FLX-treated patients compared with placebo-treated patients demonstrated significant improvement in mean MADRS scores at end point ( 11.8+/-6 . 7 [ mean+/-SD ] versus 18.7+/-10.0 , respectively ; P=0.05 ) . FLX-treated patients compared with placebo-treated patients also demonstrated greater response rate ( 62.5 % versus 33.3 % , respectively ) and greater mean decrease of MADRS ( 16.6 versus 8.4 , respectively ; P=0.02 ) . There were no differences in motor , cognitive , or functional improvement and no significant side effects after FLX treatment , except for a patient with a moderate and transient increase of transaminases . CONCLUSIONS FLX is an efficacious and well-tolerated treatment for early PSD . Further research is needed to evaluate the efficacy and safety of long-term treatment in this population ABSTRACT Objective : A r and omized , placebo-controlled fixed-dose trial was undertaken to determine the efficacy and tolerability of escitalopram in obsessive – compulsive disorder ( OCD ) , using paroxetine as the active reference . Research design and methods : A total of 466 adults with OCD from specialized clinical centres , psychiatric hospital departments , psychiatric practice s , or general practice were r and omized to one of four treatment groups : escitalopram 10 mg/day ( n = 116 ) , escitalopram 20 mg/day ( n = 116 ) , paroxetine 40 mg/day ( n = 119 ) , or placebo ( n = 115 ) for 24 weeks . The primary efficacy endpoint was the mean change in the Yale – Brown Obsessive – Compulsive Scale ( Y‑BOCS ) total score from baseline to week 12 . Secondary efficacy endpoints included remission ( defined as Y‑BOCS total score ≤10 ) , NIMH‑OCS , and CGI‑S and CGI‑I scores at weeks 12 and 24 . Tolerability was based on the incidence of adverse events , and on changes in vital signs ( blood pressure and pulse ) . Main outcome measures ; Results : Escitalopram 20 mg/day was superior to placebo on the primary and all secondary outcome endpoints , including remission . Escitalopram 10 mg/day and paroxetine 40 mg/day were also effective on the primary scale as well as some other outcome measures . In the escitalopram 20 mg/day group , the improvement in Y‑BOCS total score was significantly better than in the placebo group as early as week 6 . The most common AEs in the active treatment groups were nausea ( 19–27 % ) , headache ( 17–22 % ) , and fatigue ( 12–19 % ) . More paroxetine-treated patients withdrew due to adverse events than escitalopram- or placebo-treated patients . Conclusion : Given that escitalopram 20 mg/day was associated with an earlier onset , higher response and remission rates , improved functioning , and better tolerability than the reference drug , escitalopram deserves to be considered as one of the first-line agents in the pharmacotherapy of OCD for longer-term treatment periods BACKGROUND There have been very few controlled studies of antidepressants in dysthymia , particularly in sample s diagnosed reliably and with an adequate length of follow-up . In this investigation , we measured the long-term outcome in a large group of patients meeting DSM-III-R criteria for dysthymia . This study was design ed to investigate whether fluoxetine is effective in the treatment of dysthymia . METHOD This r and omised study including 140 patients , compared fluoxetine ( 91 patients ) and placebo ( 49 patients ) on a double-blind basis in two distinct phases : a short-term end-point ( 3 months with 20 mg/day fluoxetine ) and a medium-term end-point ( 6 months ) where the initial responders continued double-blind treatment unchanged and non-responders received an additional treatment of 20 mg/day fluoxetine . RESULTS After three months of treatment , response was seen more frequently in the fluoxetine group ( 42/72 ) than in the placebo group ( 14/39 , P < 0.0001 ) . Improved patients at 3 months were still improved at 6 months . Furthermore , 50 % of the nonresponders at 3 months improved and rated as responders at 6 months , after fluoxetine was increased to 40 mg daily . CONCLUSIONS This study showed the significant and persistent action of fluoxetine on dysthymia . The finding that 50 % of the non-responders at 3 months were improved at 6 months , after fluoxetine dosage was increased to 40 mg daily , argues in favour of treating dysthymic patients for at least 6 months , and with a higher dosage if the initial doses are ineffective The nocebo effect is the onset of untoward reactions following the administration of an indifferent substance . The oral challenge with alternative drugs plays a central role in the management of drug allergy and the use of inert substances is part of this procedure . We evaluated the occurrence and clinical characteristics of nocebo effect in patients with adverse drug reactions . Six hundred patients , seen in three different centres ( Genoa , Naples and Verona ) with a history of reactions to drugs , underwent a blind oral challenge with the administration of an indifferent substance and active drugs . The administration of an inert substance provoked untoward reactions in 54 patients ( 27 % ) in Verona , 60 ( 30 % ) in Naples and 48 ( 24 % ) in Genoa . The overall occurrence of nocebo effect was 27 % . The majority of reactions were subjective symptoms ( itching , malaise , headache etc ) , perceived as troublesome by all subjects . The occurrence was significantly higher in women than in men . Our data , collected in a large population , confirm that the nocebo effect occurs frequently in clinical practice . In managing adverse drug reactions through oral challenge the nocebo effect is m and atory to recognize false positive responses BACKGROUND A recent study conducted in triptan-naive migraine patients showed that tolerability was the second most important attribute of an acute treatment . However , the proportion of patients reporting side effects after any acute treatment may vary with regard to the method of assessment . OBJECTIVES To contrast two methods of assessing adverse events ( prompted and unprompted ) in those with headache using triptans . METHODS This study was conducted in two sites , a headache center in the United States , and a neurology office focusing on headache in Italy . We prospect ively surveyed 415 adults with headache , who had been using the same triptan for at least 3 months . Participants were asked about their headache and treatment history . Subjects then completed a st and ardized question naire , assessing adverse events in two different ways . First , subjects were asked if they had any adverse events when using the triptan . After returning the first part of the question naire , subjects received a second form , where 49 possible adverse events were listed . We contrasted and correlated both sets of answers . RESULTS Most patients ( U.S.=74.9 % , Italy=65.5 % ) reported no side effects in the unprompted question naire . However , most of them ( U.S.=62.9 % , Italy=54.1 % ) reported at least one side effect in the prompted question naire . Most patients that reported side effects in the unprompted question naire said they had just one adverse event , while most reported two or more side effects in the prompted question naire . Both in the unprompted and in the prompted question naires , most side effects were rated as mild or moderate . Interestingly , 31 ( 7.5 % ) subjects ( pooling data from both sites together ) grade d their adverse events as severe in the prompted question naire , but had not self-reported them . CONCLUSIONS ( 1 ) When assessing adverse events , the method of data collection may dramatically influence the results . ( 2 ) From those subjects who did not self-report adverse events after using a triptan , most of them will report positively if presented with a list of side effects Escitalopram , a selective serotonin reuptake inhibitor ( SSRI ) , was compared to placebo in a study of patients with major depressive disorder ( DSM-IV ) who had baseline Montgomery – Åsberg Depression Rating Scale ( MADRS ) total scores ≥22 and ≤40 . After a 1-week , single-blind placebo period , patients were r and omized to receive escitalopram 10 mg/day ( n = 191 ) or placebo ( n = 189 ) in an 8-week , double-blind period . The primary efficacy analysis of adjusted mean change in MADRS total score from baseline showed a statistically significantly larger effect for escitalopram than for placebo with a treatment difference at week 8 ( last observation carried forward , LOCF ) of 2.7 points ( SE 0.85;P = 0.002 ) . In further by-week efficacy analyses , the effect of escitalopram was consistently larger than that of placebo ( P < 0.05 ) beginning at week 1 ( Clinical Global Impression – Improvement score ) , week 2 ( MADRS score ) or week 3 ( Clinical Global Impression – Severity score ) . Escitalopram was very well tolerated with a low overall withdrawal rate similar to that for placebo . Nausea was the only adverse event reported significantly more in escitalopram-treated patients than in placebo-treated patients , although it was infrequent and transient . Escitalopram 10 mg/day had a statistically significantly better antidepressant effect than placebo as early as week 1 , and was safe and very well tolerated The efficacy of imipramine was investigated in 20 children ( ages 6 to 15 ) with separation anxiety disorder . Children were treated for a month with vigorous behavioral treatment . If they did not respond , they entered a double-blind , r and omized , 6-week trial of imipramine or placebo . Of 45 children accepted , 21 ( 47 % ) entered the trial . About half the children improved with either treatment , and no superiority for imipramine was obtained . There was no instance of clinical ly significant EKG changes . This small study failed to replicate previous findings of imipramine efficacy in a similar , but larger , clinical population BACKGROUND Generalized social anxiety disorder is an early onset , highly chronic , frequently disabling disorder with a lifetime prevalence of approximately 13 % . The goal of the current study was to evaluate the efficacy and tolerability of sertraline for the treatment of severe generalized social anxiety disorder in adults . METHOD After a 1-week single-blind placebo lead-in period , patients with DSM-IV generalized social phobia were r and omly assigned to 12 weeks of double-blind treatment with flexible doses of sertraline ( 50 - 200 mg/day ) or placebo . Primary efficacy outcomes were the mean change in the Liebowitz Social Anxiety Scale ( LSAS ) total score and the responder rate for the Clinical Global Impressions-Improvement scale ( CGI-I ) , defined as a CGI-I score < /= 2 . Data were collected in 2000 and 2001 . RESULTS 211 patients were r and omly assigned to sertraline ( intent-to-treat [ ITT ] sample , 205 ) , and 204 patients , to placebo ( ITT sample , 196 ) . At week 12 , sertraline produced a significantly greater reduction in LSAS total score compared with placebo ( mean last-observation-carried-forward [ LOCF ] change from baseline : -31.0 vs. -21.7 ; p = .001 ) and a greater proportion of responders ( CGI-I score < /= 2 : 55.6 % vs. 29 % among week 12 completers and 46.8 % vs. 25.5 % in the ITT-LOCF sample ; p < .001 for both comparisons ) . Sertraline was well tolerated , with 7.6 % of patients discontinuing due to adverse events versus 2.9 % of placebo-treated patients . CONCLUSION The results of the current study confirm the efficacy of sertraline in the treatment of severe social anxiety disorder 1 . Men and women may differ in their pharmacokinetic responses to tricyclic antidepressants ( TCAs ) , in a number of autonomic indices , and in various adrenergic receptor mediated responses . Emerging evidence also suggests that women may have a lower rate of serotonin synthesis in brain and a greater sensitivity to the depressant effects of tryptophan depletion , relative to men . However , sex-related differences in TCA-induced side-effects , including increases in heart rate ( HR ) , dry mouth , constipation , and difficulty urinating , has not been systematic ally investigated . 2 . The authors examined potential sex-related differences in the pattern of side-effects during treatment with nortriptyline ( NT ) , a TCA that is still widely used . Seventy-eight healthy out patients who met Research Diagnostic Criteria and DSM-III-R criteria for major depression participated in a double-blind , r and omized parallel trial of NT versus placebo . 3 . Each subject was acutely challenged with either placebo or 50 mg NT prior to and after a 6-week treatment with NT . NT doses were adjusted weekly to maintain therapeutic plasma levels . Patients were assessed at multiple time points to detect the presence of NT-induced side-effects . 4 . The initial , single ( 50 mg ) dose of NT significantly increased supine HR . Six-week treatment with NT was found to significantly increase supine and sitting HRs , irrespective of sex . In rechallenge with the single NT dose , there were no significant effects on HR . 5 . When sex-related differences were examined , HR increases were greater in men than women during weeks 4 through 6 of the NT treatment , although no sex-related differences were present in plasma NT levels or metabolites . In addition , there was a significant NT to placebo difference in self-rated dry mouth for women during all 6-weeks of treatment , whereas men showed a significant NT-placebo difference during weeks 3 and 5 . 6 . The results suggest the presence of sex-related differences in elevated supine HR response during the course of 6-week NT treatment . Depressed men may be more susceptible to NT-induced increases in supine HR than women BACKGROUND Social anxiety disorder is a debilitating , highly prevalent disorder in children and adolescents . If left untreated , it can interfere with emotional , social , and school functioning . OBJECTIVE To evaluate the efficacy and tolerability of paroxetine in children and adolescents with social anxiety disorder . DESIGN AND SETTING Multicenter , 16-week , r and omized , double-blind , placebo-controlled , flexible-dose , parallel-group , outpatient study . Patients A total of 322 children ( 8 - 11 years of age ) and adolescents ( 12 - 17 years of age ) with social anxiety disorder as their predominant psychiatric illness . Intervention Eligible patients were r and omized ( 1:1 ) to receive paroxetine ( 10 - 50 mg/d ) or placebo . RESULTS Four hundred twenty-five patients were screened , and 322 were r and omized to treatment . Of these , 319 were included in the intention-to-treat population ( paroxetine , n = 163 ; placebo , n = 156 ) . At the week 16 last observation carried forward end point , the odds of responding ( Clinical Global Impression-Improvement score of 1 or 2 ) were statistically significantly greater for paroxetine ( 77.6 % response [ 125/161 ] ) than for placebo ( 38.3 % response [ 59/154 ] ) ( adjusted odds ratio , 7.02 ; 95 % confidence interval , 4.07 to 12.11 ; P<.001 ) . The proportion of patients who were " very much " improved ( Clinical Global Impression-Improvement score of 1 ) was 47.8 % ( 77/161 ) for paroxetine compared with 14.9 % ( 23/154 ) for placebo . Adverse events occurring at an incidence of 5 % or greater for paroxetine and twice that for placebo were insomnia ( 14.1 % vs 5.8 % ) , decreased appetite ( 8.0 % vs 3.2 % ) , and vomiting ( 6.7 % vs 1.9 % ) . Withdrawals due to adverse events were infrequent ( 5.5 % [ 9/163 ] for paroxetine and 1.3 % [ 2/156 ] for placebo ) . CONCLUSION Paroxetine is an effective , generally well-tolerated treatment for pediatric social anxiety disorder As part of a study in which reduced rapid eye movement latency was used to predict treatment response , fluoxetine and placebo were compared in 89 out patients with major depression with ( n = 52 ) and without ( n = 37 ) DSM-III-R melancholia , to determine whether the presence or absence of melancholia predicted antidepressant and /or placebo response . Following a 2-week , single blind placebo lead-in , men and women were assigned by r and om allocation to double-blind fluoxetine , 20 mg/day , or placebo for 8 weeks . Fluoxetine was statistically significantly superior to placebo in patients with melancholia ( endpoint change in the Montgomery-åsberg Depression Rating Scale [ MADRS ] score , response rates and remission rates ) . A weekly analysis demonstrated statistical superiority of fluoxetine compared with placebo at week 3 and continuing for the remainder of the study . Fluoxetine was statistically significantly more likely to reduce suicidal ideation compared with placebo , using the MADRS item 10 ( suicidal ideation question ) CONTEXT Paroxetine controlled release ( CR ) is approved for the treatment of major depressive disorder ( MDD ) in the dosage range of 25 to 62.5 mg daily . However , lower daily doses ( 12.5 mg and 25 mg ) of this formulation have not been investigated in the treatment of MDD . If the 12.5-mg and 25-mg doses are found to be efficacious , these lower doses may well convey a superior tolerability profile for paroxetine CR in the treatment of MDD . OBJECTIVE To evaluate the antidepressant efficacy and tolerability profile of daily doses of paroxetine CR 12.5 mg and 25 mg versus placebo in the treatment of MDD . DESIGN AND SETTING R and omized , double-blind , placebo-controlled clinical trial conducted in 40 clinical investigation centers in the United States . PARTICIPANTS 447 adult ( > or = 18 years of age ) out patients who met DSM-IV criteria for MDD and with a baseline 17-item Hamilton Rating Scale for Depression ( HAM-D ) score of at least 20 comprised the intent-to-treat study population ( mean age = 38.8 years ; 58.4 % female ; 75.6 % white ) . INTERVENTION Eligible patients completing a 1-week single-blind placebo run-in period were r and omly assigned to receive once-a-day study medication ( paroxetine CR 12.5 mg [ N = 156 ] , paroxetine CR 25 mg [ N = 154 ] , or placebo [ N = 149 ] ) in an 8-week , double-blind , parallel cell comparison . MAIN OUTCOME MEASURES The primary efficacy measure was the change from baseline to study endpoint ( week 8) as measured by the HAM-D. Secondary efficacy measures included change from baseline to study endpoint as assessed by both the depressed mood item on the HAM-D and the Clinical Global Impressions ( CGI ) Severity of Illness scale ( CGI-S ) . The proportion of patients considered at study endpoint to be in response ( CGI-Improvement score of 1 or 2 ) or in remission ( HAM-D < or = 7 ) in the 3 treatment groups was also compared . Quality of life was assessed by the change from baseline in total score of the short form of the Quality of Life Enjoyment and Satisfaction Question naire ( Q-LES-Q ) . Safety observations were made by assessing the proportion of patients who had adverse experiences , including laboratory and electrocardiographic abnormalities , during the treatment period . RESULTS The primary efficacy analysis revealed that both the 12.5-mg and the 25-mg paroxetine CR treatment groups were associated with significant therapeutic effects ( change in HAM-D score ) from baseline to study endpoint ( LOCF : p = .038 , 95 % CI = -3.38 to -0.09 and p = .005 , 95 % CI = -4.06 to -0.74 , respectively ) . Results from the Wilcoxon rank sum test of the depressed mood item of the HAM-D ( p = .011 , 95 % CI = -0.57 to -0.07 ) demonstrated significant efficacy in the 25-mg treatment group but not in the 12.5-mg group . However , LOCF analysis of the CGI-S revealed significant therapeutic effects for both the 12.5-mg ( p = .018 , 95 % CI = -0.61 to -0.06 ) and 25-mg ( p < .001 , 95 % CI = -0.78 to -0.22 ) treatment groups . Significantly more patients in the 25-mg paroxetine CR-treated group than in the placebo-treated group met criteria for response ( CGI-Improvement score of 1 or 2 , p = .035 , OR = 1.68 , 95 % CI = 1.04 to 2.73 ) as well as for remission ( HAM-D score < /= 7 , p = .013 , OR = 1.96 , 95 % CI = 1.15 to 3.33 ) . Neither HAM-D remission analysis nor CGI responder analysis showed statistical separation from placebo for paroxetine CR 12.5-mg treatment . Quality of life improvements were statistically significant for the 25-mg treatment ( p = .041 , 95 % CI = 0.17 to 8.03 ) on the Q-LES-Q total score . Post hoc LOCF analyses of HAM-D sleep disturbance , psychic anxiety , and anxiety/somatization factors revealed significant improvements from baseline in the paroxetine CR 25-mg and 12.5-mg treatment groups . The types of adverse events reported in the 12.5-mg and 25-mg groups were similar to those reported with paroxetine CR at the customary 25-mg to 62.5-mg range ; however , the lower doses of paroxetine CR were associated with a relatively reduced incident rate of these adverse events and an overall improved tolerability compared with the incident rate and tolerability profile associated with the customary dose range of paroxetine CR ( 25 to 62.5 mg ) . CONCLUSION Paroxetine CR , at 12.5 mg/day and 25 mg/day , demonstrated significant antidepressant effects Rigorously design ed clinical trials have demonstrated the efficacy and safety of fluoxetine in adults with major depressive disorder and obsessive-compulsive disorder ( OCD ) but not in patients below 18 years old . This report describes a r and omized , double-blind , placebo-controlled , fixed-dose ( 20 mg qd ) trial of fluoxetine in 14 children and adolescents with OCD , ages 8 to 15 years old ; the study was 20 weeks long with crossover at 8 weeks . Obsessive-compulsive symptom severity was measured on the Children 's Yale-Brown Obsessive Compulsive Scale ( CY-BOCS ) and the Clinician 's Global Impression-Obsessive Compulsive Disorder scale ( CGI-OCD ) . The CY-BOCS total score decreased 44 % ( N = 7 , p = .003 ) after the initial 8 weeks of fluoxetine treatment , compared with a 27 % decrease ( N = 6 , p = .13 ) after placebo . During the initial 8 weeks , the magnitude of improvement for the fluoxetine group significantly exceeded that for the placebo group as measured by the CGI-OCD ( p = .01 ) but not by the CY-BOCS ( p = .17 ) . The most common drug side effects were generally well tolerated . The results suggest that fluoxetine is a generally safe and effective short-term treatment for children with OCD BACKGROUND The objective of this double-blind , placebo-controlled study was to investigate the efficacy and safety of paroxetine in out patients with posttraumatic stress disorder ( PTSD ) . METHOD Male and female out patients 18 years and older who met DSM-IV criteria for PTSD and had baseline scores of 50 or greater on the Clinician Administered PTSD Scale ( CAPS-2 ) were r and omly assigned to treatment with paroxetine ( 20 - 50 mg/day ) or placebo for 12 weeks . The primary efficacy variables were the change from baseline to the 12-week endpoint in the CAPS-2 total score and the proportion of responders on the Clinical Global Impressions-Global Improvement scale ( CGI-1 ) . Additional key outcome measures were the change from baseline in the reexperiencing , avoidance/ numbing , and hyperarousal scores of the CAPS-2 and in the total scores of the Treatment Outcome PTSD Scale and the patient-rated Davidson Trauma Scale and Sheehan Disability Scale ( SDS ) . Depressive symptoms were assessed with the Montgomery-Asberg Depression Rating Scale . The proportion of patients achieving response and remission was also determined . RESULTS 307 patients constituted the intent-to-treat population . At week 12 , compared with the placebo group ( N = 156 ) , the paroxetine group ( N = 151 ) showed significantly greater reduction of PTSD symptoms on both of the primary and all of the secondary outcome measures . Significantly greater improvement on the CAPS-2 total score was observed for paroxetine compared with placebo from week 4 ( p < .05 ) , and significantly greater proportions of paroxetine-treated patients achieved response ( p < .001 ) and remission ( p = .008 ) by week 12 . The improvement in PTSD symptoms was similar in male and female patients . Functional improvement at the study endpoint was significantly greater ( p < .05 ) in the paroxetine group in all 3 domains of the SDS ( work , social life , family life ) . Treatment with paroxetine was well tolerated , with the frequency and type of adverse events recorded for the paroxetine group corresponding to the known safety profile of this medication . CONCLUSION Paroxetine in doses of 20 to 50 mg once daily is effective as a treatment for chronic PTSD . Improvement is obtained for all 3 symptom clusters ( reexperiencing , avoidance/numbing , hyperarousal ) and is associated with significant reduction in disability after 12 weeks of treatment OBJECTIVE Escitalopram is a selective serotonin reuptake inhibitor antidepressant indicated for use in adults . This trial examined the efficacy and safety of escitalopram in pediatric depression . METHOD Patients ( 6 - 17 years old ) with major depressive disorder were r and omized to receive 8 weeks of double-blind flexibly dosed treatment with escitalopram ( 10 - 20 mg/day ; n = 131 ) or placebo ( n = 133 ) . R and omization was not stratified by age . The primary efficacy measure was the mean change from baseline to endpoint in Children 's Depression Rating Scale-Revised ( CDRS-R ) scores , using the last observation carried forward approach . RESULTS A total of 82 % of patients completed treatment . Escitalopram did not significantly improve CDRS-R scores compared to placebo at endpoint ( least squares mean difference = -1.7 , p = .31 ; last observation carried forward ) . In a post hoc analysis of adolescent ( ages 12 - 17 years ) completers , escitalopram significantly improved CDRS-R scores compared with placebo ( least squares mean difference = -4.6 , p = .047 ) . Headache and abdominal pain were the only adverse events in > 10 % of patients in the escitalopram group . Discontinuation rates caused by adverse events were 1.5 % for both groups . Potential suicide-related events were observed in one escitalopram- and two placebo-treated patients . There were no completed suicides . CONCLUSIONS Although there were no significant differences between escitalopram and placebo in the total population , the data suggest that escitalopram may have beneficial effects in adolescent patients . Escitalopram appeared to be well tolerated OBJECTIVE The purpose of this study was to determine the efficacy of fluvoxamine for the treatment of social phobia ( social anxiety disorder ) . METHOD In a 12-week multicenter , double-blind , r and omized , placebo-controlled trial , 92 patients with social phobia were treated with the selective serotonin reuptake inhibitor fluvoxamine ; 91.3 % of the patients had the generalized subtype of the disorder . The primary criterion for response was a rating of " much improved " or " very much improved " on the Clinical Global Impression of Improvement scale . Secondary response criteria were changes on three specialized rating scales for social phobia symptoms : the Brief Social Phobia Scale , the Social Phobia Inventory , and the Liebowitz Social Anxiety Scale . Psychosocial impairment was assessed in three domains ( disruption of work , social life , and home/family life ) by using the Sheehan Disability Scale . RESULTS The mean daily dose of fluvoxamine was 202 mg ( SD = 86 ) . At study end or with the last observation carried forward , within the evaluable subjects ( N = 86 ) there was a significantly higher proportion of responders in the fluvoxamine group ( 42.9 % , N = 18 ) than in the placebo group ( 22.7 % , N = 10 ) . Similarly , fluvoxamine was superior to placebo on all social phobia rating scales at week 8 and beyond . Fluvoxamine also result ed in significantly greater decreases in measures of psychosocial disability than did placebo . Overall , fluvoxamine was well tolerated and safe . CONCLUSIONS These findings indicate that fluvoxamine is efficacious in the pharmacologic management of serious forms of social phobia Effects of double-blind treatment of chronic posttraumatic stress disorder ( PTSD ) with 2 SSRIs and placebo on emotional symptoms and autonomic reactivity were assessed prospect ively . PTSD subjects received citalopram ( n=25 ) , sertraline ( n=23 ) , or placebo ( n=10 ) for 10 weeks , with psychophysiologic assessment s performed before and after treatment . Intent-to-treat analysis showed that all treatment groups improved significantly in total symptoms of PTSD ( as measured by the Clinician Administered PTSD Scale ) , all 3 PTSD symptom clusters , and sleep time . However , subtle differences in improvements in PTSD symptom clusters , physiologic reactivity , and reported adverse events were identified . Citalopram treated subjects significantly lowered systolic and diastolic blood pressures , while sertraline and placebo treated patients significantly lowered only systolic blood pressure reactivity to individualized trauma scripts . The sertraline group showed significantly more improvement in avoidance/numbing symptoms than both other groups . Considering side effects , subjects on sertraline reported more gastrointestinal problems , with early terminators having more insomnia . Early terminators on citalopram reported more fatigue and appetite changes than other treatment groups , with completers reporting more sexual dysfunction . Results support a class effect of SSRIs in treating PTSD symptoms , but suggest a possible differential effect of drugs on symptom clusters , physiologic parameters , and side effects that may have clinical relevance . Implication s of symptom reduction noted in the smaller placebo group are discussed relative to recent concerns about increasing placebo response in clinical trials BACKGROUND Paroxetine is a potent and selective serotonin reuptake inhibitor ( SSRI ) . The present study assessed the efficacy and tolerability of paroxetine against placebo in depressed out patients . METHOD A double-blind , parallel-group study was undertaken in four st and -alone centers . Patients aged 18 - 65 years , meeting DSM-III criteria for major depression , and having a Hamilton Rating Scale for Depression ( HAM-D ) score > or = 18 on the first 17 items of the HAM-D-21 were r and omized to paroxetine or placebo for 6 weeks of treatment . Efficacy outcome variables included the HAM-D , the Montgomery-Asberg Depression Rating Scale , the Clinical Global Impressions Scale ( CGI ) , and the Covi Anxiety Scale . Tolerability was assessed by asking a non-leading question . Routine laboratory safety and vital sign data from all four centers were pooled . The primary analysis used the intention-to-treat sample and for efficacy variables the last-observation-carried-forward data set was employed . Statistical methods included one-way analysis of variance for parametric and Fisher exact test for nonparametric variables . RESULTS Significant differences ( p < or = .05 ) were found between paroxetine and placebo on the HAM-D and CGI by Week 2 and on all efficacy outcome variables by Week 4 . Improvement on the HAM-D sleep factor occurred 2 weeks prior to that seen on the retardation factor . Similar results were obtained when an adequate treatment group ( therapy for > or = 28 days ) was considered . A full clinical response ( CGI-severity of illness score 1 or 2 ) was seen in over 40 % of subjects . Adverse events were more common for paroxetine compared with placebo ( p < or = .01 ) . Somnolence was twice more common than nervousness . Dropout due to adverse events was similar between therapies . Paroxetine had no clinical ly significant effect on laboratory safety data or vital signs . CONCLUSION Paroxetine was an effective , well tolerated , and safe antidepressant . Side effects were typical of the SSRI class of drugs . Symptoms indicative of a nonalerting profile were more common than those associated with alerting effects CONTEXT The serotonin reuptake inhibitors are the treatment of choice for patients with obsessive-compulsive disorder ; however , empirical support for this assertion has been weaker for children and adolescents than for adults . OBJECTIVE To evaluate the safety and efficacy of the selective serotonin reuptake inhibitor sertraline hydrochloride in children and adolescents with obsessive-compulsive disorder . DESIGN R and omized , double-blind , placebo-controlled trial . PATIENTS One hundred eighty-seven patients : 107 children aged 6 to 12 years and 80 adolescents aged 13 to 17 years r and omized to receive either sertraline ( 53 children , 39 adolescents ) or placebo ( 54 children , 41 adolescents ) . SETTING Twelve US academic and community clinics with experience conducting r and omized controlled trials . INTERVENTION Sertraline hydrochloride was titrated to a maximum of 200 mg/d during the first 4 weeks of double-blind therapy , after which patients continued to receive this dosage of medication for 8 more weeks . Control patients received placebo . MAIN OUTCOME MEASURES The Children 's Yale-Brown Obsessive Compulsive Scale ( CY-BOCS ) , the National Institute of Mental Health Global Obsessive Compulsive Scale ( NIMH GOCS ) , and the NIMH Clinical Global Impressions of Severity of Illness ( CGI-S ) and Improvement ( CGI-I ) rating scales . RESULTS In intent-to-treat analyses , patients treated with sertraline showed significantly greater improvement than did placebo-treated patients on the CY-BOCS ( adjusted mean , -6.8vs -3.4 , respectively ; P=.005 ) , the NIMH GOCS ( -2.2 vs -1.3 , respectively ; P=.02 ) , and the CGI-I ( 2.7 vs 3.3 , respectively ; P=.002 ) scales . Significant differences in efficacy between sertraline and placebo emerged at week 3 and persisted for the duration of the study . Based on CGI-I ratings at end point , 42 % of patients receiving sertraline and 26 % of patients receiving placebo were very much or much improved . Neither age nor sex predicted response to treatment . The incidence of insomnia , nausea , agitation , and tremor were significantly greater in patients receiving sertraline ; 12 ( 13 % ) of 92 sertraline-treated patients and 3 ( 3.2 % ) of 95 placebo-treated patients discontinued prematurely because of adverse medical events ( P=.02 ) . No clinical ly meaningful abnormalities were apparent on vital sign determinations , laboratory findings , or electrocardiographic measurements . CONCLUSION Sertraline appears to be a safe and effective short-term treatment for children and adolescents with obsessive-compulsive disorder OBJECTIVE To assess the efficacy and tolerability of paroxetine in pediatric major depressive disorder . METHOD Subjects 7 to 17 years old with major depressive disorder received paroxetine ( 10 - 50 mg/day ) or placebo for 8 weeks from 2000 to 2001 . The primary efficacy measure was change from baseline in the Children 's Depression Rating Scale-Revised total score at week 8 last observation carried forward ) . Safety was primarily assessed by spontaneous reporting of adverse events . RESULTS A total of 206 patients ( intent to treat ) were r and omized to paroxetine ( n = 104 ) or placebo ( n = 102 ) . Week 8 Children 's Depression Rating Scale-Revised total score adjusted mean changes from baseline for patients receiving paroxetine and placebo were -22.58 ( SE 1.47 ) and -23.38 points ( SE 1.60 ) , respectively ( 0.80 , 95 % confidence interval -3.09 to 4.69 , p = 0.684 ) . Increased cough ( 5.9 % versus 2.9 % ) , dyspepsia ( 5.9 % versus 2.9 % ) , vomiting ( 5.9 % versus 2.0 % ) , and dizziness ( 5.0 % versus 1.0 % ) occurred in > or=5 % of the paroxetine group and at least twice that of the placebo group . Six of 104 ( 5.8 % ) paroxetine patients reported serious adverse events compared to 1 placebo patient ( 1.0 % ) . The incidence of adverse events of suicidal behavior and /or ideation while taking study medication ( excluding taper ) was 1.92 % ( 2/104 ) for paroxetine versus 0.98 % ( 1/102 ) for placebo . CONCLUSIONS Paroxetine was not shown to be more efficacious than placebo for treating pediatric major depressive disorder A double-blind , placebo-controlled trial was undertaken to compare the effects of imipramine and clomipramine in the treatment of panic disorder with or without agoraphobia . The number of dropouts in the placebo-treated group was 7 ; in the imipramine-treated group , 4 ; and in the clomipramine treated group , 0 . Ten subjects fulfilled the 12 weeks of treatment in the placebo group , 25 in the imipramine group , and 22 in the clomipramine group . To minimize dropouts because of side effects , a flexible dose regimen with a careful escalation of doses was applied . The maximal dose allowed was 250 mg/day . The mean ( + /- SEM ) daily doses reached were 124 + /- 9 mg ( range , 50 - 250 mg ) of imipramine and 109 + /- 8 mg ( range , 25 - 200 mg ) of clomipramine . At the end of the trial , the number of panic attacks as well as the anxiety between attacks ( measured using the Hamilton Rating Scale for Anxiety ) were markedly reduced in patients treated with either of the two antidepressant drugs , but only slightly decreased in patients on placebo . With respect to all major outcome parameters , i.e. , full panic attacks , total number of anxiety attacks ( full plus mild ) , and anxiety between attacks , the effect of clomipramine was clearly and significantly superior to that of imipramine ( p less than 0.001 , p less than 0.002 , and p less than 0.002 , respectively ) . Moderate intake of diazepam was allowed ; in the clomipramine group ( p less than 0.006 ) , but neither in the imipramine group nor in the placebo group , a significant decrement in diazepam intake was observed during the course of the trial . The finding that clomipramine may have a higher potency and /or efficacy than imipramine in the treatment of panic disorder supports the concept that the antipanic effect of antidepressant drugs is due to the influence of these compounds on serotonergic rather than noradrenergic neurotransmission OBJECTIVE This study assesses the efficacy and tolerability of fluoxetine in the acute treatment of child and adolescent obsessive-compulsive disorder ( OCD ) during a 13-week , double-blind , placebo-controlled study . METHOD Eligible patients aged 7 to 17 ( N = 103 ) were r and omized at a ratio of 2:1 to receive either fluoxetine or placebo . Dosing was initiated at 10 mg daily for 2 weeks , then increased to 20 mg daily . After 4 weeks of treatment , and again after 7 weeks of treatment , non-responders could have their dosage increased by 20 mg daily , for a maximum possible dosage of 60 mg daily . Primary measure of efficacy was improvement in OCD symptoms as measured by the Children 's Yale-Brown Obsessive Compulsive Scale ( CY-BOCS ) . All analyses were intent-to-treat . RESULTS Fluoxetine was associated with significantly greater improvement in OCD as assessed by the CY-BOCS ( p = .026 ) and other measures than was placebo . Fluoxetine was well tolerated and had a rate of discontinuation for adverse events similar to that of placebo ( p = 1.00 ) . CONCLUSIONS Fluoxetine 20 to 60 mg daily was effective and well tolerated for treatment of OCD in this pediatric population OBJECTIVE To determine the efficacy and tolerability of the tricyclic antidepressant desipramine ( DMI ) in the treatment of DSM-III-R-diagnosed major depressive disorder in adolescents . METHOD Sixty adolescents ( 42 female , 18 male ; aged 15 to 19 years ) diagnosed with major depressive disorder using clinical interview and Schedule for Affective Disorders and Schizophrenia for School-Age Children were r and omized to receive either DMI ( 200 mg daily in divided doses ) or placebo for six consecutive weeks following a 1-week placebo period . Treatment outcome was determined using the Hamilton Depression Rating Scale and the Beck Depression Inventory . Tolerability was determined using a symptom side effects scale . In addition , a variety of laboratory and cardiovascular monitoring was performed . RESULTS No significant differences in treatment outcome between DMI- and placebo-treated groups were determined . Neither DMI , nor its metabolite 2-hydroxy-DMI , nor their ratio , was positively correlated to treatment outcome . The DMI group endorsed more side effects but there were no significant between-group differences in any laboratory , electrocardiographic , or other cardiovascular parameters apart from heart rate , which was increased in the DMI-treated group ( p = .03 ) . CONCLUSIONS Given the findings of this study and our review of previously published reports of tricyclic antidepressant treatment in this population , the routine use of short-term ( 6 weeks ) DMI in the treatment of adolescent depression is not supported by the data on h and . Further investigations into what constitutes optimal psychopharmacological treatment of adolescent depression are warranted CONTEXT Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy ( CBT ) or a selective serotonin reuptake inhibitor ( SSRI ) . However , little is known about their relative or combined effectiveness . OBJECTIVE To evaluate the effectiveness of 4 treatments among adolescents with major depressive disorder . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial of a volunteer sample of 439 patients between the ages of 12 to 17 years with a primary Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , diagnosis of major depressive disorder . The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003 . INTERVENTIONS Twelve weeks of ( 1 ) fluoxetine alone ( 10 to 40 mg/d ) , ( 2 ) CBT alone , ( 3 ) CBT with fluoxetine ( 10 to 40 mg/d ) , or ( 4 ) placebo ( equivalent to 10 to 40 mg/d ) . Placebo and fluoxetine alone were administered double-blind ; CBT alone and CBT with fluoxetine were administered unblinded . MAIN OUTCOME MEASURES Children 's Depression Rating Scale-Revised total score and , for responder analysis , a ( dichotomized ) Clinical Global Impressions improvement score . RESULTS Compared with placebo , the combination of fluoxetine with CBT was statistically significant ( P = .001 ) on the Children 's Depression Rating Scale-Revised . Compared with fluoxetine alone ( P = .02 ) and CBT alone ( P = .01 ) , treatment of fluoxetine with CBT was superior . Fluoxetine alone is a superior treatment to CBT alone ( P = .01 ) . Rates of response for fluoxetine with CBT were 71.0 % ( 95 % confidence interval [ CI ] , 62%-80 % ) ; fluoxetine alone , 60.6 % ( 95 % CI , 51%-70 % ) ; CBT alone , 43.2 % ( 95 % CI , 34%-52 % ) ; and placebo , 34.8 % ( 95 % CI , 26%-44 % ) . On the Clinical Global Impressions improvement responder analysis , the 2 fluoxetine-containing conditions were statistically superior to CBT and to placebo . Clinical ly significant suicidal thinking , which was present in 29 % of the sample at baseline , improved significantly in all 4 treatment groups . Fluoxetine with CBT showed the greatest reduction ( P = .02 ) . Seven ( 1.6 % ) of 439 patients attempted suicide ; there were no completed suicides . CONCLUSION The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder Fluvoxamine CR has been reported effective in the short-term ( 12-wk ) treatment of generalized social anxiety disorder ( social phobia ) . Social anxiety disorder ( SAD ) is , however , a chronic disorder thought to require maintenance treatment . We report on data from the extension phase of a short-term study , in order to explore the efficacy and safety profile of fluvoxamine CR ( 100 - 300 mg/d ) in the longer-term treatment of this disorder . Adult out patients with generalized social anxiety disorder ( GSAD ) at 35 centres in Europe , South Africa , and USA were included in an acute phase study ( 12 wk ) . Subjects who demonstrated at least minimal improvement by endpoint ( n=112 ) , were offered participation in an extension phase , in which medication was continued for a further 12 wk under double-blind conditions . Efficacy was assessed using the Liebowitz Social Anxiety Disorder Scale ( LSAS ) , the Clinical Global Impression Global Improvement score ( CGI-I ) , the Clinical Global Impressions Severity of Illness score ( CGI-S ) , and the Sheehan Disability Scale ( SDS ) . Safety and tolerability assessment s were also performed at regular intervals . Subjects treated with fluvoxamine CR had a numerically greater decrease in LSAS total scores than subjects treated with placebo at endpoint . Analysis of data from baseline ( day 1 ) to endpoint ( last observation carried forward ) demonstrated that this difference tended towards significance , while severity of illness on the CGI-S and disability on the SDS were significantly lower in the fluvoxamine CR group than in the placebo group . The same trends were observed when only data from weeks 12 - 24 were included in the analysis ; although the magnitude of changes was smaller in the extension phase than in the acute phase , fluvoxamine CR-treated subjects continued to show improvement compared to placebo-treated subjects . Most treatment-emergent signs and symptoms ( TESS ) were mild to moderate in severity . No unexpected abnormalities were reported on vital signs , electrocardiagrams , or laboratory investigations . These data support the long-term efficacy , safety , and tolerability of fluvoxamine CR in the treatment of GSAD . Given the prevalence , persistence , and disability associated with GSAD , and the relative paucity of long-term treatment studies of SAD , the current data set provides empirical support for the current clinical consensus that pharmacotherapy of this disorder should be continued beyond the acute phase OBJECTIVE This study assessed the efficacy of two fixed doses of paroxetine in the treatment of generalized anxiety disorder . METHOD Out patients ( N=566 ) with generalized anxiety disorder and no other axis I disorder were eligible if they scored > /=20 on the Hamilton Rating Scale for Anxiety ( with a score of 2 or higher on the anxious mood and tension items ) . Following a 1-week placebo run-in phase , patients were r and omly assigned to 8 weeks of treatment with paroxetine , 20 or 40 mg/day , or placebo . The primary outcome measure was the change from baseline in total score on the Hamilton anxiety scale . Response was defined as a rating of " very much improved " or " much improved " on the Clinical Global Impression global improvement measure ; remission was defined as a Hamilton anxiety scale score < /=7 . Change in functional impairment was measured with the Sheehan Disability Scale . RESULTS At 8 weeks , reductions in total score on the Hamilton anxiety scale were significantly greater for both paroxetine groups . Response was achieved by 62 % and 68 % of the patients receiving 20 and 40 mg of paroxetine , respectively , compared with a 46 % response rate in the placebo group . Remission was achieved by 30 % and 36 % of patients in the 20- and 40-mg paroxetine groups , respectively , compared with 20 % given placebo . For all three domains of the Sheehan Disability Scale , significantly greater improvement was seen with paroxetine than placebo . Both doses of paroxetine were well tolerated . CONCLUSIONS This study demonstrates that paroxetine is an efficacious and well-tolerated treatment for generalized anxiety disorder CONTEXT Few r and omized controlled trials have evaluated the efficacy of treatments for major depression in patients with coronary artery disease ( CAD ) . None have simultaneously evaluated an antidepressant and short-term psychotherapy . OBJECTIVE To document the short-term efficacy of a selective serotonin reuptake inhibitor ( citalopram ) and interpersonal psychotherapy ( IPT ) in reducing depressive symptoms in patients with CAD and major depression . DESIGN , SETTING , AND PARTICIPANTS The Canadian Cardiac R and omized Evaluation of Antidepressant and Psychotherapy Efficacy , a r and omized , controlled , 12-week , parallel-group , 2 x 2 factorial trial conducted May 1 , 2002 , to March 20 , 2006 , among 284 patients with CAD from 9 Canadian academic centers . All patients met Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition criteria for diagnosis of major depression of 4 weeks ' duration or longer and had baseline 24-item Hamilton Depression Rating Scale ( HAM-D ) scores of 20 or higher . INTERVENTIONS Participants underwent 2 separate r and omizations : ( 1 ) to receive 12 weekly sessions of IPT plus clinical management ( n = 142 ) or clinical management only ( n = 142 ) and ( 2 ) to receive 12 weeks of citalopram , 20 to 40 mg/d ( n = 142 ) , or matching placebo ( n = 142 ) . MAIN OUTCOME MEASURES The primary outcome measure was change between baseline and 12 weeks on the 24-item HAM-D , administered blindly during central ized telephone interviews ( tested at alpha = .033 ) ; the secondary outcome measure was self-reported Beck Depression Inventory II ( BDI-II ) score ( tested at alpha = .017 ) . RESULTS Citalopram was superior to placebo in reducing 12-week HAM-D scores ( mean difference , 3.3 points ; 96.7 % confidence interval [ CI ] , 0.80 - 5.85 ; P = .005 ) , with a small to medium effect size of 0.33 . Mean HAM-D response ( 52.8 % vs 40.1 % ; P = .03 ) and remission rates ( 35.9 % vs 22.5 % ; P = .01 ) and the reduction in BDI-II scores ( difference , 3.6 points ; 98.3 % CI , 0.58 - 6.64 ; P = .005 ; effect size = 0.33 ) also favored citalopram . There was no evidence of a benefit of IPT over clinical management , with the mean HAM-D difference favoring clinical management ( -2.26 points ; 96.7 % CI , -4.78 to 0.27 ; P = .06 ; effect size , 0.23 ) . The difference on the BDI-II did not favor clinical management ( 1.13 points ; 98.3 % CI , -1.90 to 4.16 ; P = .37 ; effect size = 0.11 ) . CONCLUSIONS This trial documents the efficacy of citalopram administered in conjunction with weekly clinical management for major depression among patients with CAD and found no evidence of added value of IPT over clinical management . Based on these results and those of previous trials , citalopram or sertraline plus clinical management should be considered as a first-step treatment for patients with CAD and major depression . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N15858091 CONTEXT The efficacy , safety , and tolerability of selective serotonin reuptake inhibitors ( SSRIs ) in the treatment of adults with major depressive disorder ( MDD ) are well established . Comparatively few data are available on the effects of SSRIs in depressed children and adolescents . OBJECTIVE To evaluate the efficacy and safety of sertraline compared with placebo in treatment of pediatric patients with MDD . DESIGN AND SETTING Two multicenter r and omized , double-blind , placebo-controlled trials were conducted at 53 hospital , general practice , and academic centers in the United States , India , Canada , Costa Rica , and Mexico between December 1999 and May 2001 and were pooled a priori . PARTICIPANTS Three hundred seventy-six children and adolescents aged 6 to 17 years with Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition-defined MDD of at least moderate severity . INTERVENTION Patients were r and omly assigned to receive a flexible dosage ( 50 - 200 mg/d ) of sertraline ( n = 189 ) or matching placebo tablets ( n = 187 ) for 10 weeks . MAIN OUTCOME MEASURES Change from baseline in the Children 's Depression Rating Scale-Revised ( CDRS-R ) Best Description of Child total score and reported adverse events . RESULTS Sertraline-treated patients experienced statistically significantly greater improvement than placebo patients on the CDRS-R total score ( mean change at week 10 , -30.24 vs -25.83 , respectively ; P = .001 ; overall mean change , -22.84 vs -20.19 , respectively ; P = .007 ) . Based on a 40 % decrease in the adjusted CDRS-R total score at study end point , 69 % of sertraline-treated patients compared with 59 % of placebo patients were considered responders ( P = .05 ) . Sertraline treatment was generally well tolerated . Seventeen sertraline-treated patients ( 9 % ) and 5 placebo patients ( 3 % ) prematurely discontinued the study because of adverse events . Adverse events that occurred in at least 5 % of sertraline-treated patients and with an incidence of at least twice that in placebo patients included diarrhea , vomiting , anorexia , and agitation . CONCLUSION The results of this pooled analysis demonstrate that sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD Objective Depression and hostility are significant risk factors for mortality and morbidity after myocardial infa rct ion ( MI ) . Much research is still needed to identify effective ways to reduce emotional distress in patients with cardiovascular disease . This double-blind , placebo-controlled study investigated the efficacy and safety of the antidepressant fluoxetine in patients with depression after their first MI . Methods Fifty-four patients with major depression after MI were r and omly assigned to receive a flexible-dose regimen of fluoxetine or placebo for the first 9 weeks of a double-blind , placebo-controlled trial . Patients without serious adverse effects who wished to continue participating in the study were given fluoxetine or placebo for an additional 16 weeks . To evaluate the efficacy of fluoxetine , the 17-item Hamilton Depression Rating Scale ( HAMD-17 ) and the Hostility Scale of the 90-item Symptom Check List ( SCL-90 ) were used as primary measures of outcome . To evaluate the safety of fluoxetine , cardiac function was measured before and after treatment with echocardiography and electrocardiography . Results The a priori difference in antidepressive efficacy ( 4-point difference in HAMD-17 scores between the fluoxetine and placebo groups ) was not met . However , the response rate among patients receiving fluoxetine was significantly greater than that among patients receiving placebo at week 25 ( 48 vs. 26 % , p = .05 ) . Among patients with mild depression ( HAMD-17 score ≤21 ) , HAMD-17 scores were significantly different ( p < .05 ) between the fluoxetine and placebo groups at weeks 9 ( by 5.4 points ) and 25 ( by 5.8 points ) . Also , hostility scores at week 25 were significantly reduced among patients receiving fluoxetine ( p = .02 ) . Analysis of electrocardiographic and echocardiographic parameters revealed no decrease in cardiac function as a result of treatment with fluoxetine . Conclusions : Although the overall difference between the fluoxetine and placebo groups was not significant , there was a trend favoring fluoxetine in this relatively small sample . The response rate in the group receiving fluoxetine was comparable with that observed in other studies of patients with cardiovascular disease . In addition , fluoxetine seemed to be particularly effective in patients with mild depression and was associated with a statistically significant reduction in hostility . The results of this study suggest that fluoxetine can be safely used to treat patients with post-MI depression beginning 3 months after the event OBJECTIVES To determine the response of physically ill elderly depressed patients to treatment . DESIGN Acute geriatric medical in patients with depression , r and omly assigned to an 8-week double-blind placebo-controlled trial of fluoxetine . MAIN OUTCOME MEASURE Response rate as defined by the 17-item Hamilton Depression Rating Scale . RESULTS Eighty-two patients entered the trial ; 62 patients ( all those who had completed at least 3 weeks of treatment ) were included in the efficacy analysis . Forty-two completed the full 8 weeks ( 21 in each group ) with response rates of 67 % in the fluoxetine group and 38 % in the placebo group . No significant difference was found between the responses of the two groups ( p = 0.12 ) . There was a trend for results in the fluoxetine group to continue to improve with time . On secondary analysis those patients with serious physical illness who completed 5 or more weeks ( N = 37 ) showed a significant improvement in mood if treated with fluoxetine ( p = 0.02 ) . CONCLUSIONS The main benefit of antidepressants is to approximately double the chances of recovery . This trial showed the response rate of the fluoxetine treated group was increased by a factor of 1.8 over the placebo group in an 8-week period . The presence of physical illness , often severe and /or multiple , did not reduce the effectiveness of the medication , which was well tolerated overall . Those with serious physical disease responded significantly better to drug treatment ; this will require further work . Psychological support was also considered to be important OBJECTIVE We investigated the effects of pain anxiety and a placebo/nocebo/neutral intervention on ice water-induced pain . DESIGN We divided 72 volunteers into high- and low-anxiety groups before r and omly assigning them to experimental and control subgroups . METHOD Participants completed preimmersion tests of pain anxiety , pain worry , and mood . We scored first immersion pain behavior , experience , and intensity . Each subgroup then received an instruction design ed to elicit a positive ( placebo ) , negative ( nocebo ) , or neutral response . After repeating the pain worry test , we gathered second immersion pain scores , and participants repeated the mood test , completed the treatment credibility measure , and were debriefed . OUTCOME MEASURES We used the Pain Anxiety Symptom Scale ; self-rating Likert-type scales for pain worry , pain intensity , and pain-coping ; the Multiple Affect Adjective Checklist ( mood ) ; timed measurements for pain threshold and pain tolerance ; and a treatment credibility scale . RESULTS Pain anxiety and the placebo interventions significantly altered participants ' pain scores , with best-to-worse scores reported by the low pain-anxiety/placebo , high anxiety/placebo , low anxiety/neutral , low anxiety/nocebo , high anxiety neutral , and high anxiety/nocebo groups . The high pain-anxiety group demonstrated the greatest response to the placebo/nocebo intervention in the expected directions in pain , worry , and anxious mood scores and in decreased self-confidence in managing pain ( this was also negatively affected by the nocebo in each pain-anxiety group ) . CONCLUSION This study demonstrates that the interaction of the personality variable of pain anxiety with the placebo/nocebo response has an impact on pain , worry , and mood Clomipramine was significantly superior to placebo in a 10-week double-blind , placebo-controlled trial in 27 out patients who met DSM-III-R criteria for obsessive-compulsive disorder BACKGROUND Although serotonin reuptake inhibitors are effective in panic disorder , questions concerning whether doses associated with antidepressant efficacy are also effective for panic disorder remain . AIMS To assess the efficacy of the usual antidepressant dose of fluoxetine in treating full panic attacks . METHOD Patients with panic disorder were r and omised to placebo or to fluoxetine initiated at 10 mg daily for 1 week and then increased to 20 mg daily . The trial lasted 12 weeks , but after 6 weeks patients who had failed to achieve a satisfactory response were eligible for dose escalation to a maximum of 60 mg of fluoxetine daily . RESULTS Fluoxetine was associated with a statistically significantly greater proportion of panic-free patients compared with placebo after 6 weeks and at end-point . CONCLUSIONS Fluoxetine at a dose of 20 mg daily is safe and efficacious in reducing symptoms of panic disorder . Patients who fail to obtain a satisfactory response at 20 mg daily may benefit from further dose increases Previous studies have shown selective and non-selective monoamine oxidase inhibitors ( MAOIs ) to be effective in the treatment of social phobia . In this study we investigated the efficacy of selective serotonin reuptake inhibitors ( SSRIs ) in social phobia . Thirty patients with social phobia ( DSM-IIIR ) were treated with the SSRI fluvoxamine ( 150 mg daily ) using a 12-week double-blind placebo controlled design . A substantial improvement was observed in seven ( 46 % ) patients on fluvoxamine and in one ( 7 % ) on placebo . Statistically significant effects were seen on measures of social anxiety and general ( or anticipatory ) anxiety in patients treated with fluvoxamine compared with placebo . The level of phobic avoidance decreased also but the difference at endpoint between fluvoxamine and placebo failed to reach statistical significance . It is concluded that treatment with the SSRI fluvoxamine has beneficial effects in patients suffering from social phobia , suggesting that serotonergic mechanisms might be implicated in social anxiety OBJECTIVE The authors evaluated the efficacy , safety , and tolerability of sertraline , a selective serotonin reuptake inhibitor , in the treatment of generalized social phobia . METHOD Adult out patients with generalized social phobia ( N=204 ) from 10 Canadian centers were r and omly assigned to receive sertraline or placebo in a 2:1 ratio for a 20-week double-blind study following a 1-week , single-blind , placebo run-in . The initial dose of sertraline was 50 mg/day with increases of 50 mg/day every 3 weeks permitted after the fourth week of treatment ( dosing was flexible up to a maximum of 200 mg/day ) . Primary efficacy assessment s were the percentage of patients rated much or very much improved on the Clinical Global Impression ( CGI ) improvement item and the mean changes from baseline to study endpoint in total score on the social phobia subscale of the Marks Fear Question naire and total score on the Brief Social Phobia Scale . RESULTS In intent-to-treat endpoint analyses of 203 of the patients , significantly more of the 134 patients given sertraline ( N=71 [ 53 % ] ) than of the 69 patients receiving placebo ( N=20 [ 29 % ] ) were considered responders according to their CGI improvement scores at the end of treatment . The mean reductions in the social phobia subscale of the Marks Fear Question naire and in the total score on the Brief Social Phobia Scale were 32.6 % and 34.3 % in the sertraline group and 10.8 % and 18.6 % in the placebo group , respectively . Analysis of covariance showed superiority of sertraline over placebo on all primary and secondary efficacy measures . Sertraline was well tolerated : 103 ( 76 % ) of the 135 sertraline-treated patients and 54 ( 78 % ) of the 69 placebo-treated patients completed the study . CONCLUSIONS Sertraline is an effective treatment for patients with generalized social phobia A placebo‐controlled , r and omized , double‐blind study was carried out in out patients suffering from major unipolar depressive disorder to assess the efficacy and tolerability of paroxetine in the treatment of depression . The study lasted for six weeks . After a placebo washout period of 4 to 14 days patients took 20 mg of paroxetine or matched placebo as a morning dose for one week ; thereafter the dose of paroxetine could be titrated between 10 and SOmg/day . Patients were evaluated at baseline , weekly during the first four weeks of the study , and at the end of sixweeks ; patients who entered a six‐week extensionphasewere evaluated at 9 and 12 weeks . Evaluations were carried out using HAMD ( including ECDEU factors ) , MADRS , HSCL , Covi anxiety and Raskin depression scales , CGI , and a seven‐point rating of global improvement . Adverse events and laboratory values were also recorded at each assessment . One hundred and eleven patients entered the study , and efficacy data were available for 102 of these ( 49 on paroxetine and 53 on placebo ) . Efficacy measurements demonstrated significantly greater clinical improvement with paroxetine than placebo after two weeks of treatment , and this became even more marked after six weeks . Patients who continued treatment for a further six weeks maintained their clinical improvement . When adverse events were examined , statistically significant differences between paroxetine and placebo were seen only for sweating , diarrhoea , nausea , and somnolence . No significant changes were seen in any of the laboratory parameters measured . If these results are confirmed in future studies , paroxetine will represent an important addition to the treatments available for depression Abstract Previous experiments found that placebos produced small decreases in neural activity of pain‐related areas of the brain , yet decreases were only statistically significant after termination of stimuli and in proximity to when subjects rated them . These changes could reflect report bias rather than analgesia . This functional magnetic resonance imaging ( fMRI ) study examined whether placebo analgesia is accompanied by reductions in neural activity in pain‐related areas of the brain during the time of stimulation . Brain activity of irritable bowel syndrome patients was measured in response to rectal distension by a balloon barostat . Large reductions in pain and in brain activation within pain‐related regions ( thalamus , somatosensory cortices , insula , and anterior cingulate cortex ) occurred during the placebo condition . Results indicate that decreases in activity were related to placebo suggestion and a second factor ( habituation/attention/conditioning ) . Although many factors influence placebo analgesia , it is accompanied by reduction in pain processing within the brain in clinical ly relevant conditions BACKGROUND Paroxetine has demonstrated efficacy in depression and anxiety disorders , including generalized anxiety disorder ( GAD ) . This 32-week study evaluated the maintained efficacy and safety of paroxetine in GAD by assessing the potential for relapse after discontinuation of medication . METHOD Adults ( N = 652 ) with DSM-IV GAD and a Clinical Global Impressions-Severity of Illness ( CGI-S ) score > or = 4 received paroxetine ( 20 - 50 mg/day ) for 8 weeks . Patients whose CGI-S score had decreased by at least 2 points to < or = 3 at week 8 were r and omly assigned to double-blind treatment with paroxetine ( N = 278 ) or placebo ( N = 288 ) for a further 24 weeks . The primary efficacy parameter was the proportion of patients relapsing ( an increase in CGI-S score of at least 2 points to a score < or = 4 or withdrawal result ing from lack of efficacy ) during double-blind treatment . RESULTS Significantly fewer paroxetine than placebo patients relapsed during the 24-week double-blind phase ( 10.9 % vs. 39.9 % ; p < .001 ) . Placebo patients were almost 5 times more likely to relapse than paroxetine patients ( estimated hazard ratio = 0.213 [ 95 % CI = 0.1 to 0.3 ] ; p < .001 ) . Statistical significance in favor of paroxetine was demonstrated for all secondary efficacy parameters , including functional status . Twice as many paroxetine patients as placebo patients ( 73 % ) achieved remission . Paroxetine was well tolerated , with no unexpected adverse events reported . CONCLUSION Paroxetine was found to be effective and well tolerated for both the short- and long-term treatment of DSM-IV GAD . Continued treatment with paroxetine significantly reduced the potential for relapse of GAD symptoms Thirty-two nondepressed patients with obsessive compulsive disorder were r and omly assigned to treatment with clomipramine ( N = 16 ) or placebo ( N = 16 ) in a 10-week double-blind study . Of the 15 patients who received at least 3 weeks of clomipramine treatment , 11 ( 73 % ) improved , 5 ( 33 % ) improved by more than 50 % , and none worsened . Only 2 ( 12.5 % ) of the 16 placebo-treated patients improved , 1 ( 6 % ) by more than 50 % ; two ( 13 % ) worsened . Clomipramine treatment was associated with statistically significant improvement on several measures of obsessive compulsive symptoms . Side effects were more frequent and severe with clomipramine than with placebo . Although most patients tolerated clomipramine well , 3 discontinued treatment because of side effects OBJECTIVE The purpose of this study was to assess the efficacy of fluoxetine , a selective serotonergic antidepressant , in the treatment of dysthymia . METHOD Thirty-five patients who met criteria for dysthymia , but not major depression , began r and omized , double-blind 8-week trials of fluoxetine or placebo . RESULTS Of 32 patients who completed the study , 10 ( 62.5 % ) of the 16 patients given fluoxetine and three ( 18.8 % ) of the 16 given placebo responded to treatment . Response was defined as 1 ) 50 % or greater decrease in Hamilton Rating Scale for Depression score and 2 ) a score of 1 or 2 on the Clinical Global Impression ( CGI ) improvement subscale . Fluoxetine subjects showed significantly greater improvement at week 8 than placebo subjects on the Hamilton depression and CGI scales , but not on the Hopkins Symptom Check-list ( 58-item ) or the Cornell Dysthymia Rating Scale . CONCLUSIONS When compared to placebo , fluoxetine showed short-term effectiveness in treating dysthymic symptoms This multicenter study compared the efficacy and safety of citalopram and placebo in a population of moderately to severely depressed patients with melancholia . This r and omized , double-blind , parallel-group study compared citalopram ( flexible dose ; 20 - 80 mg/day ) with placebo in 180 psychiatric out patients with a DSM-III diagnosis of major depression or bipolar disorder , depressed , who also met DSM-III criteria for melancholia . Following a 1-week placebo washout period , patients meeting study entry criteria were r and omized to 4 weeks of double-blind treatment with either citalopram or placebo . Efficacy measures included the Hamilton Rating Scale for Depression ( HAM-D ) , the Clinical Global Impressions ( CGI ) Scale , and the Zung Self-Rating Depression Scale . Patients treated with citalopram showed significantly greater improvement at endpoint than placebo patients on the HAM-D , CGI , and Zung scales . On the HAM-D , citalopram patients exhibited significantly greater improvement than placebo patients after 1 week of double-blind treatment and at all subsequent study visits . Endpoint analyses of the HAM-D subscales demonstrated that citalopram produced significant improvement of the psychomotor retardation , cognitive disturbance , sleep disturbance , and melancholia symptom clusters . Nausea , dry mouth , somnolence , dizziness , and increased sweating were reported at higher rates by citalopram-treated patients than by placebo-treated patients , but there were no significant citalopram-placebo differences in the incidence of activation ( e.g. , anxiety , nervousness , insomnia ) or sexual dysfunction . Analysis of electrocardiograms , vital signs , and laboratory tests did not reveal any clinical ly significant effects of citalopram treatment . The results of this study indicate that citalopram is safe and effective in the treatment of depressed patients with melancholia , and is associated with a favorable side effect profile and a potentially rapid onset of action OBJECTIVE To assess the efficacy and tolerability of controlled-release paroxetine ( paroxetine CR ) in the treatment of adults with panic disorder . METHOD Paroxetine CR ( 25 - 75 mg/day ; N = 444 ) was compared with placebo ( N = 445 ) in patients with DSM-IV panic disorder with or without agoraphobia in 3 identical , double-blind , placebo-controlled , 10-week clinical trials that were pooled for analysis . RESULTS Paroxetine CR was statistically superior to placebo in the primary outcome measure , percentage of patients who were free of panic attacks in the 2 weeks prior to endpoint . Of the total population that completed or prematurely terminated treatment , 63 % and 53 % of paroxetine CR- and placebo-treated patients , respectively , were panic-free during the final 2 weeks ( p < .005 ; odds ratio [ OR ] = 1.63 ; 95 % CI = 1.21 to 2.19 ) . For week 10 completers ( 72 % of total ) , 73 % and 60 % of paroxetine CR- and placebo-treated patients , respectively , were panic-free at week 10 ( p < .005 ; OR = 2.11 ; 95 % CI = 1.45 to 3.07 ) . Paroxetine CR was also statistically superior to placebo on the global improvement and severity items of the Clinical Global Impressions scale and in reducing anxiety symptoms as measured by the Hamilton Rating Scale for Anxiety total score and total fear and avoidance on the Marks-Sheehan Phobia Scale . Adverse events leading to study withdrawal were minimal and occurred in 11 % of the paroxetine CR group and 6 % of the placebo group . Most of the treatment-emergent adverse events were rated as mild to moderate in severity and occurred early in the study . There were no unexpected adverse events , and serious adverse events were uncommon ( 10 [ 2.3 % ] of the 444 patients treated with paroxetine CR vs. 8 [ 1.8 % ] of the 445 patients treated with placebo ) . CONCLUSION Paroxetine CR is an effective and well-tolerated treatment for panic disorder . Paroxetine CR is associated with low rates of treatment-emergent anxiety as well as low dropout rates from adverse events We report results from a multicenter , placebo-controlled , r and omized , double-blind comparison of the efficacy and tolerability of paroxetine and fluoxetine in out patients with major depression . Across five U.S. sites , 128 out patients ( mean age : 41.3 + /- 12.6 ; 63 men and 65 women ) with moderate to moderately severe major depression without a history of mania or hypomania were recruited between 1993 and 1994 . All 128 patients completed a 1-week placebo washout period , and were then r and omized to 12 weeks of double-blind treatment with paroxetine up to 50 mg/day ( n = 55 ) , fluoxetine up to 80 mg/day ( n = 54 ) , or placebo ( n = 19 ) . Subjects were evaluated weekly for the first 4 weeks , then at weeks 6 , 9 , and 12 with the 21-item HAMD and the Covi Anxiety Scale . There were no significant differences among the three treatment groups in baseline and endpoint depression and anxiety severity , as well as in the degree of depression and anxiety improvement . There were no statistically significant differences in rates or mean numbers of adverse events between paroxetine-treated patients and fluoxetine-treated patients . In summary , our results , although limited by the lack of a significant difference from placebo in treatment outcome , suggest that the SSRIs paroxetine and fluoxetine have comparable antidepressant and antianxiety efficacies among depressed out patients , as well as similar safety and tolerability profiles BACKGROUND Escitalopram 10 mg/day is an effective and well-tolerated antidepressant . Three r and omized controlled trials recently evaluated the safety and efficacy of escitalopram in the treatment of generalized anxiety disorder ( GAD ) . METHODS The trial design s were virtually identical , allowing data to be pooled across studies . Male and female out patients , ages 18 - 80 years , with DSM-IV-defined GAD were r and omized to double-blind treatment with escitalopram or placebo for 8 weeks . Escitalopram dose was fixed at 10 mg/day for the first 4 weeks , after which increases to 20 mg/day were permitted . The primary efficacy variable was the mean change from baseline in total Hamilton Anxiety Scale ( HAMA ) score . RESULTS Approximately 850 patients were r and omized to double-blind treatment . In each individual study , escitalopram was significantly superior to placebo ( p<0.05 ) as measured by change from baseline in HAMA score . By-visit analyses of data pooled across studies revealed significantly greater improvement ( p<0.05 ) in the escitalopram group beginning at week 1 or 2 and continuing through week 8 for all primary and secondary efficacy variables . The mean change in HAMA total score from baseline to endpoint also was significantly greater for patients maintained at escitalopram 10 mg/day than for those receiving placebo . Escitalopram was generally well tolerated . LIMITATIONS The studies included in this analysis were of short-term duration and excluded patients with significant medical and psychiatric comorbidities , such as major depressive disorder . CONCLUSION Results from the individual trials and the pooled analysis demonstrate that escitalopram is effective and well tolerated for the treatment of GAD OBJECTIVE Prior investigations have failed to find reliable personality differences in placebo responding . The present study tests the hypothesis that personality and situational variables interact to determine placebo responding . METHODS Optimists and pessimists were r and omly assigned to one of three conditions . In the first condition , the participants were told that they were to ingest a pill that would make them feel unpleasant ( deceptive-expectation group ) . In the second condition , the participants were told that they were to ingest a pill that would make them feel either unpleasant or was an inactive substance ( conditional-expectation group ) . Finally , a third group was told they were to ingest a pill that was inactive ( control group ) . RESULTS Pessimists were more likely than optimists to follow a negative-placebo expectation when given a deceptive expectation , but not when given a conditional expectation . CONCLUSION The personality variable optimism-pessimism relates to placebo responding when individuals are given a deceptive but not a conditional expectation . This suggests that personality and situational variables interact to determine placebo responding BACKGROUND Uncontrolled reports suggest that intravenous clomipramine hydrochloride may be effective for patients with obsessive-compulsive disorder ( OCD ) who are nonresponsive to oral clomipramine . METHODS Fifty-four patients with oral clomipramine-refractory OCD were r and omized to receive 14 infusions of either placebo or clomipramine hydrochloride , starting at 25 mg/d and increasing to 250 mg/d . Ratings were conducted double-blind after infusion 14 among 54 patients , single-blind 1 week later among 39 patients , and nonblind 1 month later among 31 patients . Response was based on a Clinical Global Impressions rating of at least " much improved . " RESULTS Six ( 21 % ) of 29 patients r and omized to receive intravenous ( i.v . ) clomipramine vs 0 of 25 patients given i.v . placebo were responders after 14 infusions ( df = 1 , P<.02 ) . Dimensional ratings after infusion 14 revealed significant ( P = .007 ) improvement on the National Institute of Mental Health-Obsessive-Compulsive Scale and the Clinical Global Impressions Scale ( P = .03 ) , but not the Yale-Brown Obsessive Compulsive Scale . One week later , all dimensional measures of OCD showed significant improvement . At 1 week post-i.v . , 9 ( 43 % ) of 21 patients initially r and omized to i.v . clomipramine and treated subsequently with oral clomipramine were responders , whereas 0 of 18 patients initially r and omized to receive i.v . placebo and treated subsequently with several days of open-label i.v . clomipramine responded ( df = 1 , P<.002 ) . Of the 31 patients assessed 1 month after i.v . infusion ( treatment not controlled ) , 18 ( 58.1 % ) were responders . Intravenous clomipramine treatment was safe with no serious adverse consequences . CONCLUSIONS Intravenous clomipramine is more effective than i.v . placebo for patients with OCD with a history of inadequate response or intolerance to oral clomipramine . Further study of this promising treatment for refractory OCD is needed BACKGROUND Citalopram , the most selective serotonin reuptake inhibitor ( SSRI ) , is a bicyclic phthalane derivative with a chemical structure that is unrelated to that of other SSRIs and available antidepressants . The drug is approved for use in 69 countries . This 6-week , fixed-dose , placebo-controlled , parallel-arm , multicenter trial was performed to confirm its efficacy and safety in treatment of out patients with major depression in the United States . METHOD Six hundred and fifty adult out patients with moderate-to-severe major depression ( DSM-III-R ) were r and omly assigned to receive citalopram at doses of 10 mg ( N = 131 ) , 20 mg ( N = 130 ) , 40 mg ( N = 131 ) , or 60 mg ( N = 129 ) or placebo ( N = 129 ) once daily . Outcome assessment s were the 21-item Hamilton Rating Scale for Depression ( HAM-D ) , the Montgomery-Asberg Depression Rating Scale ( MADRS ) , and the Clinical Global Impressions scale . RESULTS Between-group comparisons of the change from baseline to endpoint revealed significantly greater improvement in the citalopram patients relative to the placebo patients on all 3 efficacy measures . Patients r and omly assigned to 40 mg/day and 60 mg/day of citalopram showed significantly greater improvement than placebo on all efficacy measures , as well as on the HAM-D symptom clusters measuring depressed mood , melancholia , cognitive disturbance , and psychomotor retardation . Patients who received 10 mg/day and 20 mg/day of citalopram also showed consistent improvement relative to placebo on all efficacy ratings , with statistical significance demonstrated in the MADRS response rate , the HAM-D depressed mood item , and the HAM-D melancholia subscale . Citalopram was well tolerated , with only 15 % of patients discontinuing for adverse events . The side effects most commonly associated with citalopram treatment were nausea , dry mouth , somnolence , insomnia , and increased sweating . CONCLUSION Citalopram was significantly more effective than placebo in the treatment of moderate-to-severe major depression , especially symptoms of depressed mood and melancholia , with particularly robust effects shown at doses of 40 and 60 mg/day . Citalopram was well tolerated in spite of forced upward titration to fixed-dose levels , with a low incidence of anxiety , agitation , and nervousness BACKGROUND Poststroke depression is a frequent condition and important to treat . The aim of this trial was to study the efficacy and tolerability of sertraline . METHOD In 4 Swedish stroke centers , 123 patients ( aged 70.7 + /- 9.9 years ) were enrolled during the period September 1998 to January 2001 in a r and omized , double-blind , placebo-controlled 26-week trial , at a mean of 128 + /- 97 days ( range , 3 - 375 days ) after stroke , if they fulfilled DSM-IV criteria of major depressive episode ( N = 76 ) or minor depressive disorder ( N = 47 ) . The primary efficacy variable was a change in depression assessed by the Montgomery-Asberg Depression Rating Scale . The Emotional Distress Scale ( EDS ) was administered and the occurrence of emotionalism and quality of life ( QoL ) were assessed , as well as neurologic recovery . Efficacy analyses were intention-to-treat , short-term ( week 6 ) and long-term ( week 26 ) . RESULTS Of the 123 patients , 62 were treated with sertraline ( 50 - 100 mg/day ) and 61 with placebo . Both groups improved substantially , with no differences between the treatments , either for major depressive episode or minor depressive disorder , or for short- or long-term antidepressant effect and neurologic outcome . EDS revealed a better outcome with sertraline at week 6 ( p < .05 ) . At week 26 , the improvement in QoL was better in sertraline patients ( p < .05 ) and there was a trend for emotionalism ( p = .07 ) . No serious side effects were seen . CONCLUSION Poststroke depression as measured by a conventional depression rating scale improved over time irrespective of treatment . Positive effects specific to sertraline were identified in emotional distress , emotionalism , and QoL. The study indicates that poststroke emotional reactions comprise depression and other domains susceptible to pharmacologic therapy A double-blind r and omised controlled trial of the effect of low dose lofepramine ( 70 mg once daily ) against placebo was carried out on depressed elderly in patients on general medical wards for the elderly , comparing measures of depression and side-effects between the r and omised groups . Patients were identified for the study using the Geriatric Depression Scale ( GDS ) and the Brief Assessment Schedule Depression Cards ( BASDEC ) . Sixty-three subjects were r and omised : 46 patients completed the entire trial of 28 days treatment . BASDEC and GDS were administered on day 8 post-admission , and depressed patients were r and omised double-blind to either low dose lofepramine ( 70 mg daily ) ( n = 23 ) or placebo ( n = 23 ) . Assessment of changes in depressive states were made using the Montgomery Asberg Depression Rating Scale ( MADRS ) on days 8 , 18 and 36 post-admission . Both groups improved by a similar amount during the trial . Lofepramine tended to be more effective than placebo in those patients who were more depressed ( GDS > or = 18 ) . On the other h and , subjects who were less depressed ( i.e. GDS < 18 ) improved more on placebo than lofepramine . Low dose lofepramine may prove useful in moderately or severely depressed patients treated for only 4 weeks . However , low dose lofepramine is not indicated for mild ( GDS 15 - 18 ) depression Depression in the geriatric population is a frequent , serious , and potentially reversible disorder , yet relatively few blinded , controlled , antidepressant trials have been reported . A number of age related issues complicate safe and effective pharmacotherapy . In a 6-week , double-blind trial in moderately to severely depressed ( nonpsychotic ) out patients over age 60 , fluoxetine ( N = 335 ) was statistically significantly more efficacious than placebo ( N = 336 ) in overall response ( 43.9 % vs. 31.6 % , p = .002 ) and remission ( 31.6 % vs. 18.6 % , p < .001 ) rates . Analyses of early discontinuations because of an adverse drug event revealed no statistically significantly greater rate with fluoxetine ( n = 39 ; 11.6 ) than was seen with placebo ( n = 29 ; 8.6 % ) . These results corroborate that major depression in an older population is responsive to antidepressant pharmacotherapy . Specifically , fluoxetine , at a conventional 20-mg dose , was both safe and effective relative to placebo in this special population BACKGROUND Escitalopram is the single isomer responsible for the serotonin reuptake inhibition produced by the racemic antidepressant citalopram . The present r and omized , double-blind , placebo-controlled , fixed-dose multicenter trial was design ed to evaluate the efficacy and tolerability of escitalopram in the treatment of major depressive disorder . METHOD Out patients with an ongoing DSM-IV major depressive episode ( N = 491 ) were r and omly assigned to placebo , escitalopram , 10 mg/day , escitalopram , 20 mg/day , or citalopram , 40 mg/day , and entered an 8-week double-blind treatment period following a 1-week single-blind placebo lead-in . Clinical response was evaluated by the Montgomery-Asberg Depression Rating Scale ( MADRS ) , the 24-item Hamilton Rating Scale for Depression ( HAM-D ) , the Clinical Global Impressions ( CGI ) scales , the Hamilton Rating Scale for Anxiety ( HAM-A ) , and patient-rated quality -of-life scales . RESULTS Escitalopram , at both doses , produced significant improvement at study endpoint relative to placebo on all measures of depression ; significant separation of escitalopram from placebo was observed within I week of double-blind treatment . Citalopram treatment also significantly improved depressive symptomatology compared with placebo ; however , escitalopram , 10 mg/day , was at least as effective as citalopram , 40 mg/day , at endpoint . Anxiety symptoms and quality of life were also significantly improved by escitalopram compared with placebo . The incidence of discontinuations due to adverse events for the escitalopram 10 mg/day group was not different from the placebo group ( 4.2 % vs. 2.5 % ; p = .50 ) , and not different for the escitalopram 20 mg/day group and the citalopram 40 mg/day group ( 10.4 % vs. 8.8 % ; p = .83 ) . CONCLUSION Escitalopram , a single isomer SSRI , is well-tolerated and has demonstrated antidepressant efficacy at a dose of 10 mg/day BACKGROUND The selective serotonin reuptake inhibitor sertraline has been shown to be efficacious and well tolerated for the treatment of major depressive disorder . Relatively few trials , however , have examined the role of pharmacotherapy in dysthymia without concurrent major depression . The current investigation focuses on the use of sertraline for the treatment of dysthymia . METHOD In this 12-week , multicenter , double-blind study , 310 patients with a DSM-III-R diagnosis of dysthymic disorder without concurrent major depression were r and omly assigned to receive either sertraline ( N = 158 ) or placebo ( N = 152 ) . Sertraline was initiated at a dose of 50 mg daily , with titration permitted to a maximum of 200 mg daily . The primary evaluation criteria were the Structured Interview Guide for the Hamilton Depression Rating Scale , Seasonal Affective Disorder Version ( SIGH-SAD ) , the Montgomery-Asberg Depression Rating Scale ( MADRS ) , and the Clinical Global Impressions-Severity of Illness ( CGI-S ) and -Improvement ( CGI-I ) scales . RESULTS Mean percentage reductions for the intent-to-treat population in SIGH-SAD scores were 44.6 % for the sertraline-treated group and 33.2 % for the placebo-treated group ( p = .03 ) ; MADRS scores , 43.6 % and 33.0 % ( p = .02 ) ; and CGI-S scores , 32.8 % and 22.8 % ( p = .02 ) . A significantly greater proportion of the sertraline-treated group was classified as responders ( defined for HAM-D and MADRS scores as a 50 % score reduction and for CGI-I as a score of 1 or 2 by the final visit ) and remitters ( SIGH-SAD score < or = 8) relative to the placebo-treated group by the final visit . In addition , sertraline-treated patients experienced greater improvements in all 9 domains of the Battelle Quality of Life Question naire than placebo-treated patients did , with a significant difference observed in favor of sertraline in 8 of the 9 domains . The life satisfaction and social interaction quality of life domains showed significantly greater response in sertraline responders compared with placebo SIGH-SAD responders . Sertraline was well tolerated . Thirteen percent of the sertraline-treated group versus 8 % of the placebo-treated group withdrew from therapy owing to adverse events ( p = .14 ) . CONCLUSION Sertraline is efficacious and well tolerated in the short-term treatment of dysthymia without concurrent major depression The efficacy of sertraline in the treatment of civilian posttraumatic stress disorder ( PTSD ) has been established by two large placebo-controlled trials . The purpose of the current pilot study was to obtain preliminary evidence of the efficacy of sertraline in military veterans suffering from PTSD . Outpatient Israeli military veterans with a DSM-III-R diagnosis of PTSD were r and omized to 10 weeks of double-blind treatment with sertraline ( 50–200 mg/day ; N = 23 , 83 % male , mean age = 41 years ) or placebo ( N = 19 , 95 % male , mean age = 38 years ) . Efficacy was evaluated by the Clinician-Administered PTSD Scale ( CAPS-2 ) and by Clinical Global Impression Scale-Severity ( CGI-S ) and -Improvement ( CGI-I ) ratings . Consensus responder criteria consisted of a 30 % or greater reduction in the CAPS-2 total severity score and a CGI-I rating of “ much ” or “ very much ” improved . The baseline CAPS-2 total severity score was 94.3 ± 12.9 for sertraline patients , which is notably higher than that reported for most studies of civilian PTSD . On an intent-to-treat endpoint analysis , sertraline showed a numeric but not statistically significant advantage compared with placebo on the CAPS-2 total severity and symptom cluster scores . In the study completer analysis , the mean CGI-I score was 2.4 ± 0.3 for sertraline and 3.4 ± 0.3 for placebo ( t = 2.55 , df = 30 , p = 0.016 ) , CGI-I responder rates were 53 % for sertraline and 20 % for placebo ( χ2 = 3.62 , df = 1 , p = 0.057 ) , and combined CGI-I and CAPS-2 responder rates ( ≥30 % reduction in baseline CAPS-2 score ) were 41 % for sertraline and 20 % for placebo ( χ2 = 1.39 , df = 1 , p = 0.238 ) . Sertraline treatment was well tolerated , with a 13 % discontinuation rate as a result of adverse events . This pilot study suggests that sertraline may be an effective treatment in patients with predominantly combat-induced PTSD , although the effect size seems to be somewhat smaller than what has been reported in civilian PTSD studies . Adequately powered studies are needed to confirm these results and to assess whether continued treatment maintains or further improves response Objective The experiment tested whether the placebo and nocebo responses could be mediated via modulation of stress . Methods Ischemic pain was induced in healthy volunteers ( N = 59 ) . When pain reached “ 7 ” on a 10-point scale , two groups of subjects received information that a pain relieving ( the Placebo group ) or a pain increasing ( the Nocebo group ) substance was injected . All injections contained physiological saline . A third group received no information and no injection ( the Natural History group ) . Pain ratings and blood sample s for analysis of cortisol and beta-endorphin were obtained every 5 minutes after pain equal to seven until the experiment was terminated . Results Pain increased in all groups , but there were significantly lower pain ratings in the Placebo group at 15 minutes after the injection , compared with the other two groups . Cortisol increased in all groups , but mostly so in the Nocebo group . Circulating beta-endorphin increased in all groups . Pain-ratings were not correlated with beta-endorphins or cortisol . Conclusions A placebo response , ie , a reduced pain level , was seen in the Placebo group at 15 minutes after the injection . The placebo response was not related to stress or to beta-endorphin . Expectation of a pain increase in the Nocebo group led to an increase in cortisol , but the expectation of pain increase and the result ant cortisol increase had no effect on pain We performed a r and om assignment , double-blind , placebo-controlled study of nortriptyline ( NT ) in postpubertal 12- to 17-year-olds with Research Diagnostic Criteria ( RDC ) and DSM-III major depressive disorder . The protocol included a 2-week placebo washout phase and an 8-week double-blind , placebo-controlled phase with weekly plasma level monitoring . Active subjects had their plasma level placed at 80 + /- 20 ng/ml by using previously developed tables to determine the starting dose from a plasma level drawn 24 hours after a single dose administered at baseline . The study population was severely depressed and had a chronic , unremitting course prior to study ; a high percentage of family histories with affective disorder , alcoholism , and suicidality ; and a high rate of comorbidity . Of the 52 subjects enrolled , there were 17 placebo washout responders , 4 dropouts , and 31 completers ( 12 active and 19 placebo ) . Only one active subject responded ; therefore , the study was terminated early . The mean NT plasma level was 91.1 ( 18.3 SD ) ng/ml . The two treatment groups had similar post protocol severity ratings . Subjects on active drug did not evidence the anticholinergic side effects reported in adult sample s. The negative outcome in this study is similar to the findings in our previously reported NT study in prepubertal 6- to 12-year-olds OBJECTIVE This study determined the efficacy of antidepressant medication for the treatment of depression in the " old-old . " METHOD This r and omized 8-week medication trial compared citalopram , 10 - 40 mg/day , to placebo in the treatment of patients 75 and older with unipolar depression . RESULTS A total of 174 patients who were 58 % women with a mean age of 79.6 years ( SD=4.4 ) and a mean baseline Hamilton Depression Rating Scale score of 24.3 ( SD=4.1 ) were r and omly assigned to treatment at 15 sites . There was a main effect for site but not for treatment condition . The remission rate , defined as a final Hamilton depression scale score < 10 , was 35 % for the citalopram and 33 % for the placebo groups . However , patients with severe depression ( baseline Hamilton depression scale score > 24 ) tended to have a higher remission rate with medication than with placebo ( 35 % versus 19 % ) . CONCLUSIONS In the oldest group of community-dwelling patients to be studied to date , medication was not more effective than placebo for the treatment of depression . However , given the considerable psychosocial support received by all patients , the placebo condition represents more than the ingestion of an inactive pill . Across sites , there was considerable range in response to medication , 18 % to 82 % , and to placebo , 16 % to 80 % Abstract : This was a r and omized double-blind placebo-controlled multicenter study to assess the efficacy , safety , and tolerability of fluvoxamine in a controlled release ( CR ) formulation for treatment of generalized social anxiety disorder ( GSAD ) . A total of 300 subjects with GSAD were r and omly assigned to receive either fluvoxamine CR ( N = 149 ) or placebo ( N = 151 ) for 12 weeks . Mean changes from baseline to end point in Liebowitz Social Anxiety Scale ( LSAS ) , Clinical Global Impression Severity of Illness Scale ( CGI-S ) , Sheehan Disability Scale ( SDS ) , as well as the mean end point scores in Clinical Global Impression Improvement Scale ( CGI-I ) and Patient Global Impression of Improvement Scale ( PGI ) were compared between the fluvoxamine CR and placebo treatment groups . Arizona Sexual Experience Scale ( ASEX ) , adverse event , and other safety parameters were also assessed . The results demonstrated that fluvoxamine CR was significantly superior to placebo in decreasing LSAS total score ( primary measure ) starting at week 4 . At end point , there was a mean change from baseline of −36.1 ± 2.7 ( 37 % reduction ) in the LSAS total score in the fluvoxamine CR group compared with −27.3 ± 2.4 ( 28 % reduction ) in the placebo group ( P = 0.020 for mean change ) . Fluvoxamine CR was also significantly superior to placebo in SDS , CGI-S , CGI-I at end point ( secondary measures ) . When compared with placebo , fluvoxamine CR did not cause any significant weight gain or clinical ly significant sexual dysfunction as measured by ASEX . In summary , fluvoxamine CR is an efficacious , safe , and well-tolerated treatment of generalized social anxiety disorder OBJECTIVE Administration of the muscle relaxant carisoprodol and placebo was crossed with information that was agonistic or antagonistic to the effect of carisoprodol . It was investigated whether information alone induced physiological and psychological responses , and whether information modified the response to the drug . METHODS Half of the subjects received capsules containing 525 mg carisoprodol together with information that the drug acted in a specific way ( Groups Relaxant/C , Stimulant/C , and No Information/C ) . The other half of the subjects received lactose ( Groups Relaxant/L , Stimulant/L , and No Information/L ) . Dependent variables were blink reflexes and skin conductance responses , subjective measures of tension and sleepiness , and serum carisoprodol and meprobamate concentrations . Recordings were made between 15 and 130 minutes after administration of the capsules . RESULTS The Stimulant/L group reported more tension compared with the other two groups , and carisoprodol increased tension even more in the Stimulant/C group . The Relaxant/C group displayed higher levels of carisoprodol serum concentration compared with the other groups that received carisoprodol . CONCLUSIONS Reported tension was modulated in the direction suggested by the stimulant information . The effect of carisoprodol on tension was also modulated by stimulant information . Increased carisoprodol absorption in the group that received relaxant information could be a mechanism in the placebo response OBJECTIVE There have been few placebo-controlled trials of selective serotonin reuptake inhibitors for depressed elderly patients . This placebo-controlled study of sertraline was design ed to confirm the results of non-placebo-controlled trials . METHOD The subjects were out patients age 60 years or older who had a DSM-IV diagnosis of major depressive disorder and a total score on the 17-item Hamilton Depression Rating Scale of 18 or higher . The patients were r and omly assigned to 8 weeks of double-blind treatment with placebo or a flexible daily dose of 50 or 100 mg of sertraline . The primary outcome variables were the Hamilton scale and Clinical Global Impression ( CGI ) scales for severity and improvement . RESULTS A total of 371 patients assigned to sertraline and 376 assigned to placebo took at least one dose . At endpoint , the patients receiving sertraline evidence d significantly greater improvements than those receiving placebo on the Hamilton depression scale and CGI severity and improvement scales . The mean changes from baseline to endpoint in Hamilton score were -7.4 points ( SD=6.3 ) for sertraline and -6.6 points ( SD=6.4 ) for placebo . The rate of CGI-defined response at endpoint was significantly higher for sertraline ( 45 % ) than for placebo ( 35 % ) , and the time to sustained response was significantly shorter for sertraline ( median , 57 versus 61 days ) . There were few discontinuations due to treatment-related adverse events , 8 % for sertraline and 2 % for placebo . CONCLUSIONS Sertraline was effective and well tolerated by older adults with major depression , although the drug-placebo difference was not large in this 8-week trial The effects of clomipramine hydrochloride ( CMI ) versus placebo upon DSM-III-defined obsessive-compulsive disorder ( OCD ) were assessed in a 10-week double-blind multicenter trial and in a corresponding 1-year double-blind extension study . The NIMH global O-C scale , a 15-point ordinal severity scale , incorporating categorical features specific to OCD , was used to evaluate the severity of obsessive compulsive symptoms over the course of treatment , and a physician 's rating of global therapeutic effect was used to assess overall change from baseline . In the core study , patients receiving placebo demonstrated minor and non systematic changes , whereas patients who received CMI had clinical ly and statistically significant reductions in the global severity of their disorder . Findings from the extension study were consistent with continuing efficacy for CMI , whereas corresponding data for patients receiving long-term placebo were difficult to interpret . Based upon shifts in categorical severity , symptoms for over half those patients who received CMI were rendered sub clinical or within a range of normal functioning . In contast , less than 5 % of patients receiving placebo had their symptoms reduced to a sub clinical level . Generally , both treatments were well tolerated . Previous studies have indicated therapeutic potential for CMI in obsessive compulsive disorder . These findings confirm and extend previous observations BACKGROUND Posttraumatic stress disorder ( PTSD ) is a common illness associated with significant disability . Few large , placebo-controlled trials have been reported . METHODS Out patients with a DSM-III-R diagnosis of moderate-to-severe PTSD were r and omized to 12 weeks of double-blind treatment with either sertraline ( N = 100 ) in flexible daily doses in the range of 50 to 200 mg or placebo ( N = 108 ) . Primary outcome measures consisted of the Clinician-Administered PTSD Scale ( CAPS-2 ) total severity score , the patient-rated Impact of Event Scale ( IES ) , and the Clinical Global Impression-Severity ( CGI-S ) and -Improvement ( CGI-I ) ratings . RESULTS Mixed-effects analyses found significantly steeper improvement slopes for sertraline compared with placebo on the CAPS-2 ( t = 2.96 , P = .003 ) , the IES ( t = 2.26 , P = .02 ) , the CGI-I score ( t = 3.62 , P<.001 ) , and the CGI-S score ( t = 4.40 , P<.001 ) . An intent-to-treat end-point analysis found a 60 % responder rate for sertraline and a 38 % responder rate for placebo ( chi(2)(1 ) = 8.48 , P = .004 ) . Sertraline treatment was well tolerated , with a 9 % discontinuation rate because of adverse events , compared with 5 % for placebo . Adverse events that were significantly more common in subjects given sertraline compared with placebo consisted of insomnia ( 35 % vs 22 % ) , diarrhea ( 28 % vs 11 % ) , nausea ( 23 % vs 11 % ) , fatigue ( 13 % vs 5 % ) , and decreased appetite ( 12 % vs 1 % ) . CONCLUSION The results of the current study suggest that sertraline is a safe , well-tolerated , and significantly effective treatment for PTSD In a 6-week , r and omized , double-blind , multicenter trial , sertraline 50 mg , 100 mg , or 200 mg , or placebo , was administered once daily to 369 patients with DSM-III-defined major depression . Efficacy variables included changes from baseline scores for total Hamilton Rating Scale for Depression ( HAMD ) , HAMD Bech Depression Cluster , Clinical Global Impressions ( CGI ) Severity , CGI Improvement , and Profile of Mood States Depression/Dejection Factor . For the evaluable- patients analysis , all sertraline groups showed significantly ( p < 0.05 or better ) greater improvements in all efficacy variables except one when compared with the placebo group . For the all- patients analysis , all efficacy variables in the 50 mg group were statistically significantly ( p < 0.05 ) better than placebo . Side effects increased with increasing dosage but were usually mild and well tolerated . The results of this study show that sertraline 50 mg once daily is as effective as higher dosages for the treatment of major depression with fewer side effects and therapy discontinuations This 7- to 8-week , multicenter , r and omized , double-blind , placebo-controlled study was performed to determine the dose-effect relationship and minimum effective dose for fluvoxamine maleate in a titrated fixed-dose study of major depressive disorder . Gradual titration over 2 weeks to fixed maintenance doses was employed to minimize dropout due to initial side effects . The study enrolled 600 out patients , male and female , age 18 - 65 , meeting DSM-III-R criteria for major depressive disorder . A 13-item subscore of the st and ard 21-Item Hamilton Depression Scale was used to minimize the possible contribution of known side effects from serotonin reuptake inhibitors to the overall HAM-D score . Secondary efficacy assessment s included the HAM-D retardation factor , HAM-D depressed mood item , CGI-severity of illness item , and SCL depression factor . Fluvoxamine ( 50 - 150 mg/day ) was therapeutically effective and well tolerated during 6 weeks of therapy . Based on the HAM-D depressed mood item , efficacy was dose dependent . The minimum effective dose was 50 mg/day . Fluvoxamine maleate shows dose-related effectiveness in the acute treatment of major depressive disorder BACKGROUND This study was design ed to establish the efficacy of the serotonin reuptake blocker fluoxetine in the treatment of posttraumatic stress disorder ( PTSD ) . METHOD 64 subjects ( 22 women and 42 men ; 31 veterans and 33 nonveterans ) with PTSD entered a 5-week r and omized double-blind trial comparing fluoxetine ( N = 33 ) and placebo ( N = 31 ) . RESULTS By Week 5 fluoxetine , but not placebo , significantly reduced overall PTSD symptomatology , as assessed by the Clinician-Administered PTSD Scale ( CAPS ) score . Changes were most marked in the arousal and numbing symptom subcategories . Non-VA patients responded much better than VA patients . Fluoxetine was an effective antidepressant independent of its effects on PTSD . CONCLUSION Fluoxetine is an effective pharmacotherapeutic agent for treating PTSD and its associated features , particularly in patients without chronic treatment histories BACKGROUND No controlled trial of treatment of generalised social phobia has been conducted in general practice . AIMS To examine the efficacy of sertraline or exposure therapy , administered alone or in combination in this setting . METHOD Study was of a r and omised , double-blind design . Patients ( n = 387 ) received sertraline 50 - 150 mg or placebo for 24 weeks . Patients were additionally r and omised to exposure therapy or general medical care . RESULTS Sertraline-treated patients were significantly more improved than non-sertraline-treated patients ( chi(2)=12.53 , P<0.001 ; odds ratio=0.534 ; 95 % Cl 0.347 - 0.835 ) . No significant difference was observed between exposure- and non-exposure-treated patients ( chi(2)=2.18 , P=0.140 ; odds ratio=0.732 ; 95 % Cl 0.475 - 1.134 ) . In the pairwise comparisons , combined sertraline and exposure ( chi(2)=12.32 ; P<0.001 ) and sertraline ( chi(2)=10.13 ; P=0.002 ) were significantly superior to placebo . CONCLUSIONS Sertraline is an effective treatment for generalised social phobia . Combined treatment with sertraline and exposure therapy , conducted by the general practitioner , may enhance the treatment efficacy in primary care Twenty-one depressed patients with probable Alzheimer 's disease ( AD ) were r and omized to receive a 6-week treatment with clomipramine or placebo in a study with a double-blind crossover design . Main outcome measures were Hamilton Depression , Mini-Mental State ( MMSE ) , and Functional Independence Measure ( FIM ) scores . Mood improved significantly on both clomipramine and placebo , but clomipramine was significantly more effective than placebo during the first 6-week treatment period . Patients started on clomipramine maintained improvement during the washout and placebo periods , whereas patients started on placebo worsened during the washout period . However , patients on clomipramine showed significantly lower MMSE scores overall than patients on placebo . No significant drug effects were found on FIM scores . Clomipramine proved to be a useful treatment of depression in patients with probable AD BACKGROUND Limited information is available regarding optimal dosing or long-term pharmacotherapy with serotonin reuptake inhibitors in obsessive-compulsive disorder . This study evaluated the acute safety and efficacy and long-term efficacy , safety , and impact on relapse prevention of paroxetine in obsessive-compulsive disorder . METHOD We enrolled 348 out patients with DSM-III-R obsessive-compulsive disorder in phase 1 , a 12-week r and omized , double-blind , parallel study of fixed doses of paroxetine ( 20 mg/day , 40 mg/day , or 60 mg/day ) and placebo . In phase 2 , 263 phase 1 completers were enrolled in 6 months of flexibly dosed open-label paroxetine treatment . In phase 3 , 105 responders to open-label paroxetine were r and omized to 6-month double-blind , fixed-dose , parallel paroxetine/placebo treatment to evaluate long-term efficacy , safety , and impact on relapse prevention . The study was conducted from July 1991 to February 1994 . RESULTS Patients in phase 1 acute treatment receiving 40 mg/day or 60 mg/day of paroxetine improved significantly ( p < .05 ) more than those receiving placebo ; the mean reduction in Yale-Brown Obsessive-Compulsive Scale score was 25 % on 40 mg/day of paroxetine and 29 % on 60 mg/day compared with 13 % on placebo . During phase 3 , long-term treatment , a greater proportion of placebo- ( 59 % ) than paroxetine-treated ( 38 % ) patients relapsed . Paroxetine was well tolerated at all doses , with no significant increase in frequency of adverse events during long-term compared with short-term therapy . Greater adverse events in the placebo than in the paroxetine group in phase 3 probably represent a discontinuation effect . CONCLUSION Paroxetine doses of 40 mg/day and 60 mg/day ( but not 20 mg/day ) are effective in treating acute obsessive-compulsive disorder . Long-term treatment with paroxetine is effective and safe , decreases the rate of relapse , and lengthens the time to relapse BACKGROUND If symptoms are to be recognized and effectively addressed in clinical research , they must be collected using sensitive , specific , reliable , and clinical ly meaningful methods . OBJECTIVE To perform a comparison of self-administered symptom survey data with data from conventional provider-reports . DESIGN / METHODS Secondary data analysis of AIDS Clinical Trials Group Study 081 ( ACTG 081 ) , a r and omized trial taking place in 33 sites comparing three approaches to prophylaxis for Pneumocystis carinii-related pneumonia that found no difference among treatment arms . The study was performed on 842 subjects with advanced HIV infection . No intervention was undertaken as a result of this study . ACTG 081 included data on functional status , global quality of life and survival , and two methods of symptom measurement : an open-ended , provider-reported symptom assessment ( provider-report ) and a self-administered symptom survey ( self-report ) . Agreement was measured using kappa scores . Sensitivity and specificity were calculated using self-report as the st and ard . Reliability was measured by intersite variation and test-retest reliability ( 8 weeks later ) . Clinical validity was evaluated by testing expected associations with functional status , global quality of life , and survival . RESULTS Symptom data were available for 808 patients ( 96 % ) . Patient and provider agreement was poor ( mean kappa , 0.14 ; range , 0.07 - 0.25 ) . Compared with self-report , providers underreported the presence and severity of symptoms ( mean symptom count , 5.2 versus 1.3 ; mean severity score , 1.3 versus 0.74 ) . provider-report demonstrated greater variability by site ( R2 associated with site , 0.02 versus 0.16 ) and poorer test-retest reliability ( mean kappa , 0.34 versus 0.25 ) . Provider-report severity scores were less strongly associated than were self-report with functional status ( chi2 , 252 versus 80 ) , global quality of life ( R2 for model , 0.57 versus 0.15 ) , and survival ( chi2 , 38 versus 24 ) . Self-reported symptom severity was strongly correlated to patient-reported global quality of life ( p , 0.75 ; p < .0001 ) . CONCLUSIONS Provider-reported symptoms as currently collected within the ACTG are less sensitive and reproducible than a self-administered symptom survey . Provider-reported severity scores are also more weakly associated with functional status , global quality of life , and survival . A self-reported symptom survey may provide a better method of symptom measurement for HIV research BACKGROUND The tricyclic antidepressant dothiepin is well established in Europe , but clinical experience with the drug in the United States is limited . METHOD In a 10-week , multicenter , r and omized , double-blind , placebo-controlled study in the United States , the efficacy and tolerability of dothiepin and doxepin ( both administered as a 150-mg nightly dose ) were compared in 579 out patients with major depression . RESULTS Patients in both active treatment groups showed significant improvements in depressive symptoms , associated anxiety , and sleep parameters compared with the placebo-treated group . The adverse effect profile of dothiepin was superior to that of doxepin , particularly with respect to drowsiness , weight gain , and increased appetite . CONCLUSION These results confirm that dothiepin is useful when a tricyclic agent is indicated for the treatment of depression R and omised placebo-controlled trials ( RCT ) are an invaluable tool for testing the efficacy of new treatment strategies . The choice of placebo in an RCT can affect not only patients ' physical and psychological response to a particular intervention , but also the trial setting , the success of patient blinding to the intervention , and therefore the outcome of the study and the efficacy of treatment in general . Therefore the placebo is intrinsically tied to the trial 's methodology and results . However , although placebos are an important component in r and omised trials , their quality is often left un question ed . A placebo which was not properly vali date d may even have specific effects that lead to false negative results . To address this deficit , we propose a measure of placebo quality using the term placebo to assess the physical aspect of a dummy treatment used in the placebo group of a r and omised controlled trial ( RCT ) . The Placebo Quality Checklist ( PQC ) described here may help investigators select an appropriate placebo and help both investigators and critical readers interpret the findings of studies with more care Background : Interest in the role of expectation in the development of nausea and other adverse conditions has existed for decades . The purpose of this study was to examine the effects of manipulating expectations through the administration of placebos and nocebos on nausea and gastric tachyarrhythmia provoked by a rotating optokinetic drum . Method : Seventy-five participants were assigned to one of three groups . Positive-expectancy group participants were given placebo pills that would allegedly protect them against the development of nausea and motion sickness . Negative-expectancy group participants were given the same pills as nocebos ; they were led to believe there was a tendency for them to make nausea somewhat worse . Placebo-control group participants were told the pills were indeed placebos that would have no effect whatsoever . Results : Subjective symptoms of motion sickness were significantly lower among negative-expectancy group participants than positive-expectancy and placebo-control group participants ( p < 0.05 ) . Gastric tachyarrhythmia , the abnormal stomach activity that frequently accompanies nausea , was also significantly lower among negative-expectancy group participants than positive-expectancy and Placebo-Control Group participants during drum rotation ( p<.05 ) . Conclusions : Inducing negative expectations through nocebo administration reduced nausea and gastric dysrhythmia during exposure to provocative motion , whereas positive placebos were ineffective for preventing symptom development . That manipulation of expectation affected gastric physiological responses as well as reports of symptoms , suggests an unspecified psychophysiological mechanism was responsible for the observed group differences . These results also suggest that patients preparing for difficult medical procedures may benefit most from being provided with detailed information about how unpleasant their condition may become . SSMS = subjective symptoms of motion sickness ; EGG = electrogastrogram ; ANOVA = analysis of variance ; FFT = fast-Fourier transform The objective of the study was to examine the efficacy of fluoxetine in social phobia . Sixty subjects were r and omly assigned to 14 weeks of double-blind therapy with either fluoxetine or placebo . Dose was fixed at 20 mg for fluoxetine during the first 8 weeks of double-blind treatment ; during the final 6 weeks , the dose could be increased every two weeks by 20 mg to a maximum of 60 mg/day . An intentto-treat analysis was used . A significant change from baseline to endpoint was found for both fluoxetine and placebo on the Liebowitz Social Anxiety Scale . However , no significant difference was found between fluoxetine and placebo . The change for fluoxetine was somewhat lower than that found with other selective serotonin reuptake inhibitors , whereas the placebo response was greater . Fluoxetine failed to separate from placebo in this trial . It is unknown whether a larger dose for longer duration would have yielded separation from placebo . A higher than usual placebo response rate was found OBJECTIVES To determine the effectiveness of fluoxetine hydrochloride at fixed doses of 20 mg/d , 40 mg/d , and 60 mg/d in patients with obsessive-compulsive disorder ( OCD ) and to evaluate its safety . METHODS Fixed-dose fluoxetine hydrochloride ( 20 mg/d , 40 mg/d , 60 mg/d ) was compared with placebo in two r and omized , double-blind , parallel , 13-week trials of identical design in 355 out patients with OCD aged 15 to 70 years ( DSM-III-R criteria ; 1 year 's duration or longer ; depression secondary if present ) . RESULTS Fluoxetine ( all doses ) was significantly ( P < or = .001 ) superior to placebo on the Yale-Brown Obsessive Compulsive Scale ( Y-BOCS ) total score ( mean baseline-to-end-point decrease , 4.6 , 5.5 , and 6.5 vs 0.9 , respectively , studies pooled ) and other efficacy measures ( P < or = .01 ) . A trend suggesting greater efficacy at 60 mg/d was observed . Most patients ( 79.2 % ) completed the study . Eight adverse events were statistically significantly more frequent with fluoxetine and one , with placebo . For some events , incidence tended to increase with increasing dosage ; however , few patients discontinued treatment for any single event . CONCLUSION Fluoxetine was associated with a statistically significant reduction in OCD severity , including time engaged in obsessional and /or compulsive behaviors . Adverse events infrequently led to study discontinuation The efficacy of clomipramine hydrochloride in the treatment of agoraphobia was investigated in an eight-week placebo-controlled double-blind study . One hundred eight women diagnosed as agoraphobic by DSM-III guidelines were r and omly assigned to the clomipramine or placebo group ; 70 women ( mean age , 36.6 years ) completed the eight-week trial . The study medication was prescribed on the basis of weekly increments to a maximum of 300 mg/d , with a mean dosage at week 8 in the clomipramine hydrochloride group of 82.8 mg/d . Assessment s performed prior to the trial and at the four- and eight-week points included the completion of st and ardized question naires and daily diaries , as well as the administration of a Behavioral Approach Test . Clomipramine was significantly superior to the placebo on several indexes of phobic symptoms and on measures of depression and dysphoria . Results are discussed in terms of the hypothesized action of clomipramine and the pattern of significant findings OBJECTIVE The aim of this study was to examine the efficacy , safety , and tolerability of paroxetine in adolescents with unipolar major depression . METHOD Two hundred eighty-six ( 286 ) adolescents with unipolar major depression were r and omly assigned to receive either paroxetine or placebo for 12 weeks . RESULTS The proportion of Montgomery-Asberg Depression Rating Scale ( MADRS ) responders ( at least 50 % reduction from baseline ) for paroxetine and placebo were similar and not statistically different at endpoint ( p = 0.702 ) . A similar result was obtained for change from baseline on the Kiddie-Schedule for Affective Disorders and Schizophrenia for School- Age Children ( K-SADS-L ) depression subscale . Among secondary endpoints , only a significantly higher Clinical Global Impression-Improvement ( CGI-I ) response rate was reported in paroxetine-treated patients versus placebo ( 69.2 % versus 57.3 % ; p = 0.045 ) . In general , results differed by age , with patients older than 16 years demonstrating a greater response to active treatment . This age group also reported more adverse experiences ( AEs ) relative to placebo than younger adolescents . Overall , paroxetine was generally well tolerated ( 11 % discontinued owing to an AE versus 7 % of placebo-treated patients ) . A post hoc analysis of AEs related to suicidal behavior suggested a greater incidence of these events for paroxetine than for placebo ( 4.4 % versus 2.1 % ) ; however , this difference was not statistically significant ( odds ratio , 2.15 , 95 % Confidence Interval 0.45 , 10.33 ; p = 0.502 ) . CONCLUSIONS No statistically significant differences were observed for paroxetine compared with placebo on the two prospect ively defined primary efficacy variables . Paroxetine at 20 - 40 mg/day administered over a period of up to 12 weeks was generally well tolerated CONTEXT The empirical literature on treatment of obsessive-compulsive disorder ( OCD ) in children and adolescents supports the efficacy of short-term OCD-specific cognitive-behavior therapy ( CBT ) or medical management with selective serotonin reuptake inhibitors . However , little is known about their relative and combined efficacy . OBJECTIVE To evaluate the efficacy of CBT alone and medical management with the selective serotonin reuptake inhibitor sertraline alone , or CBT and sertraline combined , as initial treatment for children and adolescents with OCD . DESIGN , SETTING , AND PARTICIPANTS The Pediatric OCD Treatment Study , a balanced , masked r and omized controlled trial conducted in 3 academic centers in the United States and enrolling a volunteer outpatient sample of 112 patients aged 7 through 17 years with a primary Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition diagnosis of OCD and a Children 's Yale-Brown Obsessive-Compulsive Scale ( CY-BOCS ) score of 16 or higher . Patients were recruited between September 1997 and December 2002 . INTERVENTIONS Participants were r and omly assigned to receive CBT alone , sertraline alone , combined CBT and sertraline , or pill placebo for 12 weeks . MAIN OUTCOME MEASURES Change in CY-BOCS score over 12 weeks as rated by an independent evaluator masked to treatment status ; rate of clinical remission defined as a CY-BOCS score less than or equal to 10 . RESULTS Ninety-seven of 112 patients ( 87 % ) completed the full 12 weeks of treatment . Intent-to-treat r and om regression analyses indicated a statistically significant advantage for CBT alone ( P = .003 ) , sertraline alone ( P = .007 ) , and combined treatment ( P = .001 ) compared with placebo . Combined treatment also proved superior to CBT alone ( P = .008 ) and to sertraline alone ( P = .006 ) , which did not differ from each other . Site differences emerged for CBT and sertraline but not for combined treatment , suggesting that combined treatment is less susceptible to setting -specific variations . The rate of clinical remission for combined treatment was 53.6 % ( 95 % confidence interval [ CI ] , 36%-70 % ) ; for CBT alone , 39.3 % ( 95 % CI , 24%-58 % ) ; for sertraline alone , 21.4 % ( 95 % CI , 10%-40 % ) ; and for placebo , 3.6 % ( 95 % CI , 0%-19 % ) . The remission rate for combined treatment did not differ from that for CBT alone ( P = .42 ) but did differ from sertraline alone ( P = .03 ) and from placebo ( P<.001 ) . CBT alone did not differ from sertraline alone ( P = .24 ) but did differ from placebo ( P = .002 ) , whereas sertraline alone did not ( P = .10 ) . The 3 active treatments proved acceptable and well tolerated , with no evidence of treatment-emergent harm to self or to others . CONCLUSION Children and adolescents with OCD should begin treatment with the combination of CBT plus a selective serotonin reuptake inhibitor or CBT alone CONTEXT Major depression affects about 25 % of the patients who have Alzheimer disease and has serious adverse consequences for patients and caregivers . Results of prior antidepressant treatment studies have produced contradictory findings and have not fully assessed the benefits of depression reduction . OBJECTIVES To assess the efficacy and safety of sertraline hydrochloride for the treatment of major depression in Alzheimer disease , and to evaluate the effect of depression reduction on activities of daily living , cognition , and nonmood behavioral disturbance . DESIGN R and omized , placebo-controlled , parallel , 12-week , flexible-dose clinical trial with a 1-week , single-blind placebo phase . The study was conducted between January 1 , 1998 , and July 19 , 2001 . SETTING University outpatient clinic . PARTICIPANTS Forty-four out patients who have probable Alzheimer disease and major depressive episodes . INTERVENTION Sertraline hydrochloride , mean dosage of 95 mg/d , or identical placebo , r and omly assigned . MAIN OUTCOME MEASURES Response rate , Cornell Scale for Depression in Dementia , Hamilton Depression Rating Scale , Mini-Mental State Examination , Psychogeriatric Depression Rating Scale-activities of daily living subscale , and Neuropsychiatric Inventory to quantify patient behavior disturbance and caregiver distress . RESULTS In the sertraline-treated group 9 patients ( 38 % ) were full responders and 11 ( 46 % ) were partial responders compared with 3 ( 20 % ) and 4 ( 15 % ) , respectively , in the placebo-treated group ( P = .007 ) . The sertraline-treated group had greater improvements in the scores for the Cornell Scale for Depression in Dementia ( P = .002 ) and Hamilton Depression Rating Scale ( P = .01 ) , and a statistical trend toward less decline in activities of daily living on the Psychogeriatric Depression Rating Scale-activities of daily living subscale ( P = .07 ) . There was no difference between the treatment groups in Mini-Mental State Examination ( P = .22 ) or Neuropsychiatric Inventory ( P = .32 ) ratings over time . When full responders , partial responders , and nonresponders were compared , full responders only , or full and partial responders had significantly better ratings on activities of daily living ( P = .04 ) , behavioral disturbance ( P = .01 ) , and caregiver distress ( P = .006 ) , but not on the Mini-Mental State Examination ( P = .76 ) . Safety monitoring indicated few differences in adverse effects between the 2 treatment groups . CONCLUSIONS Sertraline is superior to placebo for the treatment of major depression in Alzheimer disease . Depression reduction is accompanied by lessened behavior disturbance and improved activities of daily living , but not improved cognition Amitriptyline hydrochloride was compared with placebo in 46 veterans with chronic posttraumatic stress disorder . Treatment continued up to 8 weeks , and efficacy was measured by five observer and two self-rated scales . Percent recovery rates were higher for amitriptyline than placebo on two measures . In patients who completed 4 weeks ( n = 40 ) , better outcome with amitriptyline was noted on the Hamilton depression scale only . In the group completing 8 weeks of treatment ( n = 33 ) , the drug was superior to placebo on Hamilton depression , Hamilton anxiety , Clinical Global Impression severity , and Impact of Event scales . There was no evidence for drug effects on the structured interview for posttraumatic stress disorder . Drug-placebo differences were greater in the presence of comorbidity in general , although recovery rates were uniformly low in the presence of major depression , panic disorder , and alcoholism . At the end of treatment , 64 % of the amitriptyline and 72 % of the placebo sample s still met diagnostic criteria for posttraumatic stress disorder CONTEXT Despite the high prevalence , chronicity , and associated comorbidity of posttraumatic stress disorder ( PTSD ) in the community , few placebo-controlled studies have evaluated the efficacy of pharmacotherapy for this disorder . OBJECTIVE To determine if treatment with sertraline hydrochloride effectively diminishes symptoms of PTSD of moderate to marked severity . DESIGN Twelve-week , double-blind , placebo-controlled trial preceded by a 2-week , single-blind placebo lead-in period , conducted between May 1996 and June 1997 . SETTING Outpatient psychiatric clinics in 8 academic medical centers and 6 clinical research centers . PATIENTS A total of 187 out patients with a Diagnostic and Statistical Manual of Mental Disorders , Revised Third Edition diagnosis of PTSD and a Clinician Administered PTSD Scale Part 2 ( CAPS-2 ) minimum total severity score of at least 50 at baseline ( mean age , 40 years ; mean duration of illness , 12 years ; 73 % were women ; and 61.5 % experienced physical or sexual assault ) . INTERVENTION Patients were r and omized to acute treatment with sertraline hydrochloride in flexible daily dosages of 50 to 200 mg/d , following 1 week at 25 mg/d ( n=94 ) ; or placebo ( n=93 ) . MAIN OUTCOME MEASURES Baseline-to-end-point changes in CAPS-2 total severity score , Impact of Event Scale total score ( IES ) , and Clinical Global Impression-Severity ( CGI-S ) , and CGI-Improvement ( CGI-I ) ratings , compared by treatment vs placebo groups . Results Sertraline treatment yielded significantly greater improvement than placebo on 3 of the 4 primary outcome measures ( mean change from baseline to end point for CAPS-2 total score , -33.0 vs -23.2 [ P = .02 ] , and for CGI-S , -1.2 vs -0.8 [ P=.01 ] ; mean CGI-I score at end point , 2.5 vs 3.0 [ P=.02 ] ) , with the fourth measure , the IES total score , showing a trend toward significance ( mean change from baseline to end point , -16.2 vs -12.1 ; P=.07 ) . Using a conservative last-observation-carried-forward analysis , treatment with sertraline result ed in a responder rate of 53 % at study end point compared with 32 % for placebo ( P=.008 , with responder defined as > 30 % reduction from baseline in CAPS-2 total severity score and a CGI-I score of 1 [ very much improved ] , or 2 [ much improved ] ) . Significant ( P<.05 ) efficacy was evident for sertraline from week 2 on the CAPS-2 total severity score . Sertraline had significant efficacy vs placebo on the CAPS-2 PTSD symptom clusters of avoidance/numbing ( P=.02 ) and increased arousal ( P=.03 ) but not on reexperiencing/intrusion ( P=.14 ) . Sertraline was well tolerated , with insomnia the only adverse effect reported significantly more often than placebo ( 16.0 % vs 4.3 % ; P=.01 ) . CONCLUSIONS Our data suggest that sertraline is a safe , well-tolerated , and effective treatment for PTSD BACKGROUND The objective of this r and omized , double-blind , placebo-controlled study was to investigate the efficacy and safety of paroxetine in out patients with generalized anxiety disorder ( GAD ) . METHOD Male and female out patients 18 years and older who met DSM-IV criteria for GAD and had baseline scores of at least 20 on the Hamilton Rating Scale for Anxiety ( HAM-A ) were r and omly assigned to treatment with paroxetine ( 20 - 50 mg/day ) or placebo for 8 weeks . The primary efficacy variable was the mean change from baseline in the total score of the HAM-A. Additional key efficacy variables were the change from baseline in the scores of the HAM-A items anxious mood and tension , the anxiety subscale of the Hospital Anxiety and Depression Scale , and the Sheehan Disability Scale ( SDS ) . The proportions of patients fulfilling response and remission criteria at week 8 were also determined . RESULTS The intent-to-treat population included 324 patients . At week 8 , compared with the placebo group ( N = 163 ) , the paroxetine group ( N = 161 ) had a significantly greater reduction of GAD symptoms on all of the above-mentioned efficacy variables . On the HAM-A anxious mood item , which encompasses the cardinal symptoms of GAD , significantly greater efficacy was observed from week 1 and on the SDS significantly greater improvement was documented in the domain " social life " as early as week 4 for paroxetine compared with placebo . In both the last-observation-carried-forward and completer data sets , significantly greater proportions of paroxetine-treated patients achieved response or remission by week 8 . Treatment with paroxetine was well tolerated , and the number and type of adverse events recorded in the paroxetine group correspond to the known safety profile of this medication . CONCLUSION Paroxetine in doses of 20 to 50 mg once daily is effective in the treatment of patients with GAD . Improvement of core symptoms of GAD occurs early and is associated with significant reduction in disability after only 8 weeks of treatment & NA ; Data from two fixed‐dose studies of sertraline in panic disorder were pooled in order to provide sufficient power for the analysis of treatment response in clinical ly relevant subgroups . Male and non‐fertile female patients meeting DSM‐III‐R criteria for moderate‐to‐severe panic disorder with or without agoraphobia completed a 1‐2 week placebo run‐in period , and then were r and omized to 12 weeks of double‐blind treatment with either placebo , or one of three fixed daily doses of sertraline ( 50 mg , 100 mg , or 200 mg ) . Eighty‐two patients were treated with placebo and 240 patients were treated with one of three doses of sertraline . All three sertraline doses produced significant efficacy compared to placebo , with no consistent evidence of a dose‐response effect . For the subset of patients with subsyndromic depression at baseline [ baseline Hamilton Depression Rating scale ( HAM‐D > 12 and ≤ 21 ] , sertraline yielded a significantly higher panic‐free rate than did placebo ( P = 0.021 ) , again , by a conservative endpoint ( Last Observation Carried Forward method , LOCF ) analysis . Sertraline was well‐tolerated at all dose levels , with no significant between‐dose differences in patients discontinuing due to adverse events . The presence of mild‐to‐moderate subsyndromic levels of depression did not reduce the anti‐panic efficacy of sertraline . Int Clin Psychopharmacol 15:335‐342 © 2000 Lippincott Williams & & NA ; Escitalopram was compared to placebo in moderately to severely depressed patients in primary care with citalopram as the active reference . Patients were r and omized to receive flexible doses of 10–20 mg/day escitalopram ( n=155 ) , 20–40 mg/day citalopram ( n=160 ) , or placebo ( n=154 ) over an 8‐week double‐blind period . The primary efficacy parameter was the change from baseline to last assessment in the Montgomery – Asberg Depression Rating Scale total score . Escitalopram produced a statistically significant therapeutic difference of 2.9 points ( P=0.002 ) compared to placebo , and escitalopram was consistently and statistically significantly more efficacious than placebo from week 1 onwards . Analysis of Clinical Global Impression – Severity and Clinical Global Impression – Improvement confirmed the primary efficacy results . By week 8 , significantly more patients had responded to treatment with escitalopram than with citalopram ( P=0.021 ) or placebo ( P=0.009 ) . Escitalopram was as well tolerated as citalopram and had a similar adverse event profile . Both escitalopram‐ and citalopram‐treated patients had placebo‐level adverse event withdrawal rates ( 3 % and 4 % , respectively ) . This study demonstrates the consistent antidepressant efficacy and excellent tolerability of escitalopram 10–20 mg/day in primary care patients with major depressive disorder OBJECTIVE Management of depression in elderly patients presents a significant medical challenge , and there is a need for further clinical trials . The authors examined the efficacy and tolerability of escitalopram and fluoxetine versus placebo in the treatment of elderly patients with major depressive disorder ( MDD ) . METHODS This was an 8-week , r and omized , double-blind comparison of the efficacy and tolerability of escitalopram ( 10 mg/day ) and fluoxetine ( 20 mg/day ) , to placebo in elderly patients with MDD . The prospect ively defined primary efficacy parameter was the change from baseline in mean Montgomery-Asberg Depression Rating Scale ( MADRS ) total score at endpoint , using last observation carried forward . RESULTS The intent-to-treat set comprised 517 patients ; the escitalopram group included 173 patients ; fluoxetine , 164 patients ; and placebo , 180 patients . Mean age was 75 years , with a range of 65 to 93 . Formally , this was a " failed study " ( i.e. , neither active treatment was superior to placebo ) , and the efficacy results should , therefore , be interpreted with caution . On the basis of the primary efficacy parameter , fluoxetine showed significantly lower efficacy than both escitalopram and placebo , which were not significantly different from each other . Rates of withdrawal because of adverse events/lack of efficacy were : placebo ( 2.8%/4.4 % , respectively ) , escitalopram ( 9.8%/1.7 % , respectively ) , and fluoxetine ( 12.2%/1.8 % , respectively ) . No single adverse event occurred at an incidence > or = 10 % in escitalopram-treated patients . CONCLUSIONS Both escitalopram and fluoxetine were well tolerated by elderly patients with MDD . Neither demonstrated superior efficacy on primary endpoint versus placebo Children and adolescents with obsessive compulsive disorder were studied in an 8-week , multicenter , double-blind , parallel groups trial of clomipramine hydrochloride ( CMI ) versus placebo . Efficacy assessment s included the child version of the Yale-Brown Obsessive Compulsive Scale and the National Institute of Mental Health Global rating scale . At the end of 8 weeks , CMI-treated patients showed a mean reduction in Yale-Brown Obsessive Compulsive Scale score of 37 % compared to 8 % in the placebo group . Side effects were typical of tricyclic antidepressants . In a 1-year open label treatment , CMI continued to be effective and well tolerated OBJECTIVE The study compared the safety and efficacy of sertraline , a selective serotonin reuptake inhibitor , and placebo in the treatment of generalized anxiety disorder in children and adolescents . METHOD The study subjects were 22 children and adolescents age 5 - 17 years who met the DSM-IV criteria for generalized anxiety disorder according to the Anxiety Disorders Interview Schedule for Children-Revised and who had a Hamilton Anxiety Rating Scale score > or = 16 . The patients underwent a 2 - 3-week pre study evaluation period , followed by a 9-week double-blind treatment phase in which they were r and omly assigned in blocks of four to receive either sertraline or pill placebo . The maximum dose of sertraline was 50 mg/day . Primary outcome measures were the Hamilton anxiety scale and the Clinical Global Impression scale . RESULTS The Hamilton anxiety scale total score , psychic factor , and somatic factor and the Clinical Global Impression severity and improvement scales showed significant differences with treatment in favor of sertraline over placebo beginning at week 4 . Self-report measures reflected these results at the end of treatment . CONCLUSIONS The results of this double-blind , placebo-controlled trial suggest that sertraline at the daily dose of 50 mg is safe and efficacious for the treatment of generalized anxiety disorder in children and adolescents Abstract In patients who reported mild postoperative pain , we evoked a nocebo response , a phenomenon equal but opposite to placebo . Patients who gave informed consent to increase their pain for 30 min received a substance known to be non – hyperalgesic ( saline solution ) and were told that it produced a pain increase . A nocebo effect was observed when saline was administered . However , if a dose of 0.5 or 5 mg of the cholecystokinin antagonist proglumide was added to the saline solution , the nocebo effect was abolished . A dose of 0.05 mg of proglumide was ineffective . The blockade of the nocebo hyperalgesic response was not reversed by 10 mg of naloxone . These results suggest that cholecystokinin mediates pain increase in the nocebo response and that proglumide blocks nocebo through mechanisms not involving opioids . Since the nocebo procedure represents an anxiogenic stimulus and previous studies showed a role for cholecystokinin in anxiety , we suggest that nocebo hyperalgesia may be due to a cholecystokinin‐dependent increase of anxiety Twenty-four depressed patients with heart disease were treated for four weeks in a double-blind trial of imipramine , doxepin , or placebo to assess the effects of tricyclic antidepressants on ventricular function and rhythm . The tricyclic antidepressants had no effect on left ventricular ejection fraction at rest or during maximal exercise , as measured by radionuclide ventriculograms obtained before and after treatment . Premature ventricular contractions were reduced by imipramine but were not consistently changed by doxepin or placebo . Treatment with imipramine and doxepin , but not placebo , was associated with significant improvement ( P less than 0.001 ) in st and ard ratings of depression . Our findings underscore the need for a re appraisal of the cardiovascular risks of tricyclic antidepressants and suggest that in the absence of severe impairment of myocardial performance , depressed patients with preexisting heart disease can be effectively treated with these agents without an adverse effect on ventricular rhythm or hemodynamic function Paroxetine is a phenylpiperidine compound that selectively inhibits neuronal serotonin uptake in man . In this study , the efficacy of paroxetine was compared with that of placebo in the treatment of 66 out patients with the diagnosis of moderate-to-severe major depression . The research was a 6-week , prospect i ve , double-blind design after a 1-week placebo baseline phase . Paroxetine was associated with a consistent pattern of greater improvement on the primary efficacy scales , but the differences were not statistically significant . Paroxetine did produce significantly greater improvement than placebo for patients whose illness had lasted more than 1 year , and there was a significant reduction in suicidal ideation . Significantly fewer dropouts were due to lack of efficacy in those patients treated with paroxetine compared with those in the placebo group . Paroxetine was well tolerated . There was no difference between paroxetine and placebo in the rate of adverse effects or in the number of patients who dropped out because of adverse effects OBJECTIVE To assess the efficacy and safety of paroxetine for the treatment of pediatric obsessive-compulsive disorder . METHOD Children ( 7 - 11 years of age ) and adolescents ( 12 - 17 years of age ) meeting DSM-IV criteria for obsessive-compulsive disorder were r and omized to paroxetine ( 10 - 50 mg/day ) or placebo for 10 weeks . The primary efficacy measure was change from baseline in the Children 's Yale-Brown Obsessive-Compulsive Scale ( CY-BOCS ) total score at week 10 last observation carried forward end point . Safety was assessed primarily through adverse event monitoring . RESULTS A total of 207 patients were r and omized to treatment . Of these , 203 were included in the intention-to-treat population . Adjusted mean changes from baseline at week 10 observation carried forward end point in CY-BOCS total score for patients receiving paroxetine and placebo were -8.78 ( SE=0.82 ) and -5.34 points ( SE=0.77 ) , respectively . The adjusted mean difference , -3.45 in favor of paroxetine , was statistically significant ( 95 % confidence interval=-5.60 to -1.29 , p=.002 ) . Adverse events were generally mild to moderate in intensity . A total of 10.2 % ( 10/98 ) of patients in the paroxetine group and 2.9 % ( 3 of 105 ) in the placebo group discontinued treatment because of adverse events . CONCLUSIONS Paroxetine is an effective and generally well-tolerated treatment for obsessive-compulsive disorder in children and adolescents Paroxetine is an investigational antidepressant that acts through selective inhibition of serotonin reuptake at the synapse . In this study , 81 out patients with major depression according to DSM-III criteria were treated with either paroxetine or placebo in a 6-week , r and omized , double-blind study . Paroxetine was significantly superior to placebo on all major efficacy variables , including depression as well as anxiety , cognitive disturbance , insomnia , psychomotor retardation , and sleep disturbance . Significant differences in favor of paroxetine were apparent by Week 2 . Paroxetine was also well tolerated . The results support the efficacy and safety of paroxetine as a treatment for patients with major depression Eighty-seven patients with a DSM-III diagnosis of obsessive-compulsive disorder ( OCD ) without depression were entered into a double-blind , placebo-controlled study of the efficacy of sertraline , a new serotonin uptake inhibitor . After a 1-week washout period , patients were r and omly assigned to receive either placebo or sertraline . After a 2-week titration period in which the once-daily sertraline dose was increased from 50 mg/day to a maximum of 200 mg/day , dosage was maintained until the end of the eighth week , then patients were titrated off medication over the next 2 weeks . Efficacy was measured by the Yale-Brown Obsessive-Compulsive Scale ( Y-BOCS ) , NIMH General Obsessive-Compulsive Scale , Maudsley Obsessive Compulsive ( MOC ) Inventory , and Clinical Global Impressions ( CGI ) Severity and Improvement scales . Results on the MOC Inventory showed trends in favor of active drug that were not statistically significant compared with placebo . Results of the Y-BOCS total score , the NIMH score , and the global severity and improvement scores demonstrated a statistically significant superiority of sertraline compared with placebo The enhanced sensitivity of the elderly to the side effects produced by tricyclic antidepressants ( TCAs ) , and the frequency and type of adverse events , have made the treatment of depression in this group difficult . The selective serotonin reuptake inhibitors ( SSRIs ) have been reported to produce significantly fewer undesirable side effects and display better tolerance than TCAs . We compared the therapeutic actions and side effects produced by citalopram , the most selective SSRI available , with amitriptyline in a group of elderly patients ( aged 65 and older ) diagnosed with major depression . In a double-blind , double-dummy , parallel-group , multicenter comparison of citalopram ( 20 or 40 mg/day ) and amitriptyline ( 50 or 100 mg/day ) , patients who did not respond to placebo during a 1-week single-blind phase were r and omly assigned to receive citalopram or amitriptyline for 8 weeks . Efficacy measures included the Montgomery-Asberg Depression Rating Scale ( MADRS ) , the Hamilton Depression Scale ( HAMD ) , and Clinical Global Impressions . Both drug treatments produced equivalent time-related declines in severity of depression , so that by 8 weeks slightly more than 50 % of the patients in each group experienced marked recovery , defined as MADRS scores < or = 12 . Amitriptyline produced a greater overall incidence of adverse events , including a significantly higher ( P < 0.001 ) percentage of patients reporting dry mouth ( 34 % vs. 7 % ) , as well as a significantly higher ( P < 0.02 ) incidence of somnolence . Constipation and fatigue also occurred more frequently in the amitriptyline than in the citalopram group . For only one event ( nausea ) did the citalopram group report a significantly greater ( P = 0.012 ) incidence ( 12.8 % vs. 4.8 % ) . On the basis of these results , it was concluded that citalopram is as effective an antidepressant as amitriptyline in the treatment of the depressed elderly . Because of its low incidence and low magnitude of side effects , citalopram seems especially useful in private practice In a multicentered study , 372 patients with mild major depressive disorder with a Hamilton Rating Scale for Depression ( HAM-D ) score of 15 to 19 were r and omly assigned to 6 weeks of treatment with placebo or 20 mg , 40 mg , or 60 mg/day of fluoxetine . Patients were rated weekly for improvement and the appearance of side effects . Pattern analysis of treatment response showed more patients in the active drug treatment groups having a persistent or a delayed persistent response , the types of response specifically associated with active treatment . Analyses of mean changes in treatment measures showed little difference among treatment groups . This may be explained in part by different distributions in outcome , placebo patients having had a higher frequency of mild improvement with fewer negative and very positive outcomes . Response rate analyses favor the active treatments numerically , but only one of the comparisons is statistically significant . These findings suggest a specific role for fluoxetine treatment in mildly depressed patients who do not respond promptly or who respond inconsistently to nonspecific treatment Serotonin reuptake inhibitors appear to be uniquely effective treatments for obsessive-compulsive disorder ( OCD ) . This double-blind , placebo-controlled study was the first trial to assess the efficacy of the most selective of the serotonin reuptake inhibitors , citalopram , in OCD . A total of 401 patients were r and omized to receive citalopram 20 , 40 or 60 mg/day or placebo for 12 weeks . All three doses of citalopram were significantly more effective than placebo measured on the Yale-Brown Obsessive Compulsive Scale ( Y-BOCS ) change score ( P < 0.01 ) . The highest response rate , defined as 25 % improvement in Y-BOCS entry score , was observed in the 60 mg group ( 65 % ) . This compared with 52 % and 57.4 % in the 40 mg and 20 mg groups . Response rate on placebo was 36.6 % ( P < 0.05 for all three doses of citalopram compared to placebo ) . There was no significant difference between the individual doses of citalopram . An advantage was seen for citalopram on the Sheehan Disability Scale compared with placebo ( P < 0.05 on all three citalopram groups versus placebo for both the work situation and the family life and home responsibilities and P < 0.05 on citalopram 60 mg and 20 mg versus placebo for the social life and home activities ) . Citalopram was well tolerated ; only 4 to 6 patients in each dose group discontinued the study prematurely due to adverse events We investigated the effects of expectation on intensity ratings and somatosensory evoked magnetic fields and electrical potentials following painful infrared laser stimuli in six healthy subjects . The stimulus series contained trials preceded by different auditory cues which either contained valid , invalid or no information about the upcoming laser intensity . High and low intensities occurred equally probable across cue types . High intensity stimuli induced greater pain than low intensity across all cue types . Furthermore , laser intensity significantly interacted with cue validity : high intensity stimuli were perceived less painful and low intensity stimuli more painful following invalid compared to valid cues . The amplitude of the evoked magnetic field localized within the contralateral secondary somatosensory cortex ( SII ) at about 165 ms after laser stimuli varied also both with stimulus intensity and cue validity . The evoked electric potential peaked at about 300 ms after laser stimuli and yielded a single dipole source within a region encompassing the caudal anterior cingulate cortex and posterior cingulate cortex . Its amplitude also varied with stimulus intensity , but failed to show any cue validity effects . This result suggests a priming of early cortical nociceptive sensitivity by cues signaling pain severity . A possible contribution of the SII cortex to the manifestation of nocebo/placebo cognitions is discussed The results of double blind trial in which 139 patients with primary depression were r and omly assigned to either lofepramine ( 46 ) , imipramine ( 48 ) , or placebo ( 45 ) are discussed . After treatment with either active drug , lofepramine or imipramine , the clinical outcome was significantly greater than with placebo . No significant differences were found in clinical responses between lofepramine and imipramine . With regard to reported side effects , however , a statistically significant lower number of severe and /or moderate side effects were reported for the lofepramine group than for the imipramine group . In particular , for severe and /or moderate occurrences of dry mouth , the statistically significant lower incidence in favor of lofepramine is by almost a factor of 3 ( 8 lofepramine vs 21 imipramine patients ) Serotonergic mechanisms have been implicated in panic disorder , and several preliminary studies suggest that fluvoxamine , a selective serotonin reuptake inhibitor ( SSRI ) , is helpful in its treatment . This 8-week double-blind parallel-group study compared fluvoxamine with a placebo in 188 patients with DSM-III-R defined panic disorder with or without agoraphobia . Efficacy assessment s included a Daily Panic Attack Inventory , the Sheehan Disability Scale , the Clinical Anxiety Scale and the Clinical Global Impression Scale . When compared with the placebo , fluvoxamine produced highly significant improvements in most measures of the frequency and severity of panic disorder and in the more global aspects of disability and distress . Significant improvement was evident as early as week 1 for some panic variables . Fluvoxamine is a potent anti-panic agent with a relatively rapid onset of action In order to investigate external factors that may influence the magnitude of placebo analgesia as well as psychological factors that mediate placebo analgesia , 13 irritable bowl syndrome ( IBS ) patients rated evoked rectal distension and cutaneous heat pain under the conditions of natural history ( NH ) , rectal placebo ( RP ) , rectal nocebo ( RN ) , rectal lidocaine ( RL ) and oral lidocaine ( OL ) . Patients were given verbal suggestions for pain relief and rated expected pain levels and desire for pain relief for both evoked visceral and cutaneous pain , respectively . Large reductions in pain intensity and pain unpleasantness ratings were found in the RP , RL and OL condition as compared to the natural history condition , whereas no significant difference in pain reduction between the three treatment conditions was found . Ratings during RN and NH were not statistically different . Compared to a previous study , which shows that rectal lidocaine reverses visceral and cutaneous hyperalgesia , these results suggest that adding a verbal suggestion for pain relief can increase the magnitude of placebo analgesia to that of an active agent . Since IBS patients rate these stimuli as much higher than do normal control subjects and since placebo effects were very large , they probably reflect anti‐hyperalgesic mechanisms to a major extent . Expected pain levels and desire for pain relief accounted for large amounts of the variance in visceral pain intensity in the RP , RL , and OL condition ( up to 81 % ) , and for lower amounts of the variance in cutaneous pain intensity . Hence , the combination of expected pain levels and desire for pain relief may offer an alternative means of assessing the contribution of placebo factors during analgesia BACKGROUND Selective serotonin reuptake inhibitors are effective in the treatment of social anxiety disorder and are currently regarded as the pharmacotherapy of choice . AIMS To investigate the efficacy and tolerability of escitalopram in the treatment of generalised social anxiety disorder . METHOD Patients with generalised social anxiety disorder were r and omised to receive placebo ( n=177 ) or 10 - 20 mg escitalopram ( n=181 ) in a 12-week , double-blind trial . The primary outcome measure was the mean change from baseline to last assessment in the Liebowitz Social Anxiety Scale ( LSAS ) total score . RESULTS The study showed a statistically superior therapeutic effect for escitalopram compared with placebo on the LSAS total score ( P=0.005 ) . There were significantly more responders to treatment for escitalopram than for placebo ( 54 % v. 39 % ; P<0.01 ) . The clinical relevance of these findings was supported by significant reduction in the work and social components of the Sheehan Disability Scale and by the good tolerability of escitalopram treatment . CONCLUSIONS Escitalopram was efficacious and well tolerated in the treatment of generalised social anxiety disorder The study was design ed to test the efficacy of desipramine in adolescents with major depression ( MDD ) . In addition , we assessed the presence of atypical features of MDD , consisting of mood reactivity and two of four associated features ( rejection sensitivity , hyperphagia , hypersomnia , and leaden paralysis ) . Patients were r and omized to desipramine ( DMI ) or placebo for 6 weeks , provided they failed to improve ( e.g. , meeting MDD criteria and a Hamilton Depression Scale score ≥18 ) after 2 weeks on single blind placebo . Of 94 adolescents ( ages 13–18 ) who were diagnosed as having MDD , 64 entered the study and 62 received placebo for 2 weeks . Of these , 45 were r and omized to DMI or placebo . Completer analyses did not reveal significant improvement for the active treatment compared to the placebo . A large proportion of adolescents responded to placebo ( 50 % ) , suggesting the need for very large sample s to detect differential treatment efficacy , should it exist . A relatively high rate of atypical depression was observed ( 47 % in the 64 patients entered ) . In view of the demonstrated specificity of monoamine oxidase inhibitor efficacy in adults with atypical features of MDD , this clinical subtype may have relevance to future investigation of therapeutic interventions in adolescent MDD . Depression and Anxiety 7:15–31 , 1998 . © 1998 Wiley‐Liss , OBJECTIVE To determine the safety and efficacy of fluvoxamine for the treatment of children and adolescents with obsessive-compulsive disorder ( OCD ) with a double-blind , placebo-controlled , multicenter study . METHOD Subjects , aged 8 to 17 years , meeting DSM-III-R criteria for OCD were recruited from July 1991 to August 1994 . After a 7- to 14-day single-blind , placebo washout/screening period , subjects were r and omly assigned to fluvoxamine 50 to 200 mg/day or placebo for 10 weeks . Subjects who had not responded after 6 weeks could discontinue the double-blind phase of the study and enter a long-term , open-label trial of fluvoxamine . Analyses used an intent-to-treat sample with a last-observation-carried-forward method . RESULTS Mean Children 's Yale-Brown Obsessive Compulsive Scale ( CY-BOCS ) scores with fluvoxamine were significantly ( p < .05 ) different from those with placebo at weeks 1 , 2 , 3 , 4 , 6 , and 10 . Significant ( p < .05 ) differences between fluvoxamine and placebo were observed for all secondary outcome measures at all visits . Based on a 25 % reduction of CY-BOCS scores , 42 % of subjects taking fluvoxamine were responders compared with 26 % taking placebo . Forty-six ( 19 fluvoxamine , 27 placebo ) of 120 r and omized subjects discontinued early . Adverse events with a placebo-adjusted rate greater than 10 % were insomnia and asthenia . CONCLUSIONS Fluvoxamine has a rapid onset of action and is well tolerated and efficacious for the short-term treatment of pediatric OCD BACKGROUND Anecdotal evidence suggests patients with obsessive-compulsive disorder ( OCD ) are treated with selective serotonin uptake inhibitors at dosages significantly higher than those used with depressed patients . The current study examined the efficacy , safety , and optimal dosing strategy of sertraline in patients with OCD . METHODS Three hundred twenty-four nondepressed out patients with OCD from 11 sites followed identical protocol s using a double-blind parallel design . Following 1 week of single-blind placebo , patients were r and omly assigned to 12 weeks of treatment with one of three fixed dosages of sertraline ( 50 , 100 , or 200 mg/d ) or placebo . RESULTS Sertraline patients exhibited significantly greater improvement ( P < .05 ) at end point than placebo patients on all three main efficacy measures in the 50-mg/d and 200-mg/d groups and on one measure in the 100-mg/d group . The placebo response was larger in this population of subjects with OCD than in those previously studied . Adverse experiences were common in the sertraline and placebo groups and appeared to be dose-related in the sertraline-treated patients . CONCLUSIONS Results support the safety and efficacy of daily dosages of 50 , 100 , and 200 mg of sertraline in the short-term treatment of patients with OCD Many agents that affect the brain 's serotonergic system appear to be at least partially effective in the treatment of patients with obsessive-compulsive disorder . However , in this 10-week double-blind trial in which 10 patients received sertraline and nine received placebo , sertraline was ineffective according to four measures of obsessive-compulsive symptoms . The authors discuss the implication s of these preliminary findings for the serotonergic theory of obsessive-compulsive disorder and the need to explore the role of other neurochemical systems in this disorder The aim of this study was to determine whether treating concomitant depression improves quality of life and exercise tolerance in COPD patients . Out- patients with moderate to severe , stable COPD completed Hospital Anxiety-Depression ( HAD ) and General Health question naires . A psychiatrist interviewed those with high scores . In a r and omised , double-blind fashion , 28 depressed COPD patients took a selective serotonin re-uptake inhibitor , Paroxetine 20 mg daily , or matched placebo for 6 weeks . Subsequently , all patients took un-blinded Paroxetine for 3 months . From these question naires , 35 % of 135 patients had significant depression , but this was confirmed by psychiatric interview in only 21 % . Throughout the study , there were no changes in laboratory lung function nor in home peak flow . Six weeks ' treatment produced no significant differences between placebo and treatment group in either depression , quality of life scores or 6-minute walking distances , although overall improvements in depression , correlated with increases in walking distance . Three months of un-blinded treatment , significantly improved depression scores ( self-complete HAD , Beck 's Depression and psychiatrist-completed Montgomery-Asberg scores ) , walking distances ( 369 to 427 m , p = 0.0003 ) and St. George 's Respiratory Question naire Total Scores ( 65 to 58 , p = 0.033 ) . Although self-complete question naires over-diagnose depression , the condition is nevertheless common in patients with moderately severe COPD . Six weeks of antidepressants is insufficient to improve either depression , quality of life or exercise tolerance . However , our study suggests that a longer course of treatment may be effective and that improvements in depression are associated with improvements in exercise tolerance . A larger , double blind study with a longer treatment period is indicated OBJECTIVE Anxiety disorders are highly prevalent in elderly persons . However , to date , the efficacy of selective serotonin reuptake inhibitors ( SSRIs ) for the treatment of anxiety disorders in this age group has not been established . METHOD Thirty-four participants age 60 and older with a DSM-IV anxiety disorder ( mainly generalized anxiety disorder ) and a Hamilton Anxiety Rating Scale score of 17 or higher were r and omly assigned under double-blind conditions to either citalopram or placebo . Response was defined as a score of 1 ( very much improved ) or 2 ( much improved ) on the Clinical Global Improvement scale or a 50 % reduction in the Hamilton anxiety scale score . Response and side effects with citalopram and placebo were compared by using chi-square tests and linear modeling . RESULTS Eleven ( 65 % ) of the 17 citalopram-treated participants responded by 8 weeks , versus four ( 24 % ) of the 17 placebo-treated participants . The most common and problematic side effect in the citalopram group was sedation . CONCLUSIONS The authors believe this to be the first prospect i ve controlled study to test the efficacy of an SSRI in the management of anxiety disorders among the elderly . These results support the efficacy of citalopram in late-life anxiety disorders . They need to be replicated in a larger study group BACKGROUND The prevalence of asthma has increased in recent years and depression is common in this population . Minimal data are available on the treatment of depressed asthma patients . METHODS Ninety adults with asthma and current major depressive disorder were r and omized to receive citalopram or placebo for 12 weeks . At each visit , the Hamilton Rating Scale for Depression ( HRSD ) , Inventory of Depressive Symptomatology - Self-Report , Asthma Control Question naire , and Asthma Quality of Life Question naire were administered , and oral corticosteroid use assessed . RESULTS In the evaluable sample ( n = 82 ) , the primary outcome , a r and om regression analysis of HRSD scores , revealed no significant between-group differences . Bonferroni corrected secondary outcomes revealed HRSD scores decreased significantly in both groups with a significantly greater decrease in the citalopram group at week 6 . Changes in asthma symptoms were similar between groups . The groups had similar rates of oral corticosteroid use at baseline , but the citalopram group had less corticosteroid use during the study . Changes in asthma symptom severity correlated with changes in depressive symptom severity . CONCLUSIONS A reduction in depressive symptoms was associated with improvement in asthma . Corticosteroid use , an important measure of severe asthma exacerbations , was lower in the citalopram group . Larger clinical trials in this population are warranted BACKGROUND This study compared the efficacy and safety of sertraline to placebo in treating panic disorder . METHOD 178 out- patients with panic disorder who exhibited at least four panic attacks during the four weeks prior to screening and three during the two weeks of lead-in were r and omly assigned to 12 weeks of double-blind treatment with sertraline ( 50 , 100 or 200 mg ) or placebo . RESULTS Sertraline was superior to placebo in reducing the number of panic attacks , situational attacks , unexpected attacks , limited symptom attacks , and time spent worrying ( all P < 0.01 ) and the Hamilton Anxiety Scale ( P < 0.05 ) , although Clinical Global Impression ( Improvement ) did not significantly differentiate groups at 12 weeks and at end-point . No serious adverse events were associated with sertraline . No dose relationship was found for adverse events ; overall drop-out rates were not different for sertraline or placebo , although more sertraline-treated subjects discontinued for adverse events , typically early in the study . Only dry mouth and ejaculation failure ( primarily ejaculation delay ) were associated significantly with sertraline . CONCLUSIONS Sertraline was effective and safe in reducing panic attacks . Higher doses were no more effective than the 50 mg dose The present study examined reports of placebo and nocebo symptoms in a college sample . The study was presented under the guise of a clinical trial to evaluate the effectiveness of an over-the-counter herbal supplement intended to enhance cognitive performance . Participants were informed they would be receiving either an herbal supplement or a placebo , and each was provided with a mock list of possible beneficial and adverse effects of the “ supplement . ” In fact , all participants received placebo . Symptoms were endorsed by a significant majority of participants following placebo ingestion . More important , results indicated that the few participants who believed they received an herbal supplement endorsed ( via self-report ) significantly more symptoms than those who believed they received a placebo . Neither anxiety nor social desirability was significantly related to symptom reporting . Results suggest that beliefs concerning treatment received may subsequently affect the degree of placebo response in a no-treatment group . Implication s for clinical trials and future research are discussed BACKGROUND Antidepressant efficacy may be compromised by early discontinuation of treatment secondary to common , treatment-emergent side effects , including nausea , agitation , and somnolence . Paroxetine controlled-release ( CR ) was developed to improve general tolerability and , in particular , gastrointestinal tolerability . OBJECTIVE To determine the antidepressant efficacy and tolerability of paroxetine CR in adult patients 18 to 65 years of age with DSM-IV major depressive disorder . METHOD Paroxetine CR ( 25 - 62.5 mg/day ; N = 212 ) and paroxetine immediate-release ( IR ; 20 - 50 mg/day ; N = 217 ) were compared with placebo ( N = 211 ) in the pooled data set from 2 identical , double-blind , 12-week clinical trials . RESULTS Both paroxetine CR and paroxetine IR exhibited efficacy in major depressive disorder as assessed by the reduction in 17-item Hamilton Rating Scale for Depression total score compared with placebo . Moreover , depressed mood and psychic anxiety symptoms improved as early as treatment week 1 in the paroxetine CR group compared with the placebo group . After 6 weeks of treatment , response and remission rates were 41.5 % and 20.5 % for placebo , 52.8 % and 29.6 % for paroxetine IR , and 58.9 % and 34.4 % for paroxetine CR , respectively . After 12 weeks of treatment , response and remission rates were 61.2 % and 44.0 % for placebo , 72.9 % and 52.5 % for paroxetine IR , and 73.7 % and 56.2 % for paroxetine CR , respectively . Rates of nausea were significantly lower for paroxetine CR ( 14 % ) than for paroxetine IR ( 23 % ; p < or = .05 ) during week 1 . Rates of dropout due to adverse events were comparable between paroxetine CR and placebo , while significantly ( p = .0008 ) more patients treated with paroxetine IR withdrew from the study prematurely compared with those treated with placebo . CONCLUSION Paroxetine CR is an effective and well-tolerated antidepressant exhibiting symptomatic improvement as early as week 1 . Paroxetine CR is associated with low rates of early-onset nausea and dropout rates due to adverse events comparable to those of placebo . The clinical improvement seen with paroxetine CR , coupled with its favorable adverse event profile , suggests a benefit for therapeutic outcome with paroxetine CR OBJECTIVE This study was design ed to determine the minimum paroxetine dose effective for treating panic disorder . METHOD Of 425 patients with DSM-III-R panic disorder with or without agoraphobia who underwent a 2-week drug-free screening period , 278 patients were r and omly assigned to double-blind treatment with a 10-week course of placebo or paroxetine at a dose of 10 , 20 , or 40 mg/day . RESULTS At 40 mg/day , paroxetine was superior to placebo across the majority of outcome measures . Despite a mean of 9.5 to 11.6 full panic attacks during the screening period , 86.0 % of the patients taking 40 mg of paroxetine , 65.2 % of those taking 20 mg , 67.4 % of those taking 10 mg , and 50.0 % of the placebo-treated patients were free of full panic attacks during the 2 weeks ending at week 10 . The 40-mg paroxetine group experienced significantly greater global improvement than the placebo group and significantly greater improvement in frequency of full and limited-symptom panic attacks , intensity of full panic attacks , phobic fear , anxiety , and depressive symptoms , usually evident by week 4 . All doses of paroxetine were well tolerated , and adverse effects were consistent with those associated with selective serotonin reuptake inhibitors . CONCLUSIONS Paroxetine is an effective and well-tolerated short-term treatment of panic disorder . The minimum dose demonstrated to be significantly superior to placebo was 40 mg/day , although some patients did respond at lower doses BACKGROUND This multicenter , double-blind , placebo-controlled study was carried out to determine the effectiveness and safety of various daily dosages of paroxetine for the treatment of generalized social anxiety disorder . METHOD A 1-week , single-blind , placebo run-in was followed by 12 weeks of double-blind treatment . 384 eligible patients meeting DSM-IV criteria for social anxiety disorder were r and omly assigned to receive paroxetine , 20 ( N = 97 ) , 40 ( N = 95 ) , or 60 mg ( N = 97 ) , or placebo ( N = 95 ) once daily in a 1:1:1:1 ratio . Primary efficacy variables included mean change from baseline in the Liebowitz Social Anxiety Scale ( LSAS ) total score and proportion of patients exhibiting a therapeutic response ( defined as a Clinical Global Impressions-Global Improvement scale [ CGI-1 ] score of 1 or 2 ) . RESULTS In the last-observation-carried-forward analyses , patients treated with paroxetine , 20 mg/day , had significantly greater improvement on mean LSAS total scores compared with those receiving placebo ( p < .001 ) , while the incidence of responders , based on the CGI-I rating , was significantly greater with paroxetine , 40 mg/day , than with placebo ( p = .012 ) . Patients treated with paroxetine , 20 and 60 mg , also had significantly better responses on the social item of the Sheehan Disability Scale than did patients treated with placebo ( p < .019 ) . The completer analyses showed a significant difference between the placebo group and the 20-mg and 40-mg paroxetine groups on LSAS total score and rate of response ( p < or = .006 ) . There were no serious adverse experiences attributed to paroxetine treatment . CONCLUSION Paroxetine , 20 mg/day , is an effective and safe treatment for patients with generalized social anxiety disorder and significantly improves social anxiety , avoidance of social interactions , social disability , and overall clinical condition . Further data analyses are needed to determine whether more specific guidelines for paroxetine dosage escalation in social anxiety disorder can be drawn BACKGROUND The purpose of this r and omized double-blind , placebo-controlled study was to compare the efficacy and safety of fluoxetine plus group psychotherapy versus group psychotherapy alone in HIV-seropositive men ( based on 1986 CDC classes II , III , and IV.C.2 ) who had been diagnosed with major depressive disorder ( DSM-III-R ) . METHOD During a 7-week trial , patients were treated with fluoxetine 20 - 60 mg or placebo 1 - 3 capsules per day and were seen in weekly supportive group psychotherapy . In addition , subjects were rated on the 17-item Hamilton Rating Scale for Depression ( HAM-D-17 ) , Clinical Global Impressions scales for Improvement ( CGI-I ) and Severity of Illness ( CGI-S ) , and the short version of the Beck Depression Inventory ( BDI-13 ) . Of the 47 patients enrolled in the study , 25 were administered fluoxetine and 22 were given placebo . RESULTS Subjects who received fluoxetine began to show significantly more improvement than patients who received placebo on both self- and observer-rated scales by the end of the first week of treatment . By endpoint , patients treated with fluoxetine experienced greater mean changes from baseline compared with placebo-treated patients on the HAM-D-17 ( 12.1 vs. 6.6 ; F = 6.53 , df = 1,45 ; p < .05 ) and BDI-13 ( 5.9 vs. 1.2 ; F = 5.73 , df = 1,45 ; p < .05 ) , and a greater percentage of fluoxetine-treated patients experienced a > or = 50 % in HAM-D-17 scores ( 64 % vs. 23 % ; chi2= 8.60 , df = 1 , p < .01 ) . Differences were particularly apparent in subjects whose initial depressive episodes were rated as severe ( i.e. , HAM-D-17 score > or = 24 ) . Severely depressed patients treated with fluoxetine had an endpoint CGI-I of 1.4 compared with an endpoint CGI-I of 2.7 for patients treated with placebo ( F = 6.02 , df = 1,11 ; p < .05 ) . Further , side effects were generally mild and transient . The most frequently noted effects reported by subjects treated with fluoxetine were nausea , dry mouth , headache , and diarrhea , in decreasing order of frequency . CONCLUSION This study supports the efficacy and safety of fluoxetine over and above group psychotherapy for the treatment of HIV-associated major depression Objective : To test the safety and efficacy of fluoxetine in patients with renal failure on dialysis . Method : Fourteen patients with major depression and end stage renal disease on hemodialysis were r and omized into two groups for an eight-week study . Subjects as well as investigators were blinded as to which subject received fluoxetine and which placebo . Patients were carefully monitored concerning adverse events , serum fluoxetine and norfluoxetine levels , and psychological measurements of degree of depression . Results : No patients discontinued treatment because of adverse events , all of which were minor . All psychological tests showed improvement in depression at the four-week and eight-weeks point , although statistical significance could only be demonstrated at the fourth week of this study . All patients in the active group had serum plasma concentrations of fluoxetine and norfluoxetine less than 250 ng/ml at eight weeks , similar to levels in patients with normal renal function in a previous open label study . Conclusions : This study confirms the relative safety of fluoxetine in depressed patients in renal failure on hemodialysis . It also suggests that fluoxetine may be efficacious in depressed patients on dialysis BACKGROUND This study compared the efficacy and tolerability of paroxetine with placebo in the treatment of panic disorder . METHOD After three weeks of placebo , patients received 12 weeks of treatment with paroxetine ( 20 , 40 , or 60 mg ) or placebo , and finally two weeks of placebo . Dosages were adjusted according to efficacy and tolerability . St and ardised cognitive therapy was given to all patients . The primary measure of outcome was reduction in the number of panic attacks . RESULTS Analysis of the results showed statistically significant differences in favour of paroxetine between the two treatment groups in two out of the three primary measures of outcome , i.e. 50 % reduction in total number of panic attacks and number of panic attacks reduced to one or zero over the study period . For the third measure of outcome , the mean change in the total number of attacks from baseline , there was a positive trend in favour of paroxetine . The results of the primary measures of outcome were strongly supported by the results of the secondary efficacy measures of outcome . In addition , paroxetine , at all doses , was very well tolerated . CONCLUSION Paroxetine plus cognitive therapy was significantly more effective than placebo plus cognitive therapy in the treatment of panic disorder To assess whether tricyclic antidepressants are useful in patients with a serious physical disorder who develop symptoms of major depression , 42 medically ill out patients who met RDC criteria for endogenous major depression and had a Raskin depression score of at least 7 were studied . The patients were r and omly assigned to a 6-week trial of trimipramine or placebo under double-blind conditions . In the placebo group , depressive symptoms improved when the physical disorder improved ; in the trimipramine group , improvement was seen in the depressive symptoms even when there was no concomitant improvement in physical condition OBJECTIVE To assess the efficacy and tolerability of fluoxetine for the acute treatment of children and adolescents with generalized anxiety disorder , separation anxiety disorder , and /or social phobia . METHOD Anxious youths ( 7 - 17 years old ) who had significant functional impairment were r and omized to fluoxetine ( 20 mg/day ) ( n = 37 ) or placebo ( n = 37 ) for 12 weeks . RESULTS Fluoxetine was effective in reducing the anxiety symptoms and improving functioning in all measures . Using intent-to-treat analysis , 61 % of patients taking fluoxetine and 35 % taking placebo showed much to very much improvement . Despite this improvement , a substantial group of patients remained symptomatic . Fluoxetine was well tolerated except for mild and transient headaches and gastrointestinal side effects . Youths with social phobia and generalized anxiety disorder responded better to fluoxetine than placebo , but only social phobia moderated the clinical and functional response . Severity of the anxiety at intake and positive family history for anxiety predicted poorer functioning at the end of the study . CONCLUSIONS Fluoxetine is useful and well tolerated for the acute treatment of anxious youths . Investigations regarding the optimization of treatment to obtain full anxiety remission and the length of treatment necessary to prevent recurrences are warranted A total of 149 patients in 7 centers in Denmark , Norway and Sweden entered a 6‐week double‐blind trial intended to assess the antidepressant effect and safety of citalopram vs placebo in depressed elderly patients ( 65 years of age or older ) who might also suffer from somatic disorders and /or senile dementia . Results of ratings on the Hamilton Rating Scale for Depression , the Montgomery‐Åsberg Depression Rating Scale and the Clinical Global Impression Scale provided consistent evidence that the citalopram‐treated patients improved more than the placebo‐treated patients . Results of ratings on the Gottfries‐Bråne‐Steen dementia rating scale indicated that both cognitive and emotional functioning improved significantly more in the citalopram‐treated subgroup of patients with dementia than in the placebo‐treated subgroup |
13,712 | 28,177,326 | We therefore hypothesised that careful assessment of tumour extension might be responsible for the high 5-year OS and 5-year DFS . | Residual or recurrent laryngeal cancer after irradiation is a difficult clinical problem with a rate that ranges from 13 % to 36 % of cases .
Supracricoid laryngectomy ( SCL ) with cricohyoidopexy ( CHP ) or cricohyoidoepiglottopexy ( CHEP ) provide reliable oncological and functional results for selected primary and recurrent patients with glottic and supraglottic carcinomas .
We conducted a systematic review and meta- analysis to assess the oncological and functional outcomes of patients treated with open partial horizontal laryngectomy types IIa and IIb ( CHEP , CHP ) in terms of the recurrence of squamocellular cancer of the larynx after radiotherapy failure . | BACKGROUND Our objectives were to determine the incidence of acute and late toxicities and to estimate the 2-year overall survival for patients treated with reirradiation and chemotherapy for unresectable squamous cell carcinoma of the head and neck ( SCCHN ) . METHODS Patients with recurrent squamous cell carcinoma or a second primary arising in a previously irradiated field were eligible . Four weekly cycles of 5-fluorouracil 300 mg/m2 IV bolus and hydroxyurea 1.5 g by mouth were used with 60 Gy at 1.5 Gy twice-daily fractions . Toxicity was scored according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer ( RTOG/EORTC ) criteria . RESULTS Seventy-nine of the 86 patients enrolled were analyzable . The worst acute toxicity was grade 4 in 17.7 % and grade 5 in 7.6 % . Grade 3 and 4 late toxicities were found in 19.4 % and 3.0 % , respectively . The estimated cumulative incidence of grade 3 to 4 late effects occurring at > 1 year was 9.4 % ( 95 % confidence interval [ CI ] : 0 , 19.7 ) at 2 and 5 years . The 2- and 5-year cumulative incidence for grade 4 toxicity was 3.1 % ( 95 % CI : 0 , 9.3 ) . The estimated 2- and 5-year survival rates were 15.2 % ( 95 % CI : 7.3 , 23.1 ) and 3.8 % ( 95 % CI : 0.8 , 8.0 ) , respectively . Patients who entered the study at > 1 year from initial radiotherapy ( RT ) had better survival than did those who were < 1 year from prior RT ( median survival , 9.8 months vs 5.8 months ; p = .036 ) . No correlation was detected between dose received and overall survival . Three patients were alive at 5 years . CONCLUSION This is the first prospect i ve multi-institutional trial testing reirradiation plus chemotherapy for recurrent or second SCCHN . The approach is feasible with acceptable acute and late effects . The results serve as a benchmark for ongoing RTOG trials BACKGROUND The purpose of this study was to evaluate long-term outcomes after induction chemotherapy followed by " risk-based " local therapy for locally-advanced squamous cell carcinoma of the head and neck ( SCCHN ) . METHODS Forty-seven patients ( stage IV ; ≥N2b ) were enrolled in a phase II trial . Baseline and 24-month functional measures included modified barium swallow ( MBS ) studies , oropharyngeal swallow efficiency ( OPSE ) , and the MD And erson Dysphagia Inventory ( MDADI ) . Functional status was assessed at 5 years . RESULTS Five-year overall survival ( OS ) was 89 % ( 95 % confidence interval [ CI ] , 81 % to 99 % ) . A nonsignificant 13 % average reduction in swallowing efficiency ( OPSE ) was observed at 24 months relative to baseline ( p = .191 ) . MDADI scores approximated baseline at 24 months . Among 42 long-term survivors ( median , 5.9 years ) , 3 patients ( 7.1 % ) had chronic dysphagia . The rate of final gastrostomy dependence was 4.8 % ( 2 of 42 ) . CONCLUSION Sequential chemoradiotherapy achieved favorable outcomes among patients with locally advanced SCCHN , mainly of oropharyngeal origin . MBS and MDADI scores found modest swallowing deterioration at 2 years , and chronic aspiration was uncommon in long-term survivors BACKGROUND The purpose of this study was to analyse the results of salvage surgery after failure of irradiation to control the primary T1-T2 glottic cancer . MATERIAL S AND METHODS Ninety-eight patients with T1 and T2 squamous cell cancer of the glottic larynx were treated with curative intent by radiotherapy . The tumour recurred in 22 of the 98 ( 22 % ) patients . Surgical management consisted of total and frontolateral laryngectomy . Survival rates were calculated from the date of the salvage operation . RESULTS Two of the 22 patients refused to undergo salvage surgery and one patient had pulmonary metastasis . Of the 19 patients who underwent salvage surgery , 14 ( 74 % ) had total laryngectomy and 5 ( 26 % ) had frontolateral laryngectomy . The operations were curative in 15 ( 79 % ) of the 19 patients . The overall 5-year survival rate after surgery was 78 % . CONCLUSION Stringent follow-up of patients with irradiated T1 and T2 glottic laryngeal cancer is essential to permit a successful salvage OBJECTIVES To determine the incidence of local control in patients with " advanced " moderately to well-differentiated endolaryngeal invasive squamous cell carcinoma classified as T3 , treated with a supracricoid partial laryngectomy ; to identify any statistical relationship ; and to analyze the consequences of local recurrence . DESIGN Retrospective nonr and omized case series . SETTING A tertiary referral care center and university teaching hospital . PATIENTS An inception cohort of 118 patients . Tumor stage was T3 N0 M0 in 90 patients , T3 N1 M0 in 21 patients , T3 N2 M0 in 5 patients , and T3 N3 M0 in 2 patients . INTERVENTIONS All patients underwent supracricoid partial laryngectomy . A platin-based induction chemotherapy regimen was used in 100 patients . Postoperative radiotherapy was used for 24 patients . MAIN OUTCOME MEASURES Local recurrence , nodal recurrence , distant metastasis , and survival ; univariate and multivariate analysis of local recurrence . RESULTS Nine patients developed a local recurrence . The 1- , 3- , and 5-year actuarial local control estimates were 97.3 % , 93.5 % , and 91.4 % , respectively . In a stepwise regression model , the presence of positive margins of resection was the only variable that statistically increased the risk of local recurrence ( P = .008 ) . Local recurrence result ed in a significant increase in nodal recurrence ( P<.001 ) and distant metastasis ( P<.001 ) and a significant decrease in survival ( P = .03 ) . An overall 89.8 % laryngeal preservation rate and 98.3 % local control rate were achieved . CONCLUSION Supracricoid partial laryngectomies should be considered when an organ preservation strategy is discussed in patients with advanced endolaryngeal squamous cell carcinoma classified as T3 OBJECTIVES /HYPOTHESES Study 1 : To assess the oncologic outcome following supracricoid partial laryngectomy ( SCPL ) . Study 2 : To compare the quality of life ( QOL ) following SCPL to total laryngectomy ( TL ) with tracheoesophageal puncture ( TEP ) . Study 3 : To analyze whole organ TL sections to determine the percentage of lesions amenable to SCPL STUDY DESIGN : Study 1 : A retrospective review of patients who underwent SCPL . Study 2 : A non-r and omized , prospect i ve study using QOL instruments to compare patients who underwent either SCPL or TL Study 3 : A retrospective histopathologic study of TL specimens assessed for the possibility of performing an SCPL . METHODS Study 1 : Twenty-five patients with carcinoma of the larynx underwent SCPL between June 1992 and June 1999 . Various rates of oncologic outcome were calculated . Study 2 : Thirty-one patients participated in the QOL assessment . This included the SF-36 general health status measure , the University of Michigan Head and Neck Quality of Life ( HNQOL ) instrument , and the University of Michigan Voice-Related Quality of Life ( VRQOL ) instrument . Study 3 : Ninety surgical specimens were obtained and studied from the total laryngectomy cases in the Tucker Collection . Multiple sites were evaluated for the presence of carcinoma A computer program was written to classify whether the patient was amenable to SCPL . RESULTS Study 1 : The overall local control rate was 96 % ( 24/25 ) . The local control rate following SCPL with cricohyoidoepiglottopexy ( CHEP ) was 95 % ( 20/21 ) . The local control rate following SCPL with cricohyoidopexy ( CHP ) was 100 % ( 4/4 ) . Study 2 : The SCPL had significantly higher domain scores than TL and TEP in the following categories for the SF-36 : physical function , physical limitations , general health , vitality , social functioning , emotional limitations , and physical health summary . The significantly higher domains for the SCPL when compared with the TL and TEP for the HNQOL were eating and pain . Finally , when voice-related QOL was assessed with the V-RQOL , the domains of physical functioning and the total score were significantly better with SCPL when compared with TL and TEP . Study 3 : Forty of 90 ( 44 % ) laryngeal whole organ specimens were determined to be resectable by SCPL . In 16 ( 18 % ) specimens , the patients could have undergone SCPL with CHEP and in 24 ( 27 % ) specimens the patients could have undergone SCPL with CHP . Among the 40 ( 44 % ) specimens determined to be able to have undergone SCPL , 19 were glottic ( 1 T1 , 15 T2 , 3 T3 ) and 21 were supraglottic ( 9 T2 , 12 T3 ) . CONCLUSIONS 1 ) A review of the literature and an analysis of the data in this study indicate that excellent local control may be expected following SCPL . 2 ) The QOL following SCPL , as measured by three vali date d QOL instruments , is superior to TL with TEP . 3 ) A histologic assessment of whole organ sections of TL specimens indicates that many patients who have been subjected to TL may have been c and i date s for SCPL . 4 ) If the indications and contraindications are rigorously adhered to , SCPLs are reasonable alternatives to TL in selected cases |
13,713 | 28,143,834 | Conclusions In women with WHO group II anovulation , letrozole and the combination of clomiphene and metformin are superior to clomiphene alone in terms of ovulation and pregnancy .
Compared with clomiphene alone , letrozole is the only treatment showing a significantly higher rate of live birth . | & NA ; Objective To compare the effectiveness of alternative first line treatment options for women with WHO group II anovulation wishing to conceive . | Clinical trials , systematic review s and guidelines compare beneficial and non-beneficial outcomes following interventions . Often , however , various studies on a particular topic do not address the same outcomes , making it difficult to draw clinical ly useful conclusions when a group of studies is looked at as a whole.1 This problem was recently thrown into sharp focus by a systematic review of interventions for preterm birth prevention , which found that among 103 r and omised trials , no fewer than 72 different outcomes were reported.2 There is a growing recognition among clinical research ers that this variability undermines consistent synthesis of the evidence , and that what is needed is an agreed st and ardised collection of outcomes – a “ core outcomes set ” – for all trials in a specific clinical area.1 Recognising that the current inconsistency is a serious hindrance to progress in our specialty , the editors of over 50 journals related to women 's health have come together to support The CROWN ( CoRe Outcomes in WomeN 's health ) Initiative ( Box 1 ) . ! [Graphic][1 ] Box 1 # # # Aims of The CROWN Initiative ( http://www.crown-initiative.org ) 1 . Form a consortium among all gynaecology-obstetrics and related journals to promote core outcome sets in all areas of our specialty . … [ 1 ] : OBJECTIVES : To compare the efficacy of letrozole and clomiphene citrate ( CC ) in patients of anovulatory polycystic ovarian syndrome ( PCOS ) with infertility . MATERIAL S AND METHODS : This prospect i ve r and omized clinical trial included 204 patients of PCOS . 98 patients ( 294 cycles ) received 2.5–5 mg of letrozole ; 106 patients ( 318 cycles ) received 50–100 mg of CC ( both orally from Days 3–7 of menstrual cycle ) . The treatment continued for three cycles in both the groups . Main outcome measures : ovulation rate , endometrial thickness , and pregnancy rate . Statistical analysis was done using SPSS 13 software . P value less than 0.05 was considered significant . RESULTS : The mean number of dominant follicles in letrozole groups and CC groups was 1.86±0.26 and 1.92±0.17 , respectively ( P=0.126 ) . Number of ovulatory cycle in letrozole group was 196 ( 66.6 % ) versus 216 ( 67.9 % ) in CC group ( P=0.712 ) . The mean mid-cycle endometrial thickness was 9.1±0.3 mm in letrozole group and 6.3±1.1 in CC group , which was statistically significant ( P=0.014 ) . The mean Estradiol [ E2 ] level in clomiphene citrate group was significantly higher in CC group ( 364.2±71.4 pg/mL ) than letrozole group ( 248.2± 42.2 pg/mL ) . 43 patients from the letrozole group ( 43.8 % ) and 28 patients from the CC group ( 26.4 % ) became pregnant . CONCLUSION : Letrozole and CC have comparable ovulation rate . The effect of letrozole showed a better endometrial response and pregnancy rate compared with CC BACKGROUND An RCT among newly diagnosed , therapy naive women with polycystic ovary syndrome ( PCOS ) showed no significant differences in ovulation rate , ongoing pregnancy rate or spontaneous abortion rate in favour of clomifene citrate plus metformin compared with clomifene citrate . We wanted to assess whether there are specific subgroups of women with PCOS in whom clomifene citrate plus metformin leads to higher pregnancy rates . METHODS Subgroup analysis based on clinical and biochemical parameters of 111 women r and omized to clomifene citrate plus metformin compared with 114 women r and omized to clomifene citrate plus placebo . The data for age , BMI , waist – hip ratio ( WHR ) and plasma testosterone were available in all women , 2 h glucose in 80 % of women and homeostatic model assessment for assessing insulin sensitivity ( HOMA ) in 50 % of women . RESULTS Of the women who were allocated to the metformin group , 44 women ( 40 % ) reached an ongoing pregnancy . In the placebo group , 52 women ( 46 % ) reached an ongoing pregnancy . There was a significantly different chance of an ongoing pregnancy for metformin versus placebo between subgroups based on age and WHR ( P = 0.014 ) . There was a positive effect of metformin versus placebo on pregnancy rate in older women ( ≥28 years ) with a high WHR , a negative effect of metformin versus placebo in young women ( < 28 years ) regardless of their WHR and no effect in older , not viscerally obese women . No significant differences in effect of treatment were found for groups based on BMI , 2 h glucose , HOMA or plasma testosterone . CONCLUSIONS Metformin may be an effective addition to clomifene citrate in infertile women with PCOS , especially in older and viscerally obese patients OBJECTIVE : To compare Letrozole ( 5 mg ) and clomiphene citrate ( 100 mg ) as first line ovulation induction drug in infertile PCOS women . STUDY DESIGN : Prospect i ve R and omised trial . SETTING : A Tertiary level infertility centre . Patients : 103 infertile PCOS women INTERVENTION(S ) : Treatment naïve infertile PCOS women were r and omised to treatment with 5 mg letrozole ( 51 patients ) or 100 mg clomiphene citrate ( 52 patients ) daily starting day 2 to day 6 of menstrual cycle . Timed intercourse or Intra Uterine Insemination ( IUI ) was advised 24 to 36 hours after Human Chorionic Gonadotropin ( HCG ) injection . MAIN OUTCOME MEASURES : Ovulation rate , mono or multi follicular rate , days to ovulation , endometrial thickness , serum progesterone , serum estrogen , pregnancy rate , miscarriage rate . RESULTS : The mean age , Body Mass Index ( BMI ) , duration of infertility in both Clomiphene Citrate ( CC ) and Letrozole groups were similar . Ovulation rate was 73.08 % in letrozole group and 60.78 % in CC , which was not statistically significant ( P=0.398 ) . There was no statistically significant difference between Endometrial thickness ( CC 7.61 ±1.96 , Let 7.65 ± 2.10 ) , Sr E2 on day of HCG ( CC 178.3 ± 94.15 , Let 162.09 ± 73.24 ) , Days to ovulation ( CC 14.2 ± 3.41 ; Let 13.13 ± 2.99 ) and Sr P4 on D21 ( CC 10.58 ± 6.65 ; Let 11.86 ± 6.51 ) . Monofolliculo genesis ( CC 54.84 , Let 79.49 % , P=0.027 ) and Pregnancy rate ( CC 7.84 % , Let 21.56 % P=0.0125 ) were statistically significantly higher in letrozole group . CONCLUSION : Our study shows that letrozole has excellent pregnancy rates compared to clomiphene citrate . Letrozole should be considered at par with clomiphene citrate as first line drug for ovulation induction in infertile PCOS women OBJECTIVE To report the baseline characteristics and racial differences in the polycystic ovary syndrome ( PCOS ) phenotype from a large multicenter clinical trial ( PPCOS ) . DESIGN Double-blind , r and omized trial of three treatment regimens ( with extended release metformin or clomiphene citrate ) . SETTING Academic medical centers . PATIENT(S ) Six hundred twenty-six infertile women with PCOS , aged 18 - 39 years , with elevated T levels and oligomenorrhea ( exclusion of secondary causes ) , seeking pregnancy , with > or = 1 patent fallopian tube , normal uterine cavity , and a partner with sperm concentration > or = 20 x 10(6)/mL in > or = 1 ejaculate . INTERVENTION(S ) Baseline characterization . MAIN OUTCOME MEASURE(S ) Historical , biometric , and biochemical measures of PCOS . RESULT ( S ) There were no significant differences in baseline variables between treatment groups . The overall mean ( + /-SD ) age of the subjects was 28.1 + /- 4.0 years , and the mean body mass index was 35.2 kg/m2 ( + /-8.7 ) . Polycystic ovaries ( PCOs ) were present in 90.3 % of the subjects , and the mean volume of each ovary was 10 cm3 or more . Of the subjects , 7 % had ovaries that were discordant for PCO morphology . At baseline , 18.3 % of the subjects had an abnormal fasting glucose level ( > 100 mg/dL ) . Asians tended to have a milder phenotype , and whites and African Americans were similar in these measures . CONCLUSION ( S ) The treatment groups were well matched for baseline parameters , and we have added further information to the PCOS phenotype OBJECTIVE Small intervention studies suggest that modest weight loss increases the chance of conception and may improve perinatal outcome , but large r and omized controlled trials ( RCT ) are lacking . Our objective was to investigate the effects of a lifestyle intervention in obese infertile women in a multicenter RCT . DESIGN We r and omly assigned infertile women with body mass index ≥ 29 k/m² to a six-month lifestyle intervention preceding infertility treatment or to prompt infertility treatment . The primary outcome was the vaginal birth of a healthy singleton at term within 2 years of r and omization . RESULTS Between June 2009-June 2102 we r and omly allocated 577 women to one of two treatment strategies : 290 to lifestyle intervention preceding infertility treatment ( intervention group ) and 287 to prompt infertility treatment ( control group ) . Three women withdrew informed consent , leaving 289 and 285 women for analysis . Discontinuation rate during the lifestyle intervention was 22 % . Mean weight loss in the intervention group was 4.4 kg and in the control group 1.1 kg ( p < 0.001 ) ; the primary outcome occurred in 76 women ( 27 % ) in the intervention group versus 100 ( 35 % ) in the control group ( RR : 0.77 , 95 % CI 0.60 to 0.99 ) . The number of natural conceptions leading to ongoing pregnancies was 73 ( 26 % ) versus 46 ( 16 % ) ( RR : 1.6 , 95 % CI 1.2 to 2.2 ) . Maternal pregnancy-related and labor-related complications and neonatal complications were comparable . CONCLUSION In obese infertile women lifestyle intervention preceding infertility treatment did not result in better rates of vaginal birth of healthy singletons at term as compared to prompt infertility treatment BACKGROUND The st and ard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate . Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates . METHODS We enrolled couples with unexplained infertility in a multicenter , r and omized trial . Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were r and omly assigned to ovarian stimulation ( up to four cycles ) with gonadotropin ( 301 women ) , clomiphene ( 300 ) , or letrozole ( 299 ) . The primary outcome was the rate of multiple gestations among women with clinical pregnancies . RESULTS After treatment with gonadotropin , clomiphene , or letrozole , clinical pregnancies occurred in 35.5 % , 28.3 % , and 22.4 % of cycles , and live birth in 32.2 % , 23.3 % , and 18.7 % , respectively ; pregnancy rates with letrozole were significantly lower than the rates with st and ard therapy ( gonadotropin or clomiphene ) ( P=0.003 ) or gonadotropin alone ( P<0.001 ) but not with clomiphene alone ( P=0.10 ) . Among ongoing pregnancies with fetal heart activity , the multiple gestation rate with letrozole ( 9 of 67 pregnancies , 13 % ) did not differ significantly from the rate with gonadotropin or clomiphene ( 42 of 192 , 22 % ; P=0.15 ) or clomiphene alone ( 8 of 85 , 9 % ; P=0.44 ) but was lower than the rate with gonadotropin alone ( 34 of 107 , 32 % ; P=0.006 ) . All multiple gestations in the clomiphene and letrozole groups were twins , whereas gonadotropin treatment result ed in 24 twin and 10 triplet gestations . There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications . CONCLUSIONS In women with unexplained infertility , ovarian stimulation with letrozole result ed in a significantly lower frequency of multiple gestation but also a lower frequency of live birth , as compared with gonadotropin but not as compared with clomiphene . ( Funded by the National Institutes of Health and others ; Clinical Trials.gov number , NCT01044862 . ) OBJECTIVE To compare the use of an aromatase inhibitor ( letrozole ) with the use of clomiphene citrate ( CC ) . DESIGN Prospect i ve r and omized study . SETTING An infertility clinic in a university hospital . PATIENT(S ) Seventy-four consecutive infertile patients with polycystic ovary syndrome were recruited . Thirty-eight patients were r and omized to the letrozole group ( 99 cycles ) , and the remaining patients were recruited to the CC group ( 95 cycles ) . INTERVENTION(S ) The aromatase inhibitor letrozole ( 2.5 mg/d ) and CC ( 100 mg/d ) were administered orally on days 3 - 7 of menses . MAIN OUTCOME MEASURE(S ) Number of follicles , endometrial thickness , E(2 ) levels on hCG day , and pregnancy rates among both groups . RESULT ( S ) Ovulation occurred in 65.7 % ( 65/99 ) of letrozole cycles and in 74.7 % ( 71/95 ) of CC cycles . The median ( minimum-maximum ) number of follicles sized > 15 mm in diameter on the day of hCG administration were 1 ( 0 - 4 ) and 1 ( 0 - 5 ) in the letrozole and CC groups , respectively . On the day of hCG administration , median serum E(2 ) concentrations in the letrozole and CC groups were statistically significantly different : 189 pg/mL ( 18 - 1,581 pg/mL ) and 386 pg/mL ( 27 - 6,190 pg/mL ) , respectively . The median serum E(2 ) concentrations per follicle sized > 15 mm in diameter on the day of hCG also statistically significantly differed between the letrozole and CC groups : 160 pg/mL ( 18 - 808 pg/mL ) and 281 pg/mL ( 27 - 2,615 pg/mL ) , respectively . The median endometrial thickness on the day of hCG did not significantly differ between the CC and letrozole groups ; it was 8 mm . Pregnancy was achieved in nine cycles ( 9.1 % ) of the letrozole group and in seven cycles ( 7.4 % ) of the CC group , which also was not a statistically significant difference . CONCLUSION ( S ) The aromatase inhibitor letrozole may be an acceptable alternative to CC as an ovulation-induction drug in patients with PCOS OBJECTIVE To determine whether insulin-sensitizing drugs would improve ovulation and T levels in women with polycystic ovary syndrome ( PCOS ) , without clinical or biochemical criteria indicating insulin resistance and whether the combination of two distinct insulin-sensitizing drugs would be of any benefit over either drug alone . DESIGN R and omized controlled double-blind trial . SETTING A referral center in Caracas , Venezuela . PATIENT(S ) One hundred twenty-eight nonobese PCOS women with normal indices of insulin sensitivity-that is , normal glucose tolerance , fasting insulin , peak insulin during an oral glucose tolerance test ( OGTT ) , and fasting glucose-to-insulin ratio . Twenty-eight women were lost to follow-up initially and did not receive any intervention . INTERVENTION(S ) One hundred women received twice daily one of the following for 6 months : metformin ( 850 mg ) , rosiglitazone ( 4 mg ) , combination of both drugs , or at least one placebo . MAIN OUTCOME MEASURE(S ) Frequencies of ovulation and serum free T after 6 months . RESULT ( S ) Frequencies of ovulation were higher after treatment with an insulin-sensitizing drug ( ovulations per subject in 6 months : metformin , 3.3 ; rosiglitazone , 2.4 ; and combination , 3.4 ) than with placebo ( 0.4 ) . Ovulatory frequencies increased significantly more with metformin than rosiglitazone , and the combination was not more potent . After treatment , serum free-T levels were comparable among all active treatment groups ( metformin : 2.34 pg/mL , rosiglitazone : 3.06 pg/mL , and combination : 2.39 pg/mL ) and were significantly lower than in the placebo group ( 7.26 pg/mL ) . Compared with placebo , fasting insulin levels , area under the insulin curve during OGTT , the homeostatic model assessment of insulin sensitivity , and OGTT-derived insulin sensitivity index improved significantly after metformin or combination therapies but not after rosiglitazone . CONCLUSION ( S ) These findings suggest that insulin-sensitizing drugs increase ovulatory frequency and ameliorate hyper and rogenemia , even in nonobese women with PCOS who appear to have normal insulin sensitivity 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 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 : Unovulation is the most common cause of infertility . The first line oral treatment has been clomiphene citrate . Another anti-estrogen used for ovulation induction is tamoxifen . Many unovulatory infertile women are resistance to anti-estrogens and need another treatment . Alternative treatments are aromatas inhibitors . Objective : This study was design ed to compare the effectiveness of clomiphene , tamoxifen and letrozole in ovulation induction outcomes in isolated non PCOS unovulatory patients . Material s and Methods : 150 unovulatory infertile women who had isolated non- polycystic ovarian syndrome ( PCOS ) , r and omized to 3 groups . Group A received clomiphene 50 mg to maximum 150 mg for 5 days , Group B received tamoxifen 10 mg to maximum 30 mg for 5 days , Group C received letrozole 2.5 mg for 5 days , to maximum 7.5 mg until ovulation was induced . If ovulation failed to occur with 5 days treatments , drug continued for 7 days . Treatment has been stopped if they became pregnant or if patient did n’t ovulate with maximum dose for 7 days ( resistant to treatment ) or failed to concept after six months despite ovulation ( failure of treatment ) . Main outcome measures were : number of mature follicles , endometrial thickness , pregnancy rate , multiple pregnancy rate , live birth and miscarriage . Results : Overall ovulation rate was 60 ( 73.4 % ) , this rate in group A was 39 ( 78 % ) , in group B it was 24 ( 68 % ) and in group C was 37 ( 74 % ) . Pregnancy rate in groups A , B and C were , 32 ( 64 % ) , 20 ( 40 % ) , and 25 ( 50 % ) respectively , and live birth rate was 22 ( 44 % ) in A , 17 ( 34 % ) in B and 21 ( 42 % ) in C. Miscarriage rate with clomiphene was 10 ( 20 % ) while this was 3 ( 6 % ) in tamoxifen and 4 ( 8 % ) in letrozole group ( p=0.05 ) . One twin pregnancy was occurred with clomiphene and one with tamoxifen , while all pregnancies with letrozole were singleton . Conclusion : Because of higher pregnancy rate with clomiphene citrate than tamoxifen and letrozole , Clomiphene citrate is still the first-line therapy for ovulation induction . Surprisingly , pregnancies after tamoxifen and letrozole have lower miscarriage rate than clomiphene Letrozole was compared with clomiphene citrate ( CC ) as a first-line treatment for ovulation induction in women with polycystic ovaries ( PCOs ) . A total of 106 women with primary infertility and a diagnosis of PCOs were r and omized to receive either 100 mg CC ( n = 55 ) or 2.5 mg letrozole ( n = 51 ) daily for 5 days . Human chorionic gonadotrophin ( hCG ) at a dose of 10 000 IU was administered when at least one follicle with a mean diameter ≥ 18 mm was observed using transvaginal ultrasound . The number of mature follicles was significantly lower , but endometrial thickness and ovulation and pregnancy rates were significantly higher in the letrozole group than in the CC group . In conclusion , letrozole is associated with a higher pregnancy rate than CC in PCO patients and may have a role as a first-line treatment for anovulatory patients with PCOs BACKGROUND Laparoscopic electrocautery of the ovaries and ovulation induction with gonadotrophins are both second line treatments for women with clomiphene citrate-resistant polycystic ovary syndrome ( PCOS ) . Long-term follow-up after electrocautery versus ovulation induction with gonadotrophins has demonstrated at least comparable chances for a first live born child with a reduced need for ovulation induction or assisted reproduction treatment and increased chances for a second live born child . In this study , we report on the long-term economic consequences of both treatment modalities . METHODS Between February 1998 and October 2001 , we performed a multi-centre r and omized controlled trial ( RCT ) comparing a strategy of laparoscopic electrocautery of the ovaries , followed by clomiphene citrate and gonadotrophins when anovulation persisted , and a strategy of ovulation induction with gonadotrophins in women with clomiphene citrate-resistant PCOS . Eight to twelve years after r and omization we performed a follow-up study on reproductive outcome in these women and the fertility treatments they had needed including data on direct medical costs of pregnancy and delivery . Clinical data included number of treatment cycles , live births , miscarriages , ectopic pregnancies and multiple pregnancies . We calculated mean costs per woman after r and omization until the first live birth . Confidence intervals ( CIs ) were estimated by bootstrapping . RESULTS We obtained data for an economic analysis on 159 of the 168 r and omized women ( 95 % ) . In total , 71 of 83 women ( 86 % ) allocated to the electrocautery strategy and 69 of 85 women ( 81 % ) allocated to the gonadotrophin strategy had at least one live birth . Given the equivalence between the two treatment strategies in terms of a first live birth-the primary outcome measure-our analysis focused on the cost difference between the two strategies within a mean follow-up time of 8 - 12 years . The mean costs per first live birth after r and omization were € 11 176 ( 95 % CI : € 9689-€12 549 ) for the electrocautery group and € 14 423 ( 95 % CI : € 12 239-€16 606 ) for the recombinant FSH group , result ing in significantly lower costs ( P < 0.05 ) per first live birth for women allocated to the electrocautery group ( mean difference € 3247 ; 95 % CI : € 650-€5814 ) . CONCLUSION In women with clomiphene-resistant PCOS , laparoscopic electrocautery of the ovaries results in significantly lower costs per live birth than ovulation induction with gonadotrophins for an at least equal effectiveness BACKGROUND Clomifene citrate ( CC ) is accepted as the first-line method for ovulation induction ( OI ) in patients with polycystic ovary syndrome ( PCOS ) associated with infertility owing to anovulation . Low-dose FSH has been reserved for women failing to conceive with CC . In this RCT , we tested the hypothesis that pregnancy rate ( PR ) and live birth rates ( LBR ) are higher after OI with low-dose FSH than with CC as first-line treatment . METHODS Infertile women ( < 40 years old ) with PCOS-related anovulation , without prior OI treatment , attending 10 centres in Europe/South America were r and omized to OI with either CC ( 50 - 150 mg/day for 5 days ) or FSH ( starting dose 50 IU ) for up to three treatment cycles . The primary outcome was clinical PR . RESULTS Patients ( n = 302 ) were r and omized to OI with FSH ( n = 132 women ; 288 cycles ) or CC ( n = 123 ; 310 cycles ) . Per protocol analysis revealed that reproductive outcome was superior after OI with FSH than with CC with respect to PR per first cycle [ 30 versus 14.6 % , respectively , 95 % confidence interval ( CI ) 5.3 - 25.8 , P = 0.003 ] , PR per woman , ( 58 versus 44 % of women , 95 % CI 1.5 - 25.8 , P = 0.03 ) , LBR per woman ( 52 versus 39 % , 95 % CI 0.4 - 24.6 , P = 0.04 ) , cumulative PR ( 52.1 versus 41.2 % , P = 0.021 ) and cumulative LBR ( 47.4 versus 36.9 % , P = 0.031 ) , within three cycles of OI . CONCLUSIONS Pregnancies and live births are achieved more effectively and faster after OI with low-dose FSH than with CC . This result has to be balanced by convenience and cost in favour of CC . FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility , particularly older patients OBJECTIVE ( S ) To evaluate the effects of metformin on insulin resistance , ovarian and rogen production , and clomiphene-induced ovulation and pregnancy rates in infertile women with polycystic ovary syndrome ( PCOS ) . STUDY DESIGN Twenty-one infertile women with PCOS were selected in this prospect i ve r and omized clinical study . Basal steroid and gonadotropin levels were measured , and oral glucose tolerance test ( OGTT ) was performed . The patients were divided r and omly into group 1 ( n = 11 ) and group 2 ( n = 10 ) . Group 1 patients were treated with 1700 mg per day of metformin for 3 months . The basal tests and OGTT were repeated after metformin therapy . Group 2 patients did not receive metformin . The patients in both groups received 100 mg of clomiphene citrate ( CC ) daily for 5 days until either a pregnancy occurred , or six CC cycles were reached . Metformin administration continued during CC therapy until the day of hCG in group 1 . Serum progesterone ( P ) level > or=5 ng/ml was considered as confirmatory of ovulation . Ovulation and pregnancy rates after six cycles were determined . RESULTS Serum and rogens and insulin response to OGTT decreased significantly after metformin therapy . Midluteal serum P level was significantly higher in cycles treated with metformin plus CC ( P < 0.05 ) . The ovulation ( 38 of 51 cycles , 74.4 % versus 34 of 55 cycles , 61.8 % ) and pregnancy rates ( 5 of 11 women , 45.5 % versus 3 of 10 women , 30 % ) were higher , but not significantly , in the metformin plus CC group than in the CC alone group . All the patients who conceived had insulin resistance in group 1 whereas non-insulin resistance in group 2 . CONCLUSION ( S ) Metformin improves insulin resistance and reduces and rogen levels . Metformin did not increase significantly the ovulation and pregnancy rates CONTEXT In overweight/obese women with polycystic ovary syndrome ( PCOS ) , the relative benefit of delaying infertility treatment to lose weight vs seeking immediate treatment is unknown . OBJECTIVE We compared the results of two , multicenter , concurrent clinical trials treating infertility in women with PCOS . DESIGN , SETTING , AND PARTICIPANTS This was a secondary analysis of two r and omized trials conducted at academic health centers study ing women 18 - 40 years of age who were overweight/obese and infertile with PCOS . INTERVENTION We compared immediate treatment with clomiphene from the Pregnancy in Polycystic Ovary Syndrome II ( PPCOS II ) trial ( N = 187 ) to delayed treatment with clomiphene after preconception treatment with continuous oral contraceptives , lifestyle modification ( Lifestyle : including caloric restriction , antiobesity medication , behavioral modification , and exercise ) or the combination of both ( combined ) from the Treatment of Hyper and rogenism Versus Insulin Resistance in Infertile Polycystic Ovary Syndrome ( OWL PCOS ) trial ( N = 142 ) . MAIN OUTCOME MEASURES Live birth , pregnancy loss , and ovulation were measured . RESULTS In PPCOS II , after four cycles of clomiphene , the cumulative per-cycle ovulation rate was 44.7 % ( 277/619 ) and the cumulative live birth rate was 10.2 % ( 19/187 ) , nearly identical to that after oral contraceptive pretreatment in the OWL PCOS trial ( ovulation 45 % [ 67/149 ] and live birth : 8.5 % [ 4/47 ] ) . In comparison , deferred clomiphene treatment preceded by lifestyle and combined treatment in OWL PCOS offered a significantly better cumulative ovulation rate compared to immediate treatment with clomiphene . ( Lifestyle : 62.0 % [ 80/129 ] ; risk ratio compared to PPCOS II = 1.4 ; 95 % confidence interval [ CI ] , 1.1 - 1.7 ; P = .003 ; combined : 64.3 % [ 83/129 ] ; risk ratio compared to PPCOS II = 1.4 ; 95 % CI , 1.2 - 1.8 ; P < .001 and a significantly better live birth rate lifestyle : 25.0 % [ 12/48 ] ; risk ratio compared to PPCOS II = 2.5 ; 95 % CI , 1.3 - 4.7 ; P = .01 and combined : 25.5 % [ 12/47 ] ; risk ratio compared to PPCOS II = 2.5 ; 95 % CI , 1.3 - 4.8 ; P = .01 ) . CONCLUSIONS These data show the benefit of improved ovulation and live birth with delayed infertility treatment with clomiphene citrate when preceded by lifestyle modification with weight loss compared with immediate treatment . Pretreatment with oral contraceptives likely has little effect on the ovulation and live birth rate compared with immediate treatment Background Polycystic ovary syndrome ( PCOS ) is a common , complex endocrine disorder for women of productive age . A high incidence of ovulation failure in women with PCOS is related to insulin resistance . Some studies have assessed the effects of hyperinsulinemia and insulin resistance in relationship with insulin sensitizing agents such as Metformin ( Met ) . These medicines have been suggested new scope for ovulation stimulation enhancement with Clomiphene Citrate ( CC ) in PCOs women . The aim of this study is to compare the effectiveness of adding Met to CC in women with PCOS . Material s and Methods This multicenter , single-blind , r and omized controlled trial study was performed on 334 PCOS patients from 2007 to 2009 . Patients were r and omly divided into two groups and ovulation induction was performed with either CC alone or CC + Met . The treatment was continued for three cycles , then the mature follicle and pregnancy rates were evaluated . Results In the CC + Met group , 68 % had at least one dominant follicle in the first cycle that was significant ( p<0.001 ) , and 31.7 % had one in the second cycle . In the CC group 54.5 % in the first cycle , 31.7 % second cycle , and 6.9 % ovulated in the third cycle . The pregnancy rate was 28.7 % in CC + Met group and 24.6 % in the CC group , with no significant differences between the two groups . Conclusion Adding Met to CC is significant for ovulation , but it does not enhance the pregnancy rate ( Registration Number : I RCT 138904174306N1 ) Background . Polycystic ovary syndrome ( PCOS ) is the most common endocrinopathy in women and is associated with the reproductive and metabolic disorders . Objectives . To compare the ovulation and conception rates after the treatment with Clomiphene Citrate ( CC ) alone and in combination with metformin in infertile patients presented with polycystic ovarian syndrome ( PCOS ) . Material & Methods . This r and omized controlled trial of independent cases and controls was conducted in the Department of Obstetrics and Gynecology , Hera General Hospital , Makkah , Saudi Arabia , during 2008 . The 42 subjects diagnosed as PCOS were divided into group A and B ( 21 subjects in each ) for the management with CC + metformin and CC alone , respectively . Group A received 500 mg of metformin continuously , three times a day from the first cycle , for 6 months or until the pregnancy was confirmed . In both groups , CC was started with a dose of 50 mg from day-2 until day-6 of the menstrual cycle . The dose of CC was increased to 100 mg in the second and 150 mg in the third cycle , and then 150 mg remained for the rest of three cycles . With ovulation , the dose of CC was unaltered in both groups . Data were analyzed by using SPSS version 16 . Results . More than 50 % of the females in both groups had a body mass index of > 25 . Group A achieved a higher rate of regular cycles , ovulation success , and conception than group B ( 71.4 % vs. 38.1 % ; p=0.03 ) , ( 76.2 % vs. 38.1 % ; p=0.021 ) and ( 66.6 % vs. 28.6 % , p=0.01 ) , respectively . Conclusion . Management with metformin + CC increased the ovulation and conception rates BACKGROUND Long-term effects of laparoscopic electrocautery of the ovaries are unknown . To study the long-term effects of laparoscopic electrocautery of the ovaries and gonadotrophins , we followed women with clomiphene-resistant polycystic ovary syndrome ( PCOS ) r and omly allocated to one of these treatments until 8 - 12 years after their initial treatment . METHODS Between February 1998 and October 2001 168 women with clomiphene citrate-resistant PCOS were included in a r and omized controlled trial comparing an electrocautery strategy to a strategy starting with rFSH . In 2009 these women were contacted about their reproductive outcome and menstrual cycle regularity . Analysis was by intention-to-treat . We compared time to conception result ing in live birth , subsequent pregnancies , ectopic and multiple pregnancies , menopause , as well as minimal and maximal menstrual cycle length . RESULTS After 8 - 12 years , the cumulative proportion of women with a first child was 86 % in women who had been allocated to electrocautery versus 81 % in women who had been allocated to immediate rFSH [ relative ratio ( RR ) : 1.1 ; 95 % confidence interval ( CI ) : 0.92 - 1.2 ] . Treatment with electrocautery result ed in a significantly lower need for stimulated cycles to reach a live birth ; 53 % after electrocautery versus 76 % after rFSH ( RR : 0.69 ; 95 % CI : 0.55 - 0.88).The cumulative proportion of women with a second child was 61 % after electrocautery versus 46 % after immediate rFSH ( RR : 1.4 ; 95 % CI : 1.00 - 1.9 ) . Overall , there were 7 twins out of 134 deliveries ( 5 % ) after electrocautery versus 10 twins out of 124 deliveries ( 8 % ) in the rFSH group ( RR : 0.65 ; 95 % CI : 0.25 - 1.6 ) . Fifty-four per cent of the women allocated to electrocautery had a regular menstrual cycle 8 - 12 years after r and omization versus 36 % in those allocated to rFSH ( RR : 1.5 ; 95 % CI : 0.87 - 2.6 ) . CONCLUSION In women with clomiphene-resistant PCOS , laparoscopic electrocautery of the ovaries is as effective as ovulation induction with FSH treatment in terms of live births , but reduces the need for ovulation induction or ART in a significantly higher proportion of women and increases the chance for a second child . Clinicians may use these data when informing clomiphene-resistant anovulatory women about treatment options 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 BACKGROUND It has been reported that women with polycystic ovary syndrome ( PCOS ) benefit from metformin therapy . METHODS A r and omized , placebo-controlled , double-blind study of obese ( body mass index > 30 kg/m2 ) , oligo-/amenorrhoeic women with PCOS . Metformin ( 850 mg ) twice daily was compared with placebo over 6 months . All received the same advice from a dietitian . The primary outcome measures were : ( i ) change in menstrual cycle ; ( ii ) change in arthropometric measurements ; and ( iii ) changes in the endocrine parameters , insulin sensitivity and lipid profile . RESULTS A total of 143 subjects was r and omized [ metformin ( MET ) = 69 ; placebo ( PL ) = 74 ] . Both groups showed significant improvements in menstrual frequency [ median increase ( MET = 1 , P < 0.001 ; PL = 1 , P < 0.001 ) ] and weight loss [ mean ( kg ) ( MET = 2.84 ; P < 0.001 and PL = 1.46 ; P = 0.011 ) ] . However , there were no significant differences between the groups . Logistic regression analysis was used to analyse the independent variables ( metformin , percentage of weight loss , initial BMI and age ) in order to predict the improvement of menses . Only the percentage weight loss correlated with an improvement in menses ( regression coefficient = 0.199 , P = 0.047 , odds ratio = 1.126 , 95 % CI 1.001 , 1.266 ) . There were no significant changes in insulin sensitivity or lipid profiles in either of the groups . Those who received metformin achieved a significant reduction in waist circumference and free and rogen index . CONCLUSIONS Metformin does not improve weight loss or menstrual frequency in obese patients with PCOS . Weight loss alone through lifestyle changes improves menstrual frequency Abstract Objective To compare the effectiveness of an electrocautery strategy with ovulation induction using recombinant follicle stimulating hormone in patients with polycystic ovary syndrome . Design R and omised controlled trial . Setting Secondary and tertiary hospitals in the Netherl and s. Participants 168 patients with clomiphene citrate resistant polycystic ovary syndrome : 83 were allocated electrocautery and 85 were allocated recombinant follicle stimulating hormone . Intervention Laparoscopic electrocautery of the ovaries followed by clomiphene citrate and recombinant follicle stimulating hormone if anovulation persisted , or induction of ovulation with recombinant follicle stimulating hormone . Main outcome measure Ongoing pregnancy within 12 months . Results . The cumulative rate of ongoing pregnancy after recombinant follicle stimulating hormone was 67 % . With only electrocautery it was 34 % , which increased to 49 % after clomiphene citrate was given . Subsequent recombinant follicle stimulating hormone increased the rate to 67 % at 12 months ( rate ratio 1.01 , 95 % confidence interval 0.81 to 1.24 ) . No complications occurred from electrocautery with or without clomiphene citrate . Patients allocated to electrocautery had a significantly lower risk of multiple pregnancy ( 0.11 , 0.01 to 0.86 ) . Conclusion The ongoing pregnancy rate from ovulation induction with laparoscopic electrocautery followed by clomiphene citrate and recombinant follicle stimulating hormone if anovulation persisted , or recombinant follicle stimulating hormone , seems equivalent to ovulation induction with recombinant follicle stimulating hormone , but the former procedure carries a lower risk of multiple pregnancy BACKGROUND Laparoscopic ovarian diathermy ( LOD ) is currently accepted as a successful second-line treatment for ovulation induction ( OI ) in clomiphene citrate (CC)-resistant women with polycystic ovary syndrome ( PCOS ) . The aim of this study was to test the hypothesis that LOD may be superior to CC as a first-line treatment . METHODS The study included 72 anovulatory women with PCOS who were r and omized to LOD ( n = 36 ) or CC ( n = 36 ) . Women who remained anovulatory after LOD were offered CC . Similarly , women receiving CC who failed to ovulate or conceive were offered LOD . Pregnancy rates were compared between the two groups using chi(2 ) and odds ratio with 95 % confidence interval ( OR , 95 % CI ) . RESULTS After r and omization , six women conceived before starting treatment and another patient postponed treatment . The remaining 65 women received the treatment ( 33 underwent LOD and 32 received CC ) . After the primary treatment , more pregnancies ( 44 % ) occurred in women receiving CC than in those undergoing LOD ( 27 % ) , although the difference did not reach statistical significance [ P = 0.13 , OR 2.1 ( 0.7 - 5.8 ) ] . After adding the second treatment , the pregnancy rate was still higher , but to a less extent , in the CC group [ 63 % versus 52 % , P = 0.2 , OR 1.6 ( 0.6 - 4.2 ) ] . CONCLUSIONS LOD is not superior to CC as a first-line method of OI in women with PCOS . The trial is registered with Clinical Trials.gov with an identifier number NCT00220545 STUDY QUESTION What is the health-related quality of life ( HRQoL ) in women with polycystic ovary syndrome ( PCOS ) undergoing ovulation induction with clomifene citrate ( CC ) combined with metformin compared with those using CC combined with placebo ? SUMMARY ANSWER Overall quality of life in women with PCOS treated with CC plus metformin was significantly lower than in women treated with CC plus placebo . WHAT IS KNOWN ALREADY There are no data on HRQoL in adult women who receive ovulation induction with the purpose of conceiving . Women with PCOS have higher scores on depression and anxiety scales and lower QoL scores than women without PCOS . STUDY DESIGN , SIZE AND DURATION This study was a secondary analysis of a multi-centre RCT completed between June 2001 and May 2004 . The r and omization was stratified per centre , and the centres received blinded , numbered containers with medication . There were172 women available for the HRQoL assessment : 85 were allocated to metformin and 87 were allocated to placebo . PARTICIPANTS , SETTING AND METHODS The Rotterdam Symptom Checklist ( RSCL ) , a st and ard self-administered question naire , was used to assess physical symptoms , psychological distress , activity levels and overall HRQoL. MAIN RESULTS AND THE ROLE OF CHANCE In the intention to treat analysis , we found differences between the treatment groups with respect to physical symptoms and overall HRQoL. Physical well-being was significantly impaired in women allocated to metformin but not in women allocated to placebo . The increase in physical symptoms in the metformin group was caused by side-effects typical of metformin , and was most pronounced at Week 1 ( mean difference 12 [ 95 % confidence interval ( CI ) : 8 - 16 ] and still apparent at Week 16 [ mean difference 7 ( 95 % CI 2 - 12 ] . Overall well-being was significantly impaired in the metformin group compared with the placebo group [ mean difference 13 ( 95 % CI 6 - 20 ) ] . LIMITATIONS AND REASONS FOR CAUTION RSCL measurements were available only for three quarters of the participants . Although the number of missing question naires and the baseline measurements , were comparable between the treatment groups , some form of selection bias can not be ruled out . WIDER IMPLICATION S OF THE FINDINGS Our finding that metformin was more burdensome than placebo , strengthens the recommendation that CC only and not CC plus metformin should be the drug of choice in this patient population . STUDY FUNDING /COMPETING INTEREST(S ) None of the authors declared a conflict of interest . There was no study funding . TRIAL REGISTRATION NUMBER IS RCT N55906981 BACKGROUND Polycystic ovarian syndrome ( PCOS ) is the most common hormonal dysfunction in women . It 's a cause of female infertility by oligoanovulation , clinical and biochemical hyper and rogenism and polycystic ovaries . Weight loss , firstly proposed in overweight or obese patient suffering from PCOS , aims to reduce hyperinsulinism and hyper and rogenism . Recently , Metformin , an insulin sensitizer , has been proposed as an alternative first line treatment for polycystic ovarian syndrome by improving hyperinsulinemia and hyper and rogenism in these women . AIM The aim of our study , and through a literature review , is to demonstrate if Metformin should be used as a first-line drug for infertile women with this syndrome or as an adjunction to Clomifene Citrate , the longest established treatment already used in this syndrome . METHODS A prospect i ve comparative study including 63 patients with PCOS has been done during 2 years . Women were r and omly allocated to clomifene + Metformin ( Metformin group , Metformin took during 8 weeks , 850 mg twice a day , plus Clomifene 100 mg per day during five days ) or Clomifene only ( 100 mg per day during five days ) . All patients underwent a two- month 's diet . RESULTS The middle age was about 30.63 years and the body mass index ( BMI ) was about 29.88 kg/ m(2 ) . We noticed a 6.2 % weight loss in both groups ( a non significant difference in p=0.04 ) . The median of infertility period was about 2.49 years . The ovulation rate in the Metformin group was 53.12 % ( significant difference for inducing ovulation p=0.02 ) and 32.25 % in Clomifene group ( non-significant difference 0.07 ) . There was also a significant difference for ongoing pregnancies ( p=0.04 ) . In fact , 11 on 32 patients ( 34 % ) achieved a full-term pregnancy in Metformin group versus only 4 ones on 31 patients ( 12.9 % ) in Clomifene group . CONCLUSION Our conclusion is that Metformin is an effective addition to Clomifene Citrate in term of reestablishment of ovulation and full-term pregnancies achievement , excluding ART cycles Objectives The objective of this study was to compare the efficacy of letrozole versus clomiphene citrate as an ovulation induction drug in polycystic ovarian syndrome ( PCOS ) patients of Indian origin . Method One hundred and forty seven infertile PCOS patients were r and omly given letrozole ( 2.5 mg ) ( n = 69 ) or clomiphene ( 100 mg ) ( n = 78 ) from day 3 to day 7 of menstrual cycle , followed-up with transvaginal serial folliculometry from day 9 . 10,000 IU of human chorionic gonadotropin ( hCG ) was administered when at least 1 ovarian follicle was ≥ 18 mm in size . Results The pertinent results of the study are as follows : on the day of hCG injection , mean E2 level was significantly higher in the clomphene citrate group ( 817 ± 286.70 pg/ml ) in comparison with letrozole group ( 444.03 ± 85.42 pg/ml ) . Mean endometrial development was 8.72 ± 1.41 mm in the letrozole and 8.78 ± 1.16 mm in the clomiphene group ( P = 0.004 ) . Conclusion Letrozole has beneficial effect on endometrium , thereby potentially increasing pregnancy rates after successful ovulation induction in women with PCOS 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 Aim : To compare clomiphene citrate ( CC ) , metformin or the combination of CC and metformin as the first line ovulation induction drug in Asian Indian women with polycystic ovary syndrome ( PCOS ) . Methods : One hundred and five newly diagnosed , treatment naive PCOS women were recruited . They were r and omized into any of the three groups : Group I ( CC 50 - 150 mg/day ) , Group II ( metformin 1700 mg/day ) , and Group III ( CC + metformin in similar dosage to Groups I and II ) . Patients underwent follicular monitoring and advice on timed intercourse . The study period was 6 months , or till pregnant , or till CC resistant . Primary outcome studied was live birth rate ( LBR ) . Secondary outcomes were ovulation rate , pregnancy rate , and early pregnancy loss rate . Results : There was no significant difference among the groups in baseline characteristics and biochemical parameters . LBR was 41.6 % , 37.5 % , and 28.1 % , respectively in Groups III , II , and I. Group III ( CC + metformin ) had the highest ovulation ( 83.3 % ) , pregnancy ( 50 % ) , and LBRs ( 41.6 % ) . Group II ( metformin ) was as good as Group I ( CC ) in all the outcomes . CC + metformin ( Group III ) had statistically significantly higher ovulation rate as compared to CC alone ( Group I ) ( P = 0.03 ; odds ratio : 95 % confidence interval : 3.888 [ 1.08 - 13.997 ] ) . Conclusion : Thus , our study shows that metformin was as good as CC in terms of " LBR " and the combination of CC and metformin gave the highest ovulation and LBR OBJECTIVE To compare the efficacy of letrazole in the induction of ovulation with clomiphene citrate in patients with polycystic ovary syndrome and primary infertility . METHODS The prospect i ve clinical trial was conducted at Basrah Maternity and Child Hospital , Basrah , Iraq , between January 2012 and April 2013 , and comprised women with polycystic ovarian syndrome and primary infertility who were r and omised into 2 groups . Group A received100 - 200 mg clomiphene citrate daily while group 2 received letrazole ( 2.5 - 5 mg ) daily . Both groups were followed by ultrasound until the dominant follicle reached a diameter > 18 mm , human chorionic gonadotropin10.000 U/L was given and timed intercourse was advised . RESULTS Of the 75 subjects in the study , 40(53.3 % ) were in group A and 35(46.6 % ) in group B. The mean age in group A was 25.3 + 2.1 years versus 26.1 + 1.3 years in group B ( p=0.05 ) . The number of mature follicles was significantly lower , but the endometrial thickness and ovulation were significantly higher in group B than in group A ( p<0.05 each ) . There was no significant difference in pregnancy rate between the two groups ( p>0.05 ) . CONCLUSIONS Letrazole may have a role as the first-line treatment for unovulatory patients with polycystic ovary syndrome BACKGROUND : Polycystic ovary syndrome ( PCOS ) is the commonest endocrinopathy in women that is associated with reproductive and metabolic disorders . OBJECTIVES : We compared the ovulation and conception rates after the treatment with clomiphene citrate ( CC ) alone and in combination with metformin in infertile patients presented with polycystic ovarian syndrome ( PCOS ) . MATERIAL S AND METHODS : This r and omized controlled trial of independent cases and controls was conducted at the Department of Obstetrics and Gynecology , Hera General Hospital , Makkah , Saudi Arabia from February 01 to December 31 , 2008 . The 42 subjects diagnosed as PCOS were divided into group A and B ( 21 subjects in each ) for management with CC + metformin and CC alone , respectively . Group A received 500 mg three times a day of metformin continuously from the first cycle for 6 months or till pregnancy was confirmed . In both groups CC was started at a dose of 50 mg from day-2 till day-6 of the menstrual cycle . The dose of CC was increased to 100 mg in second and 150 mg in third cycle , and then remained 150 mg for the remaining three cycles . With ovulation the dose of CC was unaltered in both groups . Data were analyzed using Statistical Package for the Social Sciences ( SPSS ) version 16 . RESULTS : More than 50 % females in both groups were had body mass index > 25 . Group A achieved high rate of regular cycles , ovulation success , and conception than group B ( 71.4 % vs. 38.1 % ; P = 0.03 ) , ( 76.2 % vs. 38.1 % ; P = 0.021 ) , and ( 66.6 % vs. 28.6 % ; P = 0.01 ) , respectively . CONCLUSION : Management with metformin + CC increased the ovulation and conception rates AIM Polycystic ovary syndrome ( PCOS ) is one of the most common causes of ovulatory infertility . It is an endocrine disorders characterized by a high level of male hormones ( and rogens ) and frequent anovulatory cycles associated with multiple ovarian microcysts . The aim of this paper was to evaluate effects of a Clomiphene citrate alone versus a combined treatment ( Metformin and Clomiphene citrate ) . METHODS A total of 60 women with PCOS and infertility were evaluated . Inclusion s criteria were : age 26 - 34 years , nulliparity , above 3 years of sterility , multiple ovarian microcysts , BMI > 27.5 , oligomenorrhea/amenorrhea , hyper and rogenism and normal male fertility . Four patients were excluded ( renal damage 2 , tubal occlusion 1 and Pelvic Inflammatory Disease 1 ) . The remaining 56 were divided into 2 groups : group A were inducted with Clomiphene Citrate alone , while group B were inducted with Clomiphene citrate and Metformin . RESULTS In group A we obtained ovulation in 20 women ( 71.4 % ) , 8 pregnancies ( 28.5 % ) and one ( 3.5 % ) spontaneous abortion . In group B we obtained ovulation in 24 women ( 85.7 % ) , 15 pregnancies ( 53.5 % ) and no spontaneous abortions . CONCLUSION Combined treatment was found to be more effective ( 53.5 ) in improving pregnancy rate compared to monotherapy ( 28.5 % ) CONTEXT Lifestyle modification is recommended in women with polycystic ovary syndrome ( PCOS ) prior to conception but there are few r and omized trials to support its implementation or benefit . OBJECTIVE This study aim ed to determine the relative efficacy of preconception intervention on reproductive and metabolic abnormalities in overweight/obese women with PCOS . DESIGN , SETTING , AND PARTICIPANTS This was a r and omized controlled trial of preconception and infertility treatment at Academic Health Centers in women with infertility due to PCOS , age 18 - 40 y and body mass index 27 - 42 kg/m(2 ) . INTERVENTION Women were r and omly assigned to receive either 16 weeks of 1 ) continuous oral contraceptive pills ( OCPs ) ( ethinyl estradiol 20 mcg/1 mg norethindrone acetate ) ( " OCP " ) ; 2 ) lifestyle modification consisting of caloric restriction with meal replacements , weight loss medication ( either sibutramine , or orlistat ) , and increased physical activity to promote a 7 % weight loss ( " Lifestyle " ) ; or 3 ) combined treatment with both OCP and lifestyle modification ( " Combined " ) . After preconception intervention , women underwent st and ardized ovulation induction with clomiphene citrate and timed intercourse for four cycles . Pregnancies were followed with trimester visits until delivery . MAIN OUTCOME MEASURES Weight , ovulation , and live birth were measured . RESULTS We consented 216 and r and omly assigned 149 women ( Lifestyle : n = 50 ; OCP : n = 49 ; Combined : n = 50 ) . We achieved significant weight loss with both Lifestyle ( mean weight loss , -6.2 % ; 95 % confidence interval ( CI ) , -7.4 - -5.0 ; and Combined ( mean weight loss , -6.4 % ; 95 % CI , -7.6 - -5.2 ) compared with baseline and OCP ( both P < .001 ) . There was a significant increase in the prevalence of metabolic syndrome at the end of preconception treatment compared with baseline within OCP ( odds ratio [ OR , 2.47 ; 95 % CI , 1.42 - 4.27 ) whereas no change in metabolic syndrome was detected in the Lifestyle ( OR , 1.18 ; 95 % CI , 0.63 - 2.19 ) or Combined ( OR , 0.72 ; 95 % CI , 0.44 - 1.17 ) groups . Cumulative ovulation rates were superior after weight loss : OCP , 46 % ; Lifestyle , 60 % ; and Combined , 67 % ( P < .05 ) . Live birth rates were OCP , 12 % ; Lifestyle , 26 % ; and Combined , 24 % ( P = .13 ) . CONCLUSIONS A preconception weight loss intervention eliminates the adverse metabolic oral contraceptive effects and , compared with oral contraceptive pretreatment , leads to higher ovulation rates BACKGROUND The transfer of fresh embryos is generally preferred over the transfer of frozen embryos for in vitro fertilization ( IVF ) , but some evidence suggests that frozen-embryo transfer may improve the live-birth rate and lower the rates of the ovarian hyperstimulation syndrome and pregnancy complications in women with the polycystic ovary syndrome . METHODS In this multicenter trial , we r and omly assigned 1508 infertile women with the polycystic ovary syndrome who were undergoing their first IVF cycle to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer . After 3 days of embryo development , women underwent the transfer of up to two fresh or frozen embryos . The primary outcome was a live birth after the first embryo transfer . RESULTS Frozen-embryo transfer result ed in a higher frequency of live birth after the first transfer than did fresh-embryo transfer ( 49.3 % vs. 42.0 % ) , for a rate ratio of 1.17 ( 95 % confidence interval [ CI ] , 1.05 to 1.31 ; P=0.004 ) . Women who underwent frozen-embryo transfer also had a lower frequency of pregnancy loss ( 22.0 % vs. 32.7 % ) , for a rate ratio of 0.67 ( 95 % CI , 0.54 to 0.83 ; P<0.001 ) , and of the ovarian hyperstimulation syndrome ( 1.3 % vs. 7.1 % ) , for a rate ratio of 0.19 ( 95 % CI , 0.10 to 0.37 ; P<0.001 ) , but a higher frequency of preeclampsia ( 4.4 % vs. 1.4 % ) , for a rate ratio of 3.12 ( 95 % CI , 1.26 to 7.73 ; P=0.009 ) . There were no significant between-group differences in rates of other pregnancy and neonatal complications . There were five neonatal deaths in the frozen-embryo group and none in the fresh-embryo group ( P=0.06 ) . CONCLUSIONS Among infertile women with the polycystic ovary syndrome , frozen-embryo transfer was associated with a higher rate of live birth , a lower risk of the ovarian hyperstimulation syndrome , and a higher risk of preeclampsia after the first transfer than was fresh-embryo transfer . ( Funded by the National Basic Research Program of China and others ; Clinical Trials.gov number , NCT01841528 . ) OBJECTIVE To study whether a combination of berberine and letrozole results in higher live births than letrozole alone in infertile women with polycystic ovary syndrome ( PCOS ) . DESIGN A multicenter r and omized double-blinded placebo-controlled trial . SETTING Reproductive and developmental network sites . PATIENT(S ) Eligible women had PCOS as defined by the Rotterdam criteria . We enrolled 644 participants r and omized 1:1:1 among letrozole , berberine , and combination groups . INTERVENTIONS ( S ) Berberine or berberine placebo were administrated orally at a daily dose of 1.5 g for up to 6 months . Patients received an initial dose of 2.5 mg letrozole or placebo on days 3 - 7 of the first three treatment cycles . This dose was increased to 5 mg on the last three cycles if not pregnant . MAIN OUTCOMES MEASURE(S ) Cumulative live births . RESULTS The cumulative live births were similar between the letrozole and combination groups after treatment ( 36 % and 34 % ) , and were superior to those in the berberine group ( 22 % ) . Likely , conception , pregnancy , and ovulation rates were similar between the letrozole and combination groups , and these were significantly higher than in the berberine group . There was one twin birth in the letrozole group , three twin births in the combination group , and none in the berberine group . CONCLUSION ( S ) Berberine did not add fecundity in PCOS when used in combination with the new ovulation agent letrozole . CLINICAL TRIAL REGISTRATION NUMBER ChiCTR-TRC-09000376 ( http://apps.who.int/trial search / ) 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 ] AIM Ovulation dysfunction is one of the most common causes of reproductive failure in infertile couples . The prevalence of this disorder in infertile women is about 30 to 40 % . Polycystic ovary syndrome is a common disease that is closely related to ovulation dysfunction and 7 % of women of childbearing age are afflicted with it . Ovulation induction is a way to treat infertility in PCOS which is possible through medication or surgery . This study was conducted to compare the effects of Letrozole and Clomiphene citrate for ovulation induction in women with PCOS . METHODS This intervention is a clinical trial study carried out on 100 infertile women with polycystic ovary syndrome who were referred to gynecologist 's office and Oslian hospital . The subjects were r and omly divided in to two groups including 50 patients who received letrozole and Clomiphene Citrate . Abdominal ultrasound was performed on the day 14 of the menstrual cycle to monitor the number and size of developed follicles and endometrial thickness.%age of ovulation was compared between the two groups receiving medication with χ2 test and t-test was used to compare the average number and size of follicles and endometrial thickness . Twenty-three cases ( 46 % ) in group receiving clomiphene citrate had thin endometrium and thin endometrium was observed in 1 case ( 2 % ) of group receiving letrozole . Among 50 subjects who received clomiphene citrate , 10 people ( 20 % ) reported blurred vision , 9 patients ( 18 % ) headache , 6 patients ( 12 % ) nausea and 2 patients ( 4 % ) reported vomiting and one ( 2 % ) twin pregnancies was observed , but no complications were reported in group receiving letrozole . RESULTS Mean age , parity , and the duration of infertility were similar in all patients . Ovulation rate was 88 % ; similar in both groups . The average number of follicles in the group receiving clomiphene citrate was 58/1±32/2 and in the group receiving letrezole it was 50/0±30/1 . Average follicle size in both groups was almost similar . Endometrial thickness in the group receiving letrezole was 27/1±71/9 and in the group receiving clomiphene citrate it was 06/3±08/6 . Pregnancy rate in both groups was almost similar . CONCLUSION This study showed that stimulation of letrozole and clomiphene citrate on ovulation and was almost the same and clomiphene citrate caused endometrial thinning more often than letrozole . Also the side effects reported by patients in the group receiving clomiphene citrate were higher , while in the group receiving letrozole no complication was reported . Based on these findings letrozole can be considered an appropriate alternative for clomiphene citrate without side effects OBJECTIVE To compare the effectiveness of letrozole and clomiphene citrate ( CC ) in induction of ovulation in polycystic ovary syndrome ( PCOS ) . DESIGN Prospect i ve , r and omized , not blinded , controlled trial . SETTING A tertiary level infertility care center . PATIENT(S ) Sixty-four anovulatory patients with PCOS , who failed to ovulate when taking 100 mg/day CC in previous cycles . INTERVENTION(S ) Patients were r and omly divided into two groups by lottery and treated with either 7.5 mg/day letrozole ( an aromatase inhibitor ) or 150 mg/day CC for 5 days starting from day 3 of the menstrual cycle . MAIN OUTCOME MEASURE(S ) Occurrence of ovulation , endometrial thickness , and pregnancy rate ( PR ) . RESULT ( S ) Twenty ( 62.5 % ) patients from the letrozole group and 12 ( 37.50 % ) patients from the CC group ovulated during the observation period . Mean serum E2 level was 817.75 pg/mL and 448.03 pg/mL in the CC and letrozole groups , respectively , on the day of hCG administration . The mean endometrial thickness on the day of hCG administration was 9.03 mm and 10.37 mm in the CC and letrozole groups , respectively . The mean D21 serum P was 13.09 ng/mL and 19.09 ng/mL in the CC and letrozole groups , respectively . Thirteen patients from the letrozole group ( 40.63 % ) and six patients from the CC group ( 18.75 % ) became pregnant . CONCLUSION ( S ) Letrozole has better ovulation and PR in comparison to CC in patients with PCOS OBJECTIVE To compare the rates of ovulation and pregnancy after tamoxifen citrate ( TMX ) or clomiphene citrate ( CC ) among anovulatory women with infertility . DESIGN Prospect i ve r and omized trial . SETTING Infertility clinic in a university teaching hospital . PATIENT(S ) Eighty-six anovulatory women under 40 years of age undergoing ovulation induction . INTERVENTION(S ) The women were assigned r and omly to receive either TMX or CC on cycle days 5 - 9 . MAIN OUTCOME MEASURE(S ) Rates of ovulation and pregnancy for the two treatment modalities . RESULTS ( S ) The overall rate of ovulation in the TMX group was 50 of 113 ( 44.2 % ) and in the CC group , 41 of 91 ( 45.1 % ) . There were 10 pregnancies in the TMX group and 6 pregnancies in the CC group . The cycle fecundity per ovulatory cycle was 20.0 % in the TMX group and 14.6 % in the CC group . CONCLUSION ( S ) The overall rate of ovulation and pregnancy were similar with TMX and CC . TMX is a suitable alternative agent to CC in the management of anovulatory infertility CONTEXT : Low ovulatory and pregnancy rates with clomiphene citrate ( CC ) in anovulatory polycystic ovarian syndrome ( PCOS ) . AIM : To find out the ovulatory and pregnancy rates in infertile PCOS subjects who receive CC alone and a combination of metformin and CC . SETTING AND DESIGN : A prospect i ve controlled clinical trial conducted in the outpatient department from August 2003 to August 2005 . MATERIAL S AND METHODS : Twenty-four infertile PCOS women received CC alone at incremental doses of 50 mg up to 150 mg for three cycles and then at a dose of 150 mg for another three cycles ( control group ) . The study group ( 16 PCOS ) received the same dose of CC along with 1500 mg of metformin . Ovulation was monitored by transvaginal sonography up to six cycles or till pregnancy occurred . STATISTICAL ANALYSIS : This was carried out using software SSPS , version 10 . Fisher 's exact test was used to calculate the ovulatory rates . Nine subjects of the control group who failed to conceive with CC had opted for CC and metformin and their ovulatory rate was calculated using statistical software , namely SPSS 15.0 , Stata 8.0 , MedCalc 9.0.1 and Systat 11.0 using Fischer 's exact test . RESULTS : The metformin and clomiphene combination result ed in a significantly higher rate of ovulation ( P = 0.0016 ) . The pregnancy rate was 8 % with CC and 24 % with metformin and CC . The CC failure group also ovulated at a similar rate as that of the study group . CONCLUSIONS : The ovulatory rate and the pregnancy rate with the metformin – CC combination was found to be higher when compared with CC alone . Metformin increased the ovulatory rate in CC failures , also implying increased sensitivity to CC This single centre r and omized controlled trial was undertaken to compare the efficacy and safety of clomiphene citrate and low-dose recombinant FSH as first line pharmacological therapy for anovulatory infertility associated with polycystic ovary syndrome ( PCOS ) . Seventy-six infertile patients with PCOS were r and omized to receive clomiphene citrate ( 50 - 150 mg/day for 5 days ) ( clomiphene citrate group , n = 38 ) or recombinant human FSH ( FSH group , n = 38 ) in a chronic , low-dose , step-up protocol ( daily starting dose 75 IU ) for up to three consecutive cycles . Ovarian response was monitored by transvaginal ultrasonography and human chorionic gonadotrophin ( HCG ) was given to trigger ovulation in all cycles with appropriate follicular development . The primary outcome measure was cumulative pregnancy after undergoing up to three treatment cycles . Secondary outcomes were cycle cancellation rate , ovulation rate per cycle , cumulative ovulation rate , pregnancy rate per cycle , incidence of OHSS , cumulative live birth rate , and multiple birth rate . One hundred and four clomiphene citrate cycles and 91 FSH cycles were evaluable . The relative risk and its 95 % confidence interval were 1.17 ( 0.97 - 1.46 ) for HCG cycles with ovulation , 1.78 ( 0.92 - 3.54 ) for the pregnancy rate per woman , and 1.83 ( 0.79 - 4.40 ) for live births per woman in favour of FSH . The cumulative pregnancy rate after three treatment cycles was 43 % with FSH and 24 % with clomiphene citrate ( P = 0.06 ) . By logistic regression analysis , the factors predicting ovulation included female age , serum and rostenedione and use of FSH . Predictors of pregnancy were duration of infertility and use of FSH . This r and omized controlled trial suggests that low-dose recombinant FSH may be an effective alternative to clomiphene citrate in first-line treatment for anovulatory PCOS patients . Thus , further studies , possibly multi-centre , in order to avoid problems with patient recruitment , are warranted to confirm these results OBJECTIVES To assess the adjuvant effect of metformin and N-acetylcysteine ( NAC ) to clomiphene citrate ( CC ) in induction of ovulation in Polycystic Ovary Syndrome ( PCOS ) patients . STUDY DESIGN 120 women with PCOS were r and omly divided into three equal groups : group I received CC only , group II received CC plus NAC and group III received CC plus metformin . RESULTS There was a significant difference between group II and other two groups regarding average number of ovulatory follicles > 18 mm ( 2.25 versus 1.75 and 1.89 , respectively ) , but no significant difference between the three study groups regarding number of intermediate follicles 14 - 18 mm ( 4 , 10 and 4 , respectively ) . There was no significant difference between the three study groups regarding occurrence and laterality of ovulation , pregnancy rate per cycle but a significant difference between group II and other two groups regarding pregnancy rate per patient ( 20 % versus 10 % and 10 % , respectively , p value 0.05 ) . There was a highly statistically significant difference between group II and other two groups regarding peak endometrial thickness ( 7.3 ± 1.1 versus 5.4 ± 0.6 and 5.3 ± 0.6 , respectively ) . CONCLUSIONS NAC as an adjuvant to CC for induction of ovulation improves ovulation and pregnancy rates in PCOS patients with beneficial impacts on endometrial thickness BACKGROUND The polycystic ovary syndrome is a common cause of infertility . Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation , but it is unknown whether one approach is superior . METHODS We r and omly assigned 626 infertile women with the polycystic ovary syndrome to receive clomiphene citrate plus placebo , extended-release metformin plus placebo , or a combination of metformin and clomiphene for up to 6 months . Medication was discontinued when pregnancy was confirmed , and subjects were followed until delivery . RESULTS The live-birth rate was 22.5 % ( 47 of 209 subjects ) in the clomiphene group , 7.2 % ( 15 of 208 ) in the metformin group , and 26.8 % ( 56 of 209 ) in the combination-therapy group ( P<0.001 for metformin vs. both clomiphene and combination therapy ; P=0.31 for clomiphene vs. combination therapy ) . Among pregnancies , the rate of multiple pregnancy was 6.0 % in the clomiphene group , 0 % in the metformin group , and 3.1 % in the combination-therapy group . The rates of first-trimester pregnancy loss did not differ significantly among the groups . However , the conception rate among subjects who ovulated was significantly lower in the metformin group ( 21.7 % ) than in either the clomiphene group ( 39.5 % , P=0.002 ) or the combination-therapy group ( 46.0 % , P<0.001 ) . With the exception of pregnancy complications , adverse-event rates were similar in all groups , though gastrointestinal side effects were more frequent , and vasomotor and ovulatory symptoms less frequent , in the metformin group than in the clomiphene group . CONCLUSIONS Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome , although multiple birth is a complication . ( Clinical Trials.gov number , NCT00068861 [ Clinical Trials.gov ] . ) OBJECTIVE To reevaluate the efficacy of induction of ovulation with CC versus TMX in a group of anovulatory subfertile women with PCOS in a r and omized controlled trial . STUDY DESIGN A prospect i ve r and omized controlled study in which 371 PCOS patients were r and omly allocated into two treatment groups : group A ( 187 patients ) where women received CC and group B ( 184 patients ) where they received Tamoxifen for one treatment cycle . The outcome measures were number of growing and mature follicles , serum E(2 ) ( pg/ml ) , serum progesterone ( ng/ml ) and endometrial thickness , the occurrence of pregnancy and miscarriage . RESULTS The number of stimulated follicles reaching ≥ 16 mm diameter was significantly more in the CC group compared to Tamoxifen stimulated group ( 2.1 SD ± 0.1 vs. 1.1 SD ± 0.7 , p<0.0001 ) . The endometrium at the time of hCG administration was significantly thicker in the TMX group ( 10.1 ± 0.1 mm vs. 9.3 ± 0.4 mm , p<0.0001 ) . Ovulation occurred in 120/187 cycles ( 64 % ) in the CC group and 95/184 cycles ( 51.6 % ) in the TMX group with a significant difference between two groups in favors of clomiphene ( p=0.01 ) . Serum E(2 ) , on the day of hCG administration , was significantly higher in the clomiphene group ( p<0.0001 ) . Pregnancy occurred in 35/187 cycles in group A ( 18.7 % ) and 20/184 cycles ( 10.8 % ) in group B and the difference was statistically significant ( p=0.04 ) . CONCLUSIONS Clomiphene citrate is more successful than tamoxifen as a first line therapy for ovulation induction in 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 BACKGROUND This study was carried out to determine the pattern of presentation of Polycystic ovary syndrome ( PCOS ) in patients presenting at our unit and to compare effects of clomiphene alone and in combination with metformin in management of PCOS . METHODS This study was conducted from Jan 2001 - 2003 at Military Hospital , Rawalpindi . All patients presenting with infertility were evaluated with a view to select 100 patients of PCOS with the help of history of oligomenorrhoea , hirsuitism and acne . Diagnosis was confirmed by ultrasonography and hormone analysis ( LH , FSH , prolactin , testosterone along with LH : FSH>2 ) . The 100 selected patients were divided into two equal groups . One was given combined clomiphene citrate ( CC ) and metformin for ovulation induction and the other CC alone . These patients were followed for six cycles for ovulation and conception . Follicle tracking on ultrasonography and day-21 serum progesterone level were used to detect ovulation while conception was confirmed by urine pregnancy test , serum B-HCG level and ultrasonography for gestational sac . RESULTS Hirsuitism and oligomenorrhoea were the two most common clinical features of PCOS . In the first group 34 patients ( 68 % ) ovulated as compared with 18 ( 36 % ) in the second group . In the first group 18 out of 34 women ( 52.9 % ) conceived as compared with only 8 out of 18 ( 44 % ) in the second group . The difference was significant at > 0.05 when ovulatory and pregnancy responses were compared among two groups . All patients tolerated metformin well and no teratogenic effects were observed in patients who conceived after treatment with metformin . CONCLUSION A combination of metformin and clomiphene citrate significantly increases the ovulation and conception rates in these patients In a controlled treatment study of 49 anovulatory infertile women , responses to clomiphene citrate ( CC ) and placebo treatments were compared and associations of behavioral and emotional factors with treatment responses were investigated . In the first treatment series , ovulation occurred in 20 of 24 women in the CC group and 8 of 22 women in the placebo group . Pregnancy was achieved by 11 women during CC treatment and 3 women during placebo treatment . Overall , 28 women completed the protocol and 21 withdrew . Those who achieved pregnancy ( n = 14 ) did not differ significantly from the ovulation-only group ( n = 22 ) on pretreatment measures of emotional , behavioral , and personality factors including the Hopkins Symptom Checklist ( HSCL-90 ) , Eysenck Personality Inventory , Langner Screening Scale , Mood Analog Scale , Social Adjustment Scale , Mooney Problem Checklist , and the Minnesota Multiphasic Personality Inventory ( MMPI ) . Conclusions were that a placebo response was observed in both ovulation and pregnancy , but psychologic factors as measured in this sample were not associated with these treatment outcomes 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 OBJECTIVE To compare the effects of letrozole ( 5 mg ) and clomiphene citrate ( 100 mg ) for ovulation induction in women with polycystic ovary syndrome ( PCOS ) . DESIGN Prospect i ve r and omized trial . SETTING University teaching hospital and private practice setting . PATIENT(S ) The study comprised a total of 438 infertile women ( 1063 cycles ) with PCOS . INTERVENTION(S ) Patients were r and omized to treatment with 5 mg of letrozole daily ( 218 patients , 545 cycles ) or 100 mg of clomiphene citrate daily ( 220 patients , 518 cycles ) for 5 days starting on day 3 of menses . Timed intercourse was advised 24 to 36 hours after hCG injection . MAIN OUTCOME MEASURE(S ) Number of follicles , serum estradiol , serum progesterone , endometrial thickness , and pregnancy and miscarriage rates . RESULT ( S ) The mean age , parity , and duration of infertility in both groups were similar . The total number of follicles was statistically significantly greater in the clomiphene citrate group ( 6.8 + /- 0.3 versus 4.4 + /- 0.4 ) . Endometrial thickness at the time of hCG administration was statistically significantly greater in the CC group ( 9.2 + /- 0.7 mm versus 8.1 + /- 0.2 mm ) . The duration to reach a dominant follicle was statistically significantly longer in the letrozole group ( 12.1 + /- 1.3 versus 8.8 + /- 2.9 days ) . Ovulation occurred in 365 out of 540 cycles ( 67.5 % ) in letrozole group and 371 out of 523 cycles ( 70.9 % ) without a statistically significant difference . Levels of serum estradiol and progesterone were statistically significantly higher in the clomiphene citrate group . The pregnancy rate per cycle was 15.1 % in the letrozole group and 17.9 % in the clomiphene citrate group without statistically difference between the groups . CONCLUSION ( S ) The results of this study did not show any advantage to the use of letrozole over clomiphene citrate as a first-line treatment for induction of ovulation in women with PCOS Cisclomiphene , one of the two isomers of clomiphene , has been previously used for induction of ovulation . This paper describes the use of cisclomiphene in 5-mg and 10-mg dose schedules , and compares its effectiveness to that of a placebo in a double-blind study . A significant observation was that patients receiving the placebo apparently responded with ovulation as frequently as those subjects given cisclomiphene . In this limited series , cisclomiphene does not appear to be more effective in ovulation induction or in pregnancy rate than clomiphene citrate . The importance of dose level is pointed out as well as the numerous factors that may be involved in successful use of clomiphene-like drugs OBJECTIVE To compare the effect of clomiphene citrate , metformin , and lifestyle modification on treatment of patients with polycystic ovary syndrome ( PCOS ) . DESIGN Prospect i ve r and omized double-blind study . SETTING University-based infertility clinic and research center . PATIENT(S ) Three hundred forty-three overweight infertile women with PCOS . INTERVENTION(S ) The participating women were assigned to four groups : clomiphene ( n = 90 ) , metformin ( n = 90 ) , clomiphene + metformin ( n = 88 ) , and lifestyle modification ( n = 75 ) . The patients in each group received st and ardized dietary and exercise advice from a dietitian . MAIN OUTCOME MEASURE(S ) The primary outcome variables were change in menstrual cycle , waist circumference measurements , endocrine parameters , and lipid profile . The main secondary outcome variable was clinical pregnancy rate . RESULT ( S ) The clinical pregnancy rate was 12.2 % in clomiphene group , 14.4 % in metformin group , 14.8 % in clomiphene + metformin group , and 20 % in lifestyle modification group . Lifestyle modification group achieved a significant reduction in waist circumference , total and rogen , and lipid profile . CONCLUSION ( S ) Lifestyle modification improves the lipid profile in PCOS patients . Therefore , lifestyle modification may be used as the first line of ovulation induction in PCOS patients |
13,714 | 25,431,307 | Discussion This study was design ed to clarify whether industry-sponsored trials report more positive outcomes than non-industry trials .
It will be the first study to evaluate this topic in general and abdominal surgery . | Background Industry sponsorship has been identified as a factor correlating with positive research findings in several fields of medical science .
To date , the influence of industry sponsorship in general and abdominal surgery has not been fully studied .
This protocol describes the rationale and planned conduct of a systematic review to determine the association between industry sponsorship and positive outcome in r and omised controlled trials in general and abdominal surgery . | Financial and other competing interests have recently received increasing attention . In particular clinical research in plastic surgery attracts for-profit organizations , thus , explaining the increasing number of financial sponsorships . However , research articles often lack sufficient description of study design as well as disclosure of the source of funding . Furthermore , debate exists whether industry funding influences research findings and is leading to pro-industry results .A h and search was conducted identifying all r and omized controlled ( RCT ) and controlled clinical trials ( CCT ) in 4 plastic surgery journals ( Plastic and Reconstructive Surgery , British Journal of Plastic Surgery , Annals of Plastic Surgery , and AestheticPlastic Surgery ) between 1990 and 2005 . Subsequently , the influence of financial support on study outcome was analyzed . A total of 10,476 original articles were analyzed , result ing in the identification of 346 clinical trials which meet the Cochrane criteria for RCTs and CCTs . One hundred eighty-three trials and 163 studies were found to be RCTs and CCTs , respectively . Hereof , only 70 trials ( 20.2 % ) reported on grant support . Of these , 42 trials ( 60 % ) were supported by the industry . Depending on the topic addressed marked differences were detected regarding grant support . Studies with a focus on reconstructive plastic surgery were supported by the industry and by public institutions in almost equal shares ( 18 trials vs. 15 trials ) , whereas aesthetic surgical topics were predominantly funded by the industry ( 13 trials vs. 6 trials ) . Industry-funded trials reported more often statistically significant differences between treatment arms ( 28 trials vs. 16 trials ) . Authors ' conclusions were found to be positively associated with financial competing interests . However , trial funding is rarely declared in the plastic surgery literature . Thus , the quality of reporting needs to be improved to be able to investigate these relationships in greater detail and draw more representative conclusions The current report tests the hypotheses that commercial funding , country of origin , and presence of a coinvestigator with training in statistics are related to the likelihood of a published orthopaedic study arriving at a positive conclusion . All articles from the Journal of Bone and Joint Surgery ( American ) , the Journal of Arthroplasty , and the American Journal of Sports Medicine published in 1 year were review ed . The blinded review process classified each article as to study design and outcome ( positive or negative ) , according to previously published definitions . Commercial funding was significantly associated with a positive outcome ; 78.9 % of commercially funded studies concluded with a positive outcome , compared with 63.3 % of nonfunded studies . The presence of a statistician or epidemiologist as a coinvestigator , and the place of origin of the study were not associated with outcome . Only 21 % of published studies were prospect i ve , 3.5 % were r and omized , and 10.5 % stated an experimental hypothesis ; these factors were not associated with study outcome . Published studies that received funding from commercial parties were significantly more likely to report a positive outcome than studies that received no such funding . This does not imply the presence of a corrupting or causative influence of industry sponsorship on research outcomes ; additional research is needed to determine whether such nonscientific factors actually affect study outcome or likelihood of publication Compared with nonfunded or peer- review ed funded projects , industry-sponsored clinical trials have traditionally been associated with more positive results . This relationship has been extensively studied in the nonsurgical literature . Although a few authors have addressed specialties , little has been reported on orthopedic clinical trials and their association with funding , study outcome , and efforts to reduce bias after r and omization across journals of multiple subspecialties . For the study reported here , we selected 5 major orthopedic subspecialty journals : Journal of Bone and Joint Surgery ( American Volume ) , Spine , Journal of Arthroplasty , Journal of Orthopaedic Trauma , and American Journal of Sports Medicine . We chose a 2-year limit for investigation ( 2002 - 2004 ) ; included all original r and omized clinical trials reported in these 5 journals ; and examined these trials for their study design , funding source , outcome , bias potential , and conclusion reached . Support for the 100 eligible orthopedic clinical trials was stated as coming from industry ( 26 trials , 26 % ) , nonprofit sources ( 19 trials , 19 % ) , and mixed sources ( 5 trials , 5 % ) ; no support was stated in 46 trials ( 46 % ) , and support was not reported in 4 trials ( 4 % ) . Of the 26 trials reporting industry support , 22 ( 85 % ) were grade d as indicating an outcome favorable to the new treatment . The association between industry funding and favorable outcome was strong and significant ( P<.001 ) . In almost half of the studies reported in Journal of Bone and Joint Surgery and Spine , measures taken to reduce bias were not documented BACKGROUND AND OBJECTIVE To conduct a pilot study to compare the frequency of errors that accompany single vs. double data extraction , compare the estimate of treatment effect derived from these methods , and compare the time requirements for these methods . METHODS Review ers were r and omized to the role of data extractor or data verifier , and were blind to the study hypothesis . The frequency of errors associated with each method of data extraction was compared using the McNemar test . The data set for each method was used to calculate an efficacy estimate by each method , using st and ard meta-analytic techniques . The time requirement for each method was compared using a paired t-test . RESULTS Single data extraction result ed in more errors than double data extraction ( relative difference : 21.7 % , P = .019 ) . There was no substantial difference between methods in effect estimates for most outcomes . The average time spent for single data extraction was less than the average time for double data extraction ( relative difference : 36.1 % , P = .003 ) . CONCLUSION In the case that single data extraction is used in systematic review s , review ers and readers need to be mindful of the possibility for more errors and the potential impact these errors may have on effect estimates Objective To identify trends in r and omized controlled trials ( RCTs ) in leading otolaryngology journals . Study Design and Setting We review ed all RCTs of treatment efficacy from 2000 through 2005 in 4 major otolaryngology journals . Data included study quality , author 's conclusions , adverse events , and study support/ funding . Results Of 5467 total articles , 202 ( 3.7 % ) were RCTs of treatment efficacy . Slightly more than half of the trials were supported by for-profit organizations ( 25 % ) , not-for-profit groups ( 21 % ) , or both ( 7 % ) . Intent-to-treat analysis was used in 58 percent of trials , P values in 88 percent , and confidence intervals in 11 percent . Conclusions favoring the experimental group were unrelated to presence or absence of industry funding , and conclusions suggesting equivalence were unrelated to sample size . Conclusions RCTs are uncommon in otolaryngology journals , but they demonstrate frequent use of intent-to-treat analysis , no evidence of publication bias for funded studies , and no evidence of low power in studies suggesting equivalence . Significance This study has implication s for both the otolaryngology research er design ing studies and the practicing clinician interpreting them Objectives To investigate the degree to which Cochrane review s of drug interventions published in 2010 reported conflicts of interest from included trials and , among review s that reported this information , where it was located in the review documents . Design Cross sectional study . Data sources Cochrane Data base of Systematic Review s. Selection criteria Systematic review s of drug interventions published in 2010 in the Cochrane Data base of Systematic Review s , with review content classified as up to date in 2008 or later and with results from one or more r and omised controlled trials . Results Of 151 included Cochrane review s , 46 ( 30 % , 95 % confidence interval 24 % to 38 % ) reported information on the funding sources of included trials , including 30 ( 20 % , 14 % to 27 % ) that reported information on trial funding for all included trials and 16 ( 11 % , 7 % to 17 % ) that reported for some , but not all , trials . Only 16 of the 151 Cochrane review s ( 11 % , 7 % to 17 % ) provided any information on trial author-industry financial ties or trial author-industry employment . Information on trial funding and trial author-industry ties was reported in one to seven locations within each review , with no consistent reporting location observed . Conclusions Most Cochrane review s of drug trials published in 2010 did not provide information on trial funding sources or trial author-industry financial ties or employment . When this information was reported , location of reporting was inconsistent across review BACKGROUND Conflicting reports exist in the medical literature regarding the association between industry funding and published research findings . In this study , we examine the association between industry funding and the statistical significance of results in recently published medical and surgical trials . METHODS We examined a consecutive series of 332 r and omized trials published between January 1999 and June 2001 in 8 leading surgical journals and 5 medical journals . Each eligible study was independently review ed for method ological quality using a 21-point index with 5 domains : r and omization , outcomes , eligibility criteria , interventions and statistical issues . Our primary analysis included studies that explicitly identified the primary outcome and reported it as statistically significant . For studies that did not explicitly identify a primary outcome , we defined a " positive " study as one with at least 1 statistically significant outcome measure . We used multivariable regression analysis to determine whether there was an association between reported industry funding and trial results , while controlling for study quality and sample size . RESULTS Among the 332 r and omized trials , there were 158 drug trials , 87 surgical trials and 87 trials of other therapies . In 122 ( 37 % ) of the trials , authors declared industry funding . An unadjusted analysis of this sample of trials revealed that industry funding was associated with a statistically significant result in favour of the new industry product ( odds ratio [ OR ] 1.9 , 95 % confidence interval [ CI ] 1.3 - 3.5 ) . The association remained significant after adjustment for study quality and sample size ( adjusted OR 1.8 , 95 % CI 1.1 - 3.0 ) . There was a nonsignificant difference between surgical trials ( OR 8.0 , 95 % CI 1.1 - 53.2 ) and drug trials ( OR 1.6 , 95 % CI 1.1 - 2.8 ) , both of which were likely to have a pro-industry result ( relative OR 5.0 , 95 % CI 0.7 - 37.5 , p = 0.14 ) . INTERPRETATION Industry-funded trials are more likely to be associated with statistically significant pro-industry findings , both in medical trials and surgical interventions |
13,715 | 25,890,337 | This appears to be the first systematic review of physical activity , diet and weight loss interventions targeting university and college students . | To examine the effectiveness of interventions aim ed at improving physical activity , diet , and /or weight-related behaviors amongst university/college students . | The transition to college has been identified as a critical period for increases in overweight status . Overweight college students are at-risk of becoming obese adults , and , thus prevention efforts targeting college age individuals are key to reducing adult obesity rates . The current study evaluated an Internet intervention with first year college students ( N=170 ) r and omly assigned to one of four treatment conditions : 1 ) no treatment , 2 ) 6-week online intervention 3 ) 6-week weight and caloric feedback only ( via email ) , and 4 ) 6-week combined feedback and online intervention . The combined intervention group had lower BMI s at post-testing than the other three groups . This study demonstrated the effectiveness and feasibility of an online intervention to prevent weight gain among college students Background Epidemiologic data indicate most adolescents and adults experience multiple , simultaneous risk behaviors . Purpose The purpose of this study is to examine the efficacy of a brief image-based multiple-behavior intervention ( MBI ) for college students . Methods A total of 303 college students were r and omly assigned to : ( 1 ) a brief MBI or ( 2 ) a st and ard care control , with a 3-month postintervention follow-up . Results Omnibus treatment by time multivariate analysis of variance interactions were significant for three of six behavior groupings , with improvements for college students receiving the brief MBI on alcohol consumption behaviors , F(6 , 261 ) = 2.73 , p = 0.01 , marijuana-use behaviors , F(4 , 278 ) = 3.18 , p = 0.01 , and health-related quality of life , F(5 , 277 ) = 2.80 , p = 0.02 , but not cigarette use , exercise , and nutrition behaviors . Participants receiving the brief MBI also got more sleep , F(1 , 281 ) = 9.49 , p = 0.00 , than those in the st and ard care control . Conclusions A brief image-based multiple-behavior intervention may be useful in influencing a number of critical health habits and health-related quality -of-life indicators of college students Objective : The authors ' purpose in this study was to compare the effects of macronutrient intake on systemic glucose levels in previously sedentary participants who followed 1 of 4 diets that were either higher protein or high carbohydrate , while initiating an exercise program . Participants and Methods : The authors r and omly assigned 94 sedentary participants to 1 of 4 diet groups consisting of Diet 1 ( 55 % carbohydrate , 30 % fat , 15 % protein ) , Diet 2 ( 55 % carbohydrate , 30 % fat , 15 % protein and caloric restriction ) , Diet 3 ( 40 % carbohydrate , 30 % fat , 25 % protein ) , and Diet 4 ( 40 % carbohydrate , 30 % fat , 25 % protein and caloric restriction ) and followed recommended aerobic exercise prescriptions . Results : Repeated measures analyses of variance ( ANOVA ) revealed a significant time factor ( p = .021 ) but no significant differences between diet groups ( p = .207 ) . A trend was evident in the higher protein groups , with a 5.2 % decrease in glucose levels with Diet 3 and 5.0 % with Diet 4 . Although glucose levels changed over time with the greatest changes in the 2 higher protein diets , levels were not significantly different within participants . Conclusions : The results of the study indicate that systemic glucose availability was affected by higher protein consumption in Diet 3 participants , with the same trend in Diet 4 participants , although nonsignificant . These findings demonstrate that consuming a lower carbohydrate diet for 12 weeks can possibly change systemic glucose levels PURPOSE This study examined the effects of brief image-based interventions , including a multiple behavior health contract , a one-on-one tailored consultation , and a combined consultation plus contract intervention , for impacting multiple health behaviors of students in a university health clinic . METHODS A total of 155 college students attending a major southern university were recruited to participate in a study evaluating a health promotion program titled Project Fitness during the fall 2005 and spring 2006 . Participants were r and omly assigned to one of three treatments as they presented at the clinic : 1 ) a multiple behavior health contract , 2 ) a one-on-one tailored consultation , or 3 ) a combined consultation plus contract intervention . Baseline and 1-month post-intervention data were collected using computer-assisted question naires in a quiet office within the student health clinic . RESULTS Omnibus repeated- measures analyses of variance were significant for drinking driving behaviors , F(2,136 ) = 4.43 , p = .01 , exercise behaviors , F(5,140 ) = 6.12 , p = .00 , nutrition habits , F(3,143 ) = 5.37 , p = .00 , sleep habits , F(2,144 ) = 5.03 , p = .01 , and health quality of life , F(5,140 ) = 3.09 , p = .01 , with improvements on each behavior across time . Analysis of group-by-time interaction effects showed an increase in the use of techniques to manage stress , F(2,144 ) = 5.48 , p = .01 , and the number of health behavior goals set in the last 30 days , F(2,143 ) = 5.35 , p = .01 , but only among adolescents receiving the consultation , or consultation plus contract . Effect sizes were consistently larger across health behaviors , and medium in size , when both consult and contract were used together . CONCLUSIONS Brief interventions using a positive goal image of fitness , and addressing a number of health habits using a contract and consultation strategy alone , or in combination , have the potential to influence positive changes in multiple health behaviors of college students attending a university primary health care clinic BACKGROUND This study examined the effect of using physical activity homework on physical activity levels of college students . METHODS Students in r and omly assigned sections of a university health course were assigned 30 minutes of physical activity homework 3 days a week or no homework for 12 weeks . Participants completed self-reports of physical activity before the homework intervention and again at the conclusion of the 12 weeks of physical activity homework . RESULTS Participants in all course sections reported significant increases in the number of days per week of moderate and vigorous physical activity . Participants in homework sections additionally showed significant increases in the days they engaged in muscular strength/endurance training and activities to manage weight . Participants in sections without homework showed a significant increase in the number of days engaged in flexibility training . Comparison of gain scores showed statistically significant increases by the homework group in the days they participated in activities design ed to manage weight . CONCLUSION Physical activity homework was deemed to be an effective method of increasing college students ' levels of physical activity Purpose . Examine the impact of “ point of decision ” messages on fruit selection in a single dining hall setting . Setting . Competitive undergraduate liberal arts college in the southeastern United States . Intervention . “ Point of decision ” messages were compiled into a 35-slide multimedia PowerPoint presentation . Messages were displayed on a computer screen at a “ point of decision ” between the cookie and fruit stations during lunch for a total of 9 days . Measures . Baseline cookie and fruit consumption was measured 9 days prebaseline and 9 days postbaseline . A r and om sample of students completed surveys 1 week after the intervention . Analysis . t-tests were used to examine differences between prelevels of fruit consumption and levels measured simultaneously during “ point of decision ” messages . Descriptive statistics were used to examine perceptions of survey items 1 week postintervention . Results . A significant mean difference in daily fruit consumption was found following the slide presentation ( df-8 , t = − 2.800 ; p = .023 ) . Average daily fruit consumption at baseline was 408 ( SD = 73.43 ) . Postbaseline average daily fruit consumption significantly increased ( 533 ; SD = 102 ) . No significant prebaseline and postbaseline cookie differences were found ( p = .226 ) . Approximately 71 % of women and 68 % of men noticed the “ point of decision ” messages . Nineteen percent of women and 10 % of males reported modifying their food selection as a result of viewing the messages . Conclusion . The “ point of decision ” messaging significantly influenced fruit selection in a single dining hall setting . ( Am J Health Promot 2011;25[5]:298 - 300 . BACKGROUND Recent public health initiatives have promoted accumulating 10,000 steps per day . Little previous research has evaluated its effects in young adults . The aim of this study was to determine the effects of taking 10,000 steps per day on fitness and cardiovascular risk factors in sedentary university students . METHODS Healthy , sedentary students ( mean age 21.16 ± SD 6.17 ) were r and omly allocated to take 10,000 steps per day or to a control group who maintained their habitual activity . Members of the 10,000 step group wore a pedometer and reported daily step count in a diary . Outcome measurements ( 20-meter multistage shuttle run , BMI , and blood pressure ) were measured before and after 6 weeks . RESULTS There were no significant differences between the groups at baseline . After 6 weeks , the 10,000 steps group were taking significantly more steps ( 8824.1 ± SD 5379.3 vs. 12635.9 ± SD 6851.3 ; P = .03).No changes were observed in fitness , or BMI ( P > .05 ) . Significant reductions in blood pressure ( P = .04 ) in the 10,000 step group . CONCLUSIONS A daily target of 10,000 steps may be an appropriate intervention in sedentary university students to increase their physical activity levels . The positive health benefits of simple everyday physical activity should be promoted among health professionals Purpose . The purpose of this pilot study was to conduct an impact evaluation of a 10-week Web-based physical activity intervention . Design . Quasi-experimental , three-group pretest , posttest design . Setting . Large Midwestern university . Subjects . Participants ( N = 233 ) included college students registered for three courses . The study employed a convenience sample consisting of a Web-based group ( n = 108 ) , a physical activity group ( n = 64 ) , and a general health group ( n = 61 ) . Intervention . The Web-based group received a Social Cognitive Theory behavioral skill-building intervention and exercised 3 days per week in their leisure time . The physical activity group received exercise instruction and was required to attend three physical activity labs per week . The comparison group received health instruction . Measures . Outcome variables included moderate and vigorous physical activity , self-regulation , social support , self-efficacy , and outcome expectations and expectancies . Analysis . Differences between groups were assessed at pretest and posttest using multiple analyses of variance . Results . Vigorous physical activity , self-regulation , and outcome expectancy value changed significantly in the Web-based and physical activity course groups ( p < .01 ) . Conclusions . Even with consideration of limitations such as small sample size and lack of r and omization , the Web-based and traditional physical activity lecture and activity lab interventions were superior in eliciting changes in vigorous physical activity , self-regulation , and outcome expectancy value than a traditional health course . ( Am J Health Promot 2011;25[4]:227–230 . This study investigates the importance of peer effects in explaining weight gain among freshman college students . We exploit a natural experiment that takes place on most college campuses in the US -- r and omized roommate assignments . While previous studies suggest that having an obese spouse , friend , or sibling increases one 's likelihood of becoming obese , these social interactions are clearly non-r and om . We collect data from female students living on campus at a private Midwestern university at the beginning and end of their first year of college . Our findings suggest that the amount of weight gained during the freshman year is strongly and negatively correlated to the roommate 's initial weight . Further , our analysis of behaviors suggests that female students adopt some of their roommates ' weight-loss behaviors which cause them to gain less weight than they otherwise would have . In particular , we find evidence that this effect may be through influences in eating , exercise , and use of weight loss supplements BACKGROUND Research has shown that many college students do not meet recommended national guidelines for physical activity . The objective of this pilot study was to examine the short-term efficacy of a brief motivational intervention ( BMI ) design ed to increase physical activity . METHODS Participants were 70 college students who reported low physical activity ( 83 % women , 60 % African American ) . Participants were r and omly assigned to either the BMI condition or to an education-only ( EO ) condition . They completed measures of physical activity at baseline and 1-month follow-up . RESULTS Those in the BMI condition reported more vigorous-intensity physical activity at a 1-month follow-up than those in the EO condition . CONCLUSIONS The findings from this study provide preliminary support for the efficacy of a BMI design ed to increase physical activity among college students . Future studies should continue to examine and refine the intervention in an effort to improve health-related behaviors among this group Abstract Objective : To determine the impact of My Student Body (MSB)–Nutrition , an Internet-based obesity prevention program for college students . Participants : Three hundred and twenty ethnically diverse undergraduate students were r and omly assigned to 1 of 3 conditions : MSB-Nutrition program , an on-campus weight management course , and a comparison group . Methods : Students completed baseline and follow-up surveys regarding their nutrition and physical activity behaviors , self-efficacy , stress , attitudes , and body weight . Results : Compared with the on-campus course and a comparison group , the MSB-Nutrition program increased fruit and vegetable consumption , reduced stress , and increased fruit and vegetable self-efficacy but had no significant effect on students ’ exercise self-efficacy , exercise behavior , or weight loss . Conclusions : The MSB-Nutrition program was effective in changing students ’ nutrition behaviors but had no effect on physical activity behaviors or weight loss . Suggestions for improving Internet-based interventions aim ed at decreasing obesity rates among college students are offered Brief planning interventions , usually delivered within paper and pencil question naires , have been found to be effective in changing health behaviours . Using a double-blind r and omised controlled trial , this study examined the efficacy of two types of planning interventions ( action plans and coping plans ) in increasing physical activity levels when they are delivered via the internet . Following the completion of self-reported physical activity ( primary outcome ) and theory of planned behaviour ( TPB ) measures at baseline , students ( N = 1273 ) were r and omised into one of four conditions on the basis of a 2 ( received instructions to form action plans or not ) × 2 ( received instructions to form coping plans or not ) factorial design . Physical activity ( primary outcome ) and TPB measures were completed again at two-month follow-up . An objective measure ( attendance at the university 's sports facilities ) was employed 6 weeks after a follow-up for a duration of 13 weeks ( secondary outcome ) . The interventions did not change self-reported physical activity , attendance at campus sports facilities or TPB measures . This might be due to low adherence to the intervention protocol ( ranging from 58.8 to 76.7 % ) . The results of this study suggest that the planning interventions under investigation are ineffective in changing behaviour when delivered online to a sample of participants unaware of the allocation to different conditions . Possible moderators of the effectiveness of planning interventions in changing health behaviours are discussed OBJECTIVES To evaluate the effectiveness of a theoretically based and Web-delivered intervention using common course technology for increasing physical activity in a college student sample . METHODS One hundred four students r and omly participated in either a Web-based intervention involving 7 theory-based learning lessons or a control group that received minimal physical activity information . Participants reported levels of physical activity and social cognitive theory ( SCT ) constructs at baseline and after 6 weeks of the intervention . RESULTS Relative to controls , intervention participants reported increased days of moderate and vigorous physical activity , but few changes in SCT constructs . CONCLUSIONS Web-based interventions can successfully increase physical activity among college students Project GRAD ( Graduate Ready for Activity Daily ) evaluates a university course to promote physical activity . In a r and omized study , 338 university seniors participated in either an intervention or control course for academic credit , and posttest data were collected on 321 . The control course was knowledge-oriented . The intervention course taught behavior change skills in weekly lectures and peer-led labs . Physical activity was assessed with 7-Day Physical Activity Recall interviews . The intervention had no significant effects on men . Among women , the intervention increased total physical activity during leisure , strengthening exercises , and flexibility exercise . This university course had the intended effects of promoting healthful patterns of physical activity among women , but no effects were observed on men , who were more active than women at baseline OBJECTIVES To describe activity patterns associated with a pedometer intervention in university freshmen and compare the intervention participants to controls for several health outcomes . METHODS Forty-six university freshmen were r and omized to a group that wore a pedometer across the academic year with a goal of 10,000 steps/day or to a control group . RESULTS Pedometer counts were highest initially but decreased over the academic year . December presented the fewest counts . There was little difference between groups in fitness or body composition . CONCLUSIONS Consideration of high-risk months and recommended steps/day may be important to effectively use pedometers to influence some health outcomes in university freshmen Objective : The authors examined the effect of certified personal trainer services on exercise behavior by using the transtheoretical model of behavioral change . Participants : Female college students ( n = 449 ) completed surveys during the first week ( T1 ) and last week ( T2 ) of the fall semester . Methods : Students receiving personal trainer services during the fall semester ( experimental group , n = 31 ) were cross-matched with students who had not received services ( control group , n = 31 ) . Results : The control group demonstrated a statistically significant regression in stage of exercise change scores ; the experimental group did not . The authors found the 2 groups to have a statistically significant difference in the pattern of exercise behavior change over the course of the semester , with more active maintainers and progressors in the experimental group . Conclusions : Cognitive and behavioral processes of change , decisional balance , and scheduling self-efficacy significantly decreased in the control group , whereas cognitive processes of change , decisional balance , and scheduling self-efficacy remained statistically unchanged in the experimental group The impact of a required college health and physical education course on selected health knowledge , attitudes , and behaviors of alumni was evaluated . The design was a cross-sectional study ( mail out/mail back survey ) using a stratified r and om sample of 2,000 college alumni . The overall response rate was 50 % . Results were analyzed by college of graduation ( college with a required health/physical education course versus no required course ) . Alumni who took the course were more likely to know their blood pressure , blood cholesterol , and recommended dietary fat intake than the comparison group were . They also reported that the course positively influenced their attitudes toward exercise , eating , and smoking They were more likely to engage in aerobic exercise and less likely to smoke ; and they had lower intakes of dietary fat , cholesterol , and sodium . The results suggested that a required college course enhanced selected health-related knowledge , attitudes , and behaviors of alumni BACKGROUND Online social networks , such as Facebook ™ , have extensive reach , and they use technology that could enhance social support , an established determinant of physical activity . This combination of reach and functionality makes online social networks a promising intervention platform for increasing physical activity . PURPOSE To test the efficacy of a physical activity intervention that combined education , physical activity monitoring , and online social networking to increase social support for physical activity compared to an education-only control . DESIGN RCT . Students ( n=134 ) were r and omized to two groups : education-only controls receiving access to a physical activity-focused website ( n=67 ) and intervention participants receiving access to the same website with physical activity self-monitoring and enrollment in a Facebook group ( n=67 ) . Recruitment and data collection occurred in 2010 and 2011 ; data analyses were performed in 2011 . SETTING / PARTICIPANTS Female undergraduate students at a large southeastern public university . INTERVENTION Intervention participants were encouraged through e-mails , website instructions , and moderator communications to solicit and provide social support related to increasing physical activity through a physical activity-themed Facebook group . Participants received access to a dedicated website with educational material s and a physical activity self-monitoring tool . MAIN OUTCOME MEASURES The primary outcome was perceived social support for physical activity ; secondary outcomes included self-reported physical activity . RESULTS Participants experienced increases in social support and physical activity over time but there were no differences in perceived social support or physical activity between groups over time . Facebook participants posted 259 times to the group . Two thirds ( 66 % ) of intervention participants completing a post- study survey indicated that they would recommend the program to friends . CONCLUSIONS Use of an online social networking group plus self-monitoring did not produce greater perceptions of social support or physical activity as compared to education-only controls . Given their promising features and potential reach , efforts to further underst and how online social networks can be used in health promotion should be pursued . TRIAL REGISTRATION This study is registered at clinical trials.govNCT01421758 |
13,716 | 24,205,253 | CONCLUSIONS Anti-VEGF agents result in a promising gain of visual acuity , but require a high injection frequency .
Dexamethasone implant might be an alternative , but comparison is impaired as the effect is temporary and it has not yet been tested in PRN regimen .
The ocular risk profile seems to be favorable for anti-VEGF agents in comparison to steroids . | BACKGROUND Intravitreal agents have replaced observation in macular edema in central ( CRVO ) and grid laser photocoagulation in branch retinal vein occlusion ( BRVO ) .
We conducted a systematic review to evaluate efficacy and safety outcomes of intravitreal therapies for macular edema in CRVO and BRVO . | PURPOSE To evaluate intravitreal aflibercept injections ( IAI ; also called VEGF Trap-Eye ) for patients with macular edema secondary to central retinal vein occlusion ( CRVO ) . DESIGN R and omized controlled trial . METHODS This multicenter study r and omized 189 patients ( 1 eye/patient ) with macular edema secondary to CRVO to receive 6 monthly injections of either 2 mg intravitreal aflibercept ( IAI 2Q4 ) ( n = 115 ) or sham ( n = 74 ) . From week 24 to week 52 , all patients received 2 mg intravitreal aflibercept as needed ( IAI 2Q4 + PRN and sham + IAI PRN ) according to retreatment criteria . The primary endpoint was the proportion of patients who gained ≥15 ETDRS letters from baseline at week 24 . Additional endpoints included visual , anatomic , and quality -of-life NEI VFQ-25 outcomes at weeks 24 and 52 . RESULTS At week 24 , 56.1 % of IAI 2Q4 patients gained ≥15 letters from baseline compared with 12.3 % of sham patients ( P < .001 ) . At week 52 , 55.3 % of IAI 2Q4 + PRN patients gained ≥15 letters compared with 30.1 % of sham + IAI PRN patients ( P < .001 ) . At week 52 , IAI 2Q4 + PRN patients gained a mean of 16.2 letters of vision vs 3.8 letters for sham + IAI PRN ( P < .001 ) . The most common adverse events for both groups were conjunctival hemorrhage , eye pain , reduced visual acuity , and increased intraocular pressure . CONCLUSIONS Monthly injections of 2 mg intravitreal aflibercept for patients with macular edema secondary to CRVO result ed in a statistically significant improvement in visual acuity at week 24 , which was largely maintained through week 52 with intravitreal aflibercept PRN dosing . Intravitreal aflibercept injection was generally well tolerated Background : To compare the effectiveness of subthreshold grid laser treatment ( SGLT ) with infrared micropulse diode laser alone or in combination with intravitreal triamcinolone injection ( SGLT-IVTJ ) for the treatment of macular oedema ( MO ) secondary to branch retinal vein occlusion ( BRVO ) . Methods : Pilot r and omised clinical trial including 24 patients ( 24 eyes ) who were r and omised either to the SGLT ( 13 eyes ) or to SGLT-IVTJ ( 11 eyes ) . Complete ophthalmic examinations , including Early Treatment of Diabetic Retinopathy Study visual acuity , OCT and fluorescein angiography , were performed at the moment of the study entry and at 3-month intervals , with a planned follow-up of 12 months . Main outcome measures were the decrease in mean foveal thickness ( MFT ) on OCT , and the proportion of eyes that gained at least 10 letters ( approximately two or more lines of visual acuity gain ) at the 12-month examination . Secondary outcomes were the decrease in mean total macular volume on OCT , and the timing of MO resolution . Results : The change in MFT from the initial values was statistically significant for the SGLT-IVTJ from the 3-month examination and for the SGLP from the 6-month examination ( p<0.001 ) . At the 12-month evaluation , 10 patients of the SGLT-IVTJ group ( 91 % ) and eight of the SGLT group ( 62 % ) gained at least 10 letters ( two lines ) in visual acuity . The mean number of lines gained was 3.4 and 1.3 in the SGLT-IVTJ and in the SGLT group , respectively . Conclusions : The combined SGLT-IVT treatment of MO secondary to BRVO allows a significant visual acuity improvement , when compared with simple grid laser treatment OBJECTIVE To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment . DESIGN Multicenter , r and omized clinical trial . PARTICIPANTS Patients ( n = 1107 ) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial . INTERVENTIONS At enrollment , patients were assigned to 4 treatment groups defined by drug ( ranibizumab or bevacizumab ) and dosing regimen ( monthly or as needed ) . At 1 year , patients initially assigned to monthly treatment were reassigned r and omly to monthly or as-needed treatment , without changing the drug assignment . MAIN OUTCOME MEASURES Mean change in visual acuity . RESULTS Among patients following the same regimen for 2 years , mean gain in visual acuity was similar for both drugs ( bevacizumab-ranibizumab difference , -1.4 letters ; 95 % confidence interval [ CI ] , -3.7 to 0.8 ; P = 0.21 ) . Mean gain was greater for monthly than for as-needed treatment ( difference , -2.4 letters ; 95 % CI , -4.8 to -0.1 ; P = 0.046 ) . The proportion without fluid ranged from 13.9 % in the bevacizumab-as-needed group to 45.5 % in the ranibizumab monthly group ( drug , P = 0.0003 ; regimen , P < 0.0001 ) . Switching from monthly to as-needed treatment result ed in greater mean decrease in vision during year 2 ( -2.2 letters ; P = 0.03 ) and a lower proportion without fluid ( -19 % ; P < 0.0001 ) . Rates of death and arteriothrombotic events were similar for both drugs ( P > 0.60 ) . The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab ( 39.9 % vs. 31.7 % ; adjusted risk ratio , 1.30 ; 95 % CI , 1.07 - 1.57 ; P = 0.009 ) . Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor ( VEGF ) . CONCLUSIONS Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period . Treatment as needed result ed in less gain in visual acuity , whether instituted at enrollment or after 1 year of monthly treatment . There were no differences between drugs in rates of death or arteriothrombotic events . The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF PURPOSE Assess 12-month efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after branch retinal vein occlusion ( BRVO ) . DESIGN Prospect i ve , r and omized , sham injection-controlled , double-masked , multicenter trial . PARTICIPANTS A total of 397 patients with macular edema after BRVO . METHODS Eligible patients were r and omized 1:1:1 to 6 monthly injections of 0.3 mg or 0.5 mg ranibizumab or sham injections . After 6 months , all patients with study eye best-corrected visual acuity ( BCVA ) ≤20/40 or central subfield thickness ≥250 μm were to receive ranibizumab . Patients could receive rescue laser treatment once during the treatment period and once during the observation period if criteria were met . MAIN OUTCOME MEASURES The main efficacy outcome reported is mean change from baseline BCVA letter score at month 12 . Additional visual and anatomic parameters were assessed . RESULTS Mean ( 95 % confidence interval ) change from baseline BCVA letter score at month 12 was 16.4 ( 14.5 - 18.4 ) and 18.3 ( 15.8 - 20.9 ) in the 0.3 mg and 0.5 mg groups , respectively , and 12.1 ( 9.6 - 14.6 ) in the sham/0.5 mg group ( P<0.01 , each ranibizumab group vs. sham/0.5 mg ) . The percentage of patients who gained ≥15 letters from baseline BCVA at month 12 was 56.0 % and 60.3 % in the 0.3 mg and 0.5 mg groups , respectively , and 43.9 % in the sham/0.5 mg group . On average , there was a marked reduction in central foveal thickness ( CFT ) after the first as-needed injection of 0.5 mg ranibizumab in the sham/0.5 mg group , which was sustained through month 12 . No new ocular or nonocular safety events were identified . CONCLUSIONS At month 12 , treatment with ranibizumab as needed during months 6 - 11 maintained , on average , the benefits achieved by 6 monthly ranibizumab injections in patients with macular edema after BRVO , with low rates of ocular and nonocular safety events . In the sham/0.5 mg group , treatment with ranibizumab as needed for 6 months result ed in rapid reduction in CFT to a similar level as that in the 0.3 mg ranibizumab treatment group and an improvement in BCVA , but not to the extent of that in the 2 ranibizumab groups . Intraocular injections of ranibizumab provide an effective treatment for macular edema after BRVO . FINANCIAL DISCLOSURE(S ) Proprietary or commercial disclosure may be found after the references PURPOSE Assess the 12-month efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after central retinal vein occlusion ( CRVO ) . DESIGN Prospect i ve , r and omized , sham injection-controlled , double-masked , multicenter clinical trial . PARTICIPANTS We included 392 patients with macular edema after CRVO . METHODS Eligible patients were r and omized 1:1:1 to receive 6 monthly intraocular injections of 0.3 mg or 0.5 mg of ranibizumab or sham injections . After 6 months , all patients with BCVA ≤20/40 or central subfield thickness ≥250 μm could receive ranibizumab . MAIN OUTCOME MEASURES Mean change from baseline best-corrected visual acuity ( BCVA ) letter score at month 12 , additional parameters of visual function , central foveal thickness ( CFT ) , and other anatomic changes were assessed . RESULTS Mean ( 95 % confidence interval ) change from baseline BCVA letter score at month 12 was 13.9 ( 11.2 - 16.5 ) and 13.9 ( 11.5 - 16.4 ) in the 0.3 mg and 0.5 mg groups , respectively , and 7.3 ( 4.5 - 10.0 ) in the sham/0.5 mg group ( P<0.001 for each ranibizumab group vs. sham/0.5 mg ) . The percentage of patients who gained ≥15 letters from baseline BCVA at month 12 was 47.0 % and 50.8 % in the 0.3 mg and 0.5 mg groups , respectively , and 33.1 % in the sham/0.5 mg group . On average , there was a marked reduction in CFT after the first as-needed injection of 0.5 mg ranibizumab in the sham/0.5 mg group to the level of the ranibizumab groups , which was sustained through month 12 . No new ocular or nonocular safety events were identified . CONCLUSIONS On average , treatment with ranibizumab as needed during months 6 through 11 maintained the visual and anatomic benefits achieved by 6 monthly ranibizumab injections in patients with macular edema after CRVO , with low rates of ocular and nonocular safety events . After sham injections for 6 months , treatment with ranibizumab as needed for 6 months result ed in rapid reduction in CFT in the sham/0.5 mg group to a level similar to that in the 2 ranibizumab treatment groups and an improvement in BCVA , but not to the same level as that in the 2 ranibizumab groups . Intraocular injections of ranibizumab provide an effective treatment for macular edema after CRVO . FINANCIAL DISCLOSURE(S ) Proprietary or commercial disclosure may be found after the references Purpose To evaluate long-term efficacy of intravitreal bevacizumab ( IVB ) versus combined IVB and macular grid laser photocoagulation for the treatment of macular edema secondary to branch retinal vein occlusion ( BRVO ) . Methods In this prospect i ve study , 18 eyes were r and omized into 2 groups according to treatment : Group 1 ( 9 eyes ) underwent IVB at baseline , at month 1 , and at month 2 ; Group 2 ( 9 eyes ) underwent same IVB protocol combined with macular grid laser photocoagulation . Macular edema and visual acuity represented the endpoints of the study . IVB reinjections were performed in both groups if recurrent macular edema was diagnosed . Spectral domain optical coherence tomography examination as well as visual acuity examination were performed during follow-up . Statistical evaluation was performed for a matched-pair analysis . Results In Group 1 , median baseline central retinal thickness ( CRT ) decreased from 420 μm ( 95 % confidence interval 355.6 - 484.4 ) to 323 μm ( 261.44 - 384.56 ) at month 12 ( p=0.06 ) ; median baseline BCVA improved from 0.7 logMAR ( 0.54 - 0.86 ) to 0.4 logMAR ( 0.29 - 0.51 ) at month 12 ( p<0.01 ) . In Group 2 , baseline CRT decreased from 386 μm ( 353.91 - 418.09 ) to 238 μm ( 200.58 - 275.42 ) at month 12 ( p<0.01 ) ; median BCVA improved from 0.6 logMAR ( 0.45 - 0.75 ) to 0.2 logMAR ( 0.12 - 0.28 ) at month 12 ( p<0.01 ) . A statistically significant difference ( p=0.03 ) was found regarding the median number of injections ( Group 1 : 4±1.1 ; Group 2 : 3±0.4 ) . Conclusions Both treatment modalities appeared effective to control BRVO-induced macular edema . In the combined-treatment Group , we observed a lower number of reinjections during follow-up , suggesting the efficacy of grid laser photocoagulation to reduce the number of intravitreal injections and maintain short- and long-term results of the therapy PURPOSE To evaluate the efficacy of intraocular injections with bevacizumab in patients with macular edema ( ME ) secondary to central retinal vein occlusion ( CRVO ) . DESIGN Prospect i ve , r and omized , sham injection-controlled , double-masked clinical trial . PARTICIPANTS Sixty patients with ME secondary to CRVO . METHODS At baseline , patients were r and omized 1:1 to receive intraocular injections of bevacizumab or sham injections every 6 weeks for 6 months . MAIN OUTCOME MEASURES The primary outcome measure was the proportion of patients gaining at least 15 letters at 6 months . Secondary outcome measures included mean change from baseline best-corrected visual acuity ( BCVA ) , foveal thickness , and neovascular glaucoma . RESULTS At the end of follow-up , 18 of 30 patients ( 60.0 % ) in the study group had gained ≥15 letters compared with 6 of 30 patients ( 20.0 % ) in the control group ( P=0.003 ) . The BCVA improved by 14.1 letters at 24 weeks compared with a decrease of 2.0 letters in the control group ( P < 0.003 ) . The mean decrease in central retinal thickness ( CRT ) was significantly greater in the study group ( 426 μm ) than in the control group ( 102 μm ) at all time points up to week 24 ( P < 0.001 ) . No residual edema , defined as CRT < 300 μm at 24 weeks , was found in 26 of 30 patients ( 86.7 % ) in the treatment group compared with 6 of 30 patients ( 20 % ) in the control group ( P < 0.001 ) . In the sham group , 5 of 30 patients ( 16.7 % ) had developed iris rubeosis at week 24 . No patients in the study group had rubeosis at week 24 ( P=0.052 ) . There were no events of endophthalmitis , retinal tear , or retinal detachment during the 24-week treatment period . No serious non-ocular adverse events were reported . CONCLUSIONS Intraocular injections of bevacizumab given every 6 weeks for 6 months improve visual acuity ( VA ) and reduce ME significantly compared with sham . FINANCIAL DISCLOSURE(S ) Proprietary or commercial disclosure may be found after the references Aim To evaluate intravitreal VEGF Trap-Eye ( VTE ) in patients with macular oedema secondary to central retinal vein occlusion ( CRVO ) . Methods In this double-masked study , 177 patients were r and omised ( 3:2 ratio ) to intravitreal injections of VTE 2 mg or sham procedure every 4 weeks for 24 weeks . Best-corrected visual acuity was evaluated using the Early Treatment Diabetic Retinopathy Study chart . Central retinal thickness ( CRT ) was measured with optical coherence tomography . Results From baseline until week 24 , more patients receiving VTE ( 60.2 % ) gained ≥15 letters compared with those receiving sham injections ( 22.1 % ) ( p<0.0001 ) . VTE patients gained a mean of 18.0 letters compared with 3.3 letters with sham injections ( p<0.0001 ) . Mean CRT decreased by 448.6 and 169.3 µm in the VTE and sham groups ( p<0.0001 ) . The most frequent ocular adverse events in the VTE arm were typically associated with the injection procedure or the underlying disease , and included eye pain ( 11.5 % ) , increased intraocular pressure ( 9.6 % ) and conjunctival haemorrhage ( 8.7 % ) . Conclusions VTE 2 mg every 4 weeks was efficacious in CRVO with an acceptable safety profile . Vision gains with VTE were significantly higher than with observation/panretinal photocoagulation if needed . Based on these data , VTE may provide a new treatment option for CRVO PURPOSE To assess long-term visual outcomes and adverse events from a fluocinolone acetonide ( FA ) sustained drug delivery implant in eyes with chronic macular edema from central retinal vein occlusion ( CRVO ) . DESIGN Prospect i ve interventional case series . PARTICIPANTS A total of 24 eyes of 23 subjects with vision loss associated with chronic macular edema from CRVO . INTERVENTION Implantation of an intravitreal FA sustained drug delivery system . MAIN OUTCOME MEASURES The primary outcome measure was mean Early Treatment of Diabetic Retinopathy Study ( ETDRS ) visual acuity letter score at 36 months after implantation . Secondary outcome measures included number of subjects with ≥ 10-letter improvement in ETDRS letter score , central foveal thickness ( CFT ) , total macular volume , and intraocular pressure ( IOP ) . RESULTS At 1 , 2 , and 3 years after implantation , mean visual acuity showed gains of 4.5 ( P = 0.52 ) , 8.2 ( P = 0.07 ) , and 3.4 ( P = 0.64 ) letters , respectively , and 32 % , 56 % , and 50 % of study eyes , respectively , showed at least a 10-letter gain in ETDRS score . At these same time points , mean CFT improved by 247 ( 44 % ; P = 0.002 ) , 212 ( 38 % ; P < 0.001 ) , and 250 μm ( 45 % ; P<0.001 ) , respectively . During the study period , all phakic eyes ultimately underwent cataract extraction , and 5 eyes underwent glaucoma surgery . CONCLUSIONS The FA drug delivery system provided sustained visual acuity and anatomic benefit in patients with macular edema from CRVO , and it has promise as a therapeutic option for selected patients with this condition . The main complications were cataract and elevated IOP . FINANCIAL DISCLOSURE(S ) The authors have no proprietary or commercial interest in any of the material s discussed in this article OBJECTIVE To evaluate the safety and efficacy of 1 or 2 treatments with dexamethasone intravitreal implant ( DEX implant ) over 12 months in eyes with macular edema owing to branch or central retinal vein occlusion ( BRVO or CRVO ) . DESIGN Two identical , multicenter , prospect i ve studies included a r and omized , 6-month , double-masked , sham-controlled phase followed by a 6-month open-label extension . PARTICIPANTS We included 1256 patients with vision loss owing to macular edema associated with BRVO or CRVO . METHODS At baseline , patients received DEX implant 0.7 mg ( n = 421 ) , DEX implant 0.35 mg ( n = 412 ) , or sham ( n = 423 ) in the study eye . At day 180 , patients could receive DEX implant 0.7 mg if best-corrected visual acuity ( BCVA ) was < 84 letters or retinal thickness was > 250 μm . MAIN OUTCOME MEASURES The primary outcome for the open-label extension was safety ; BCVA was also evaluated . RESULTS At day 180 , 997 patients received open-label DEX implant . Except for cataract , the incidence of ocular adverse events was similar in patients who received their first or second DEX implant . Over 12 months , cataract progression occurred in 90 of 302 phakic eyes ( 29.8 % ) that received 2 DEX implant 0.7 mg injections versus 5 of 88 sham-treated phakic eyes ( 5.7 % ) ; cataract surgery was performed in 4 of 302 ( 1.3 % ) and 1 of 88 ( 1.1 % ) eyes , respectively . In the group receiving two 0.7-mg DEX implants ( n = 341 ) , a ≥ 10-mmHg intraocular pressure ( IOP ) increase from baseline was observed in ( 12.6 % after the first treatment , and 15.4 % after the second ) . The IOP increases were usually transient and controlled with medication or observation ; an additional 10.3 % of patients initiated IOP-lowering medications after the second treatment . A ≥ 15-letter improvement in BCVA from baseline was achieved by 30 % and 32 % of patients 60 days after the first and second DEX implant , respectively . CONCLUSIONS Among patients with macular edema owing to BRVO or CRVO , single and repeated treatment with DEX implant had a favorable safety profile over 12 months . In patients who qualified for and received 2 DEX implant injections , the efficacy and safety of the 2 implants were similar with the exception of cataract progression . FINANCIAL DISCLOSURE(S ) Proprietary or commercial disclosure may be found after the references OBJECTIVE To evaluate the safety and efficacy of dexamethasone intravitreal implant ( DEX implant ; OZURDEX , Allergan , Inc. , Irvine , CA ) compared with sham in eyes with vision loss due to macular edema ( ME ) associated with branch retinal vein occlusion ( BRVO ) or central retinal vein occlusion ( CRVO ) . DESIGN Two identical , multicenter , masked , r and omized , 6-month , sham-controlled clinical trials ( each of which included patients with BRVO and patients with CRVO ) . PARTICIPANTS A total of 1267 patients with vision loss due to ME associated with BRVO or CRVO . INTERVENTION A single treatment with DEX implant 0.7 mg ( n = 427 ) , DEX implant 0.35 mg ( n = 414 ) , or sham ( n = 426 ) . MAIN OUTCOME MEASURES The primary outcome measure for the pooled data from the 2 studies was time to achieve a > or = 15-letter improvement in best-corrected visual acuity ( BCVA ) . Secondary end points included BCVA , central retinal thickness , and safety . RESULTS After a single administration , the time to achieve a > or = 15-letter improvement in BCVA was significantly less in both DEX implant groups compared with sham ( P<0.001 ) . The percentage of eyes with a > or = 15-letter improvement in BCVA was significantly higher in both DEX implant groups compared with sham at days 30 to 90 ( P<0.001 ) . The percentage of eyes with a > or = 15-letter loss in BCVA was significantly lower in the DEX implant 0.7-mg group compared with sham at all follow-up visits ( P < or = 0.036 ) . Improvement in mean BCVA was greater in both DEX implant groups compared with sham at all follow-up visits ( P < or = 0.006 ) . Improvements in BCVA with DEX implant were seen in patients with BRVO and patients with CRVO , although the patterns of response differed . The percentage of DEX implant-treated eyes with intraocular pressure ( IOP ) of > or = 25 mmHg peaked at 16 % at day 60 ( both doses ) and was not different from sham by day 180 . There was no significant between-group difference in the occurrence of cataract or cataract surgery . CONCLUSIONS Dexamethasone intravitreal implant can both reduce the risk of vision loss and improve the speed and incidence of visual improvement in eyes with ME secondary to BRVO or CRVO and may be a useful therapeutic option for eyes with these conditions PURPOSE To investigate in The St and ard Care versus COrticosteroid for REtinal Vein Occlusion ( SCORE ) Study : ( 1 ) incidences of neovascular events and retinal capillary nonperfusion ( abbreviated as " nonperfusion " ) , and their relationship with treatment groups ; ( 2 ) neovascular incidences by nonperfusion status ; and ( 3 ) pertinent baseline factors for their potential risk for neovascular events . DESIGN Two multicenter , r and omized clinical trials , 1 evaluating participants with central retinal vein occlusion ( CRVO ) and the other evaluating participants with branch retinal vein occlusion ( BRVO ) . PARTICIPANTS At 36 months , data were available for 81 participants with CRVO and 128 with BRVO . INTERVENTION St and ard care ( observation or grid photocoagulation ) versus 1 or 4 mg intravitreal triamcinolone . MAIN OUTCOME MEASURES Neovascularization of the iris ( NVI ) , neovascular glaucoma ( NVG ) , disc or retinal neovascularization ( NVD/NVE ) , preretinal or vitreous hemorrhage ( PRH/VH ) , and nonperfusion . RESULTS The cumulative 36-month incidences for CRVO and BRVO eyes , respectively , were 8.5 % and 2.4 % for NVI or NVG ; 8.8 % and 7.6 % for NVD/NVE or PRH/VH . There were no differences in incidences of neovascular events or risk of nonperfusion when comparing the 3 treatment groups within diseases . For CRVO at 36 months , 16.6 % of eyes with ≥5.5 disc areas of nonperfusion versus 4.0 % of eyes with < 5.5 disc areas of nonperfusion developed NVG ( P = 0.0003 ) ; for BRVO at 36 months , 14.6 % versus 2.4 % developed NVD/NVE ( P<0.0001 ) . Similar results were noted for most other neovascular events . Nonperfusion was the only significant baseline factor for neovascularization in BRVO , with the risk of a neovascular event increasing with greater disc areas of nonperfusion , and the highest risk noted at ≥5.5 disc areas . CONCLUSIONS In the SCORE Study , triamcinolone treatment was not associated with lower incidences of neovascular events or nonperfusion status compared with observation or grid photocoagulation . Cumulative 36-month incidences for most neovascular events were significantly higher for nonperfused than perfused eyes . Greater baseline disc areas of nonperfusion increased the risk of neovascularization in BRVO but not CRVO eyes , possibly owing to obscuration of retinal capillary details caused by dense hemorrhage at baseline for CRVO eyes . Increased risk of neovascularization was noted below the historical threshold of 10 disc areas of nonperfusion for retinal vein occlusion OBJECTIVE To describe the baseline characteristics of the participants in the St and ard Care versus COrticosteroid for REtinal Vein Occlusion ( SCORE ) Study and to compare with cohorts from other retinal vein occlusion trials . The design of the SCORE Study is also described . DESIGN Two , multicenter , Phase III , r and omized clinical trials , one involving participants with central retinal vein occlusion ( CRVO ) and one involving participants with branch retinal vein occlusion ( BRVO ) . PARTICIPANTS A total of 682 participants , including 271 with CRVO and 411 with BRVO . METHODS Demographic and study eye characteristics are summarized and compared between the CRVO and BRVO study participants . MAIN OUTCOME MEASURES Baseline ophthalmic characteristics , including visual acuity and duration of macular edema before enrollment , and medical history characteristics , including diabetes mellitus and hypertension . RESULTS In the CRVO trial , at baseline , mean visual acuity letter score was 51 ( approximately 20/100 ) , mean optical coherence tomography (OCT)-measured central subfield thickness was 595 microns , mean area of retinal thickening in the macular grid on color photography was 12.3 disc areas ( DA ) , and mean area of fluorescein leakage was 11.0 DA . In the BRVO trial , at baseline , mean visual acuity letter score was 57 ( approximately 20/80 ) , mean OCT-measured central subfield thickness was 491 microns , mean area of retinal thickening in the macular grid on color photography was 7.5 DA , and the mean area of fluorescein leakage was 6.1 DA . CONCLUSIONS Differences observed in baseline visual acuity , OCT-measured retinal thickness , area of retinal thickening on color photography , and area of fluorescein leakage support the evaluation of CRVO and BRVO in separate trials . FINANCIAL DISCLOSURE(S ) The authors have no proprietary or commercial interest in any of the material s discussed in this article PURPOSE To compare the efficacy and safety of ranibizumab and bevacizumab intravitreal injections to treat neovascular age-related macular degeneration ( nAMD ) . DESIGN Multicenter , noninferiority factorial trial with equal allocation to groups . The noninferiority limit was 3.5 letters . This trial is registered ( IS RCT N92166560 ) . PARTICIPANTS People > 50 years of age with untreated nAMD in the study eye who read ≥ 25 letters on the Early Treatment Diabetic Retinopathy Study chart . METHODS We r and omized participants to 4 groups : ranibizumab or bevacizumab , given either every month ( continuous ) or as needed ( discontinuous ) , with monthly review . MAIN OUTCOME MEASURES The primary outcome is at 2 years ; this paper reports a prespecified interim analysis at 1 year . The primary efficacy and safety outcome measures are distance visual acuity and arteriothrombotic events or heart failure . Other outcome measures are health-related quality of life , contrast sensitivity , near visual acuity , reading index , lesion morphology , serum vascular endothelial growth factor ( VEGF ) levels , and costs . RESULTS Between March 27 , 2008 and October 15 , 2010 , we r and omized and treated 610 participants . One year after r and omization , the comparison between bevacizumab and ranibizumab was inconclusive ( bevacizumab minus ranibizumab -1.99 letters , 95 % confidence interval [ CI ] , -4.04 to 0.06 ) . Discontinuous treatment was equivalent to continuous treatment ( discontinuous minus continuous -0.35 letters ; 95 % CI , -2.40 to 1.70 ) . Foveal total thickness did not differ by drug , but was 9 % less with continuous treatment ( geometric mean ratio [ GMR ] , 0.91 ; 95 % CI , 0.86 to 0.97 ; P = 0.005 ) . Fewer participants receiving bevacizumab had an arteriothrombotic event or heart failure ( odds ratio [ OR ] , 0.23 ; 95 % CI , 0.05 to 1.07 ; P = 0.03 ) . There was no difference between drugs in the proportion experiencing a serious systemic adverse event ( OR , 1.35 ; 95 % CI , 0.80 to 2.27 ; P = 0.25 ) . Serum VEGF was lower with bevacizumab ( GMR , 0.47 ; 95 % CI , 0.41 to 0.54 ; P<0.0001 ) and higher with discontinuous treatment ( GMR , 1.23 ; 95 % CI , 1.07 to 1.42 ; P = 0.004 ) . Continuous and discontinuous treatment costs were £ 9656 and £ 6398 per patient per year for ranibizumab and £ 1654 and £ 1509 for bevacizumab ; bevacizumab was less costly for both treatment regimens ( P<0.0001 ) . CONCLUSIONS The comparison of visual acuity at 1 year between bevacizumab and ranibizumab was inconclusive . Visual acuities with continuous and discontinuous treatment were equivalent . Other outcomes are consistent with the drugs and treatment regimens having similar efficacy and safety . FINANCIAL DISCLOSURE(S ) Proprietary or commercial disclosures may be found after the references PURPOSE To assess the efficacy and safety of intravitreous pegaptanib sodium ( Macugen ; EyeTech Pharmaceuticals/Pfizer Inc , New York , New York , USA ) for macular edema secondary to branch retinal vein occlusion ( BRVO ) . DESIGN Prospect i ve , r and omized , dose-finding study . METHODS Twenty subjects from three clinical practice s in the United States with BRVO of more than 1 month 's and fewer than 6 months ' duration ; best-corrected visual acuity ( BCVA ) 70 to 25 Early Treatment Diabetic Retinopathy Study letters inclusive ( approximately 20/40 to 20/320 Snellen ) ; and central foveal thickness of 250 microm or more were included . Subjects were r and omized 3:1 to intravitreous injections of pegaptanib 0.3 or 1 mg at baseline and at weeks 6 and 12 with subsequent injections at 6-week intervals at investigator discretion until week 48 . Principal efficacy outcomes were change from baseline to week 54 in BCVA , center point thickness , central subfield thickness , and macular volume as measured by optical coherence tomography . RESULTS Fifteen subjects received pegaptanib 0.3 mg and 5 received pegaptanib 1 mg . Eighteen subjects completed the 54-week follow-up . Results were similar in both the 0.3- and 1-mg groups . Overall improvements from baseline to week 54 occurred in mean BCVA ( + 14 + /- 13 letters ) , center point thickness ( -205 + /- 195 mum ) , central subfield thickness ( -201 + /- 153 mum ) , and macular volume ( -2.2 + /- 1.6 mm(3 ) ) . The response was rapid after the first injection , with a mean BCVA improvement of 11 + /- 7 letters at 1 week from the baseline of 56 + /- 12 letters ( approximately 20/80 Snellen ) . One retinal detachment and no cases of endophthalmitis or traumatic cataract were seen . CONCLUSIONS Intravitreous pegaptanib offers a promising alternative as a treatment for macular edema secondary to BRVO OBJECTIVE To evaluate the efficacy of a second year of pegaptanib sodium therapy in patients with neovascular age-related macular degeneration ( AMD ) . DESIGN Two concurrent , multicenter , r and omized , double-masked , sham-controlled studies ( V.I.S.I.O.N. [ Vascular Endothelial Growth Factor Inhibition Study in Ocular Neovascularization ] trials ) . PARTICIPANTS Patients with all angiographic neovascular lesion compositions of AMD were enrolled . In combined analyses , 88 % ( 1053/1190 ) were re-r and omized at week 54 , and 89 % ( 941/1053 ) were assessed at week 102 . INTERVENTIONS At week 54 , those initially assigned to pegaptanib were re-r and omized ( 1:1 ) to continue or discontinue therapy for 48 more weeks ( 8 injections ) . Those initially assigned to sham were re-r and omized to continue sham , discontinue sham , or receive 1 of 3 pegaptanib doses . MAIN OUTCOME MEASURES Mean change in visual acuity ( VA ) over time and mean change in the st and ardized area under the curve of VA and proportions of patients experiencing a loss of > or = 15 letters from week 54 to week 102 ; losing < 15 letters ( responders ) from baseline to week 102 ; gaining > or = 0 , > or = 1 , > or = 2 , and > or =3 lines of VA ; and progressing to legal blindness ( 20/200 or worse ) . RESULTS In combined analysis , mean VA was maintained in patients continuing with 0.3-mg pegaptanib compared with those discontinuing therapy or receiving usual care . In patients who continued pegaptanib , the proportion who lost > 15 letters from baseline in the period from week 54 to week 102 was half ( 7 % ) that of patients who discontinued pegaptanib or remained on usual care ( 14 % for each ) . Kaplan-Meier analysis showed that patients continuing 0.3-mg pegaptanib for a second year were less likely to lose > or = 15 letters than those re-r and omized to discontinue after 1 year ( P<0.05 ) . The proportion of patients gaining vision was higher for those assigned to 2 years of 0.3-mg pegaptanib than receiving usual care . Progression to legal blindness was reduced for patients continuing 0.3-mg pegaptanib for 2 years . CONCLUSIONS Continuing visual benefit was observed in patients who were r and omized to receive therapy with pegaptanib in year 2 of the V.I.S.I.O.N. trials when compared with 2 years ' usual care or cessation of therapy at year 1 OBJECTIVES To assess the safety and efficacy of intravitreous pegaptanib sodium for the treatment of macular edema following central retinal vein occlusion ( CRVO ) . DESIGN This dose-ranging , double-masked , multicenter , phase 2 trial included subjects with CRVO for 6 months ' or less duration r and omly assigned ( 1:1:1 ) to receive pegaptanib sodium or sham injections every 6 weeks for 24 weeks ( 0.3 mg and 1 mg , n=33 ; sham , n=32 ) . MAIN OUTCOME MEASURE Visual acuity at week 30 . RESULTS In the primary analysis at week 30 , 12 of 33 ( 36 % ) subjects treated with 0.3 mg of pegaptanib sodium and 13 of 33 ( 39 % ) treated with 1 mg gained 15 or more letters from baseline vs 9 of 32 ( 28 % ) sham-treated subjects ( P= .48 for 0.3 mg and P= .35 for 1 mg of pegaptanib sodium vs sham ) . In secondary analyses , subjects treated with pegaptanib sodium were less likely to lose 15 or more letters ( 9 % and 6 % ; 0.3-mg and 1-mg pegaptanib sodium groups , respectively ) compared with sham-treated eyes ( 31 % ; P= .03 for 0.3 mg and P= .01 for 1 mg of pegaptanib sodium vs sham ) and showed greater improvement in mean visual acuity ( + 7.1 and + 9.9 , respectively , vs -3.2 letters with sham ; P= .09 for 0.3 mg and P= .02 for 1 mg of pegaptanib sodium vs sham ) . By week 1 , the mean central retinal thickness decreased in the 0.3-mg and 1-mg pegaptanib sodium groups by 269 microm and 210 microm , respectively , vs 5 microm with sham ( P < .001 ) . CONCLUSIONS Based on this 30-week study , intravitreous pegaptanib sodium appears to provide visual and anatomical benefits in the treatment of macular edema following CRVO . APPLICATION TO CLINICAL PRACTICE Benefits accrued with intravitreous pegaptanib sodium treatment of macular edema following CRVO suggest a role for vascular endothelial growth factor in the pathogenesis of this condition . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00088283 OBJECTIVE To assess the efficacy and safety of intravitreal vascular endothelial growth factor ( VEGF ) Trap-Eye in eyes with macular edema secondary to central retinal vein occlusion ( CRVO ) . DESIGN Multicenter , r and omized , prospect i ve , controlled trial . PARTICIPANTS One hundred eighty-nine eyes with macular edema secondary to CRVO . METHODS Eyes were r and omized 3:2 to receive VEGF Trap-Eye 2 mg or sham injection monthly for 6 months . MAIN OUTCOME MEASURES The proportion of eyes with a ≥15-letter gain or more in best-corrected visual acuity ( BCVA ) at week 24 ( primary efficacy end point ) , mean changes in BCVA and central retinal thickness ( CRT ) , and proportion of eyes progressing to neovascularization of the anterior segment , optic disc , or elsewhere in the retina . RESULTS At week 24 , 56.1 % of VEGF Trap-Eye treated eyes gained 15 letters or more from baseline versus 12.3 % of sham-treated eyes ( P<0.001 ) . The VEGF Trap-Eye treated eyes gained a mean of 17.3 letters versus sham-treated eyes , which lost 4.0 letters ( P<0.001 ) . Central retinal thickness decreased by 457.2 μm in eyes treated with VEGF Trap-Eye versus 144.8 μm in sham-treated eyes ( P<0.001 ) , and progression to any neovascularization occurred in 0 and 5 ( 6.8 % ) of eyes treated with VEGF Trap-Eye and sham-treated eyes , respectively ( P = 0.006 ) . Conjunctival hemorrhage , reduced visual acuity , and eye pain were the most common adverse events ( AEs ) . Serious ocular AEs were reported by 3.5 % of VEGF Trap-Eye patients and 13.5 % of sham patients . Incidences of nonocular serious AEs generally were well balanced between both groups . CONCLUSIONS At 24 weeks , monthly intravitreal injection of VEGF Trap-Eye 2 mg in eyes with macular edema result ing from CRVO improved visual acuity and CRT , eliminated progression result ing from neovascularization , and was associated with a low rate of ocular AEs related to treatment OBJECTIVE To compare the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with observation for eyes with vision loss associated with macular edema secondary to perfused central retinal vein occlusion ( CRVO ) . METHODS Multicenter , r and omized , clinical trial of 271 participants . MAIN OUTCOME MEASURE Gain in visual acuity letter score of 15 or more from baseline to month 12 . RESULTS Seven percent , 27 % , and 26 % of participants achieved the primary outcome in the observation , 1-mg , and 4-mg groups , respectively . The odds of achieving the primary outcome were 5.0 times greater in the 1-mg group than the observation group ( odds ratio [ OR ] , 5.0 ; 95 % confidence interval [ CI ] , 1.8 - 14.1 ; P = .001 ) and 5.0 times greater in 4-mg group than the observation group ( OR , 5.0 ; 95 % CI , 1.8 - 14.4 ; P = .001 ) ; there was no difference identified between the 1-mg and 4-mg groups ( OR , 1.0 ; 95 % CI , 0.5 - 2.1 ; P = .97 ) . The rates of elevated intraocular pressure and cataract were similar for the observation and 1-mg groups , but higher in the 4-mg group . CONCLUSIONS Intravitreal triamcinolone is superior to observation for treating vision loss associated with macular edema secondary to CRVO in patients who have characteristics similar to those in the SCORE-CRVO trial . The 1-mg dose has a safety profile superior to that of the 4-mg dose . Application to Clinical Practice Intravitreal triamcinolone in a 1-mg dose , following the retreatment criteria applied in the SCORE Study , should be considered for up to 1 year , and possibly 2 years , for patients with characteristics similar to those in the SCORE-CRVO trial . Trial Registration clinical trials.gov Identifier : NCT00105027 PURPOSE To evaluate the efficacy of intraocular injections with bevacizumab over 12 months in patients with macular edema ( ME ) secondary to central retinal vein occlusion ( CRVO ) . DESIGN A prospect i ve study including a r and omized 6-month , sham injection-controlled , double-masked clinical trial followed by a 6-month open-label extension . PARTICIPANTS Sixty patients with ME secondary to CRVO . METHODS At baseline , patients were r and omized 1:1 to receive intraocular injections of bevacizumab or sham injections every 6 weeks for 6 months . From month 6 , all patients received intraocular injections of bevacizumab every 6 weeks for 6 months . MAIN OUTCOME MEASURES The primary outcome measure was the proportion of patients gaining at least 15 letters at 12 months . Secondary outcome measures included mean change from baseline best-corrected visual acuity ( BCVA ) , change in foveal thickness , and development of neovascular glaucoma . RESULTS At the end of follow-up , 18 of 30 patients ( 60.0 % ) in the bevacizumab/bevacizumab ( bz/bz ) group had gained ≥ 15 letters compared with 10 of 30 patients ( 33.3 % ) in the sham/bevacizumab ( sh/bz ) group ( P < 0.05 ) . The BCVA improved by 16.0 letters at 12 months in the bz/bz group compared with 4.6 letters in the sh/bz group ( P < 0.05 ) . In an unplanned retrospective analysis , patients aged > 70 years had a significantly worse outcome when receiving delayed treatment , losing 1.4 letters ( 95 % confidence interval [ CI ] , -9.7 to 8.4 ) in the sh/bz group compared with a gain of 20.1 letters ( 95 % CI , 13.9 - 26.3 ) in the bz/bz group in patients aged < 70 years ( P < 0.003 ) . The mean decrease in central retinal thickness ( CRT ) was 435 μm in the bz/bz group compared with 404 μm in the sh/bz group ( P = not significant ) . No patients developed iris rubeosis during the 6-month open-label extension period . There were no events of endophthalmitis , retinal tear , or retinal detachment during the 12-month treatment period . No serious nonocular adverse events were reported . CONCLUSIONS Intraocular injections of bevacizumab given every 6 weeks for 12 months improve visual acuity ( VA ) and reduce ME significantly . Patients receiving delayed treatment have a limited visual improvement . FINANCIAL DISCLOSURE(S ) Proprietary or commercial disclosure may be found after the references |
13,717 | 28,439,739 | Quantitative differences in mistrust and CRC screening by gender were mixed , but qualitative studies highlighted fear of experimentation and intrusiveness of screening methods as unique themes among African American men . | Despite well-documented benefits of colorectal cancer ( CRC ) screening , African Americans are less likely to be screened and have higher CRC incidence and mortality than Whites .
Emerging evidence suggests medical mistrust may influence CRC screening disparities among African Americans .
The goal of this systematic review was to summarize evidence investigating associations between medical mistrust and CRC screening among African Americans , and variations in these associations by gender , CRC screening type , and level of mistrust . | We determined the barriers to and facilitators of colorectal cancer ( CRC ) screening among two faith-based , inner city neighborhood health centers in Southwestern Pennsylvania . Data from a r and om sample of patients 50 years and older ( n=375 ) were used to estimate logistic regression equations to compare and contrast the predictors of four different CRC screening protocol s : ( 1 ) fecal occult blood test ( FOBT ) ≤ 2 years ago , ( 2 ) colonoscopy ≤ 10 years ago , ( 3 ) lower endoscopy ( colonoscopy or sigmoidoscopy ) ≤ 10 years ago , and ( 4 ) any of these screening measures . Racial differences ( between African Americans or Caucasians ) in type of colon cancer screening were not found . Controlling for covariates , logistic regression equations showed that a physician ’s support of colon cancer screening was positively associated with the receipt of colonoscopy ( OR : 19.47 , 95 CI : 5.45–69.54 ) , lower endoscopy ( OR : 10.96 , 95 CI : 3.77–31.88 ) and any colon cancer screening ( OR : 10.12 , 95 CI : 3.36–30.46 ) . Patients who see their physicians more frequently were also more likely to be screened for CRC . Unlike other studies , the faith-based environment in which these patients are treated may explain the lack of racial disparity specific to our measures of CRC screening Little is known about how minority groups react to public information that highlights racial disparities in cancer . This double-blind r and omized study compared emotional and behavioral reactions to four versions of the same colon cancer ( CRC ) information presented in mock news articles to a community sample of African-American adults ( n = 300 ) . Participants read one of four articles that varied in their framing and interpretation of race-specific CRC mortality data , emphasizing impact ( CRC is an important problem for African-Americans ) , two dimensions of disparity ( Blacks are doing worse than Whites and Blacks are improving , but less than Whites ) , or progress ( Blacks are improving over time ) . Participants exposed to disparity articles reported more negative emotional reactions to the information and were less likely to want to be screened for CRC than those in other groups ( both P < 0.001 ) . In contrast , progress articles elicited more positive emotional reactions and participants were more likely to want to be screened . Moreover , negative emotional reaction seemed to mediate the influence of message type on individuals wanting to be screened for CRC . Overall , these results suggest that the way in which disparity research is reported in the medium can influence public attitudes and intentions , with reports about progress yielding a more positive effect on intention . This seems especially important among those with high levels of medical mistrust who are least likely to use the health care system and are thus the primary target of health promotion advertising . ( Cancer Epidemiol Biomarkers Prev 2008;17(11):2946–53 Low-income minorities often face system-based and personal barriers to screening colonoscopy ( SC ) . Culturally targeted patient navigation ( CTPN ) programs employing professional navigators ( Pro-PNs ) or community-based peer navigators ( Peer-PNs ) can help overcome barriers but are not widely implemented . In East Harlem , NY , USA , where approximately half the residents participate in SC , 315 African American patients referred for SC at a primary care clinic with a Direct Endoscopic Referral System were recruited between May 2008 and May 2010 . After medical clearance , 240 were r and omized to receive CTPN delivered by a Pro-PN ( n = 106 ) or Peer-PN ( n = 134 ) . Successful navigation was measured by SC adherence rate , patient satisfaction and navigator trust . Study enrollment was 91.4 % with no significant differences in SC adherence rates between Pro-PN ( 80.0 % ) and Peer-PN ( 71.3 % ) ( P = 0.178 ) . Participants in both groups reported high levels of satisfaction and trust . These findings suggest that CTPN Pro-PN and Peer-PN programs are effective in this urban primary care setting . We detail how we recruited and trained navigators , how CTPN was implemented and provide a preliminary answer to our questions of the study aims : can peer navigators be as effective as professionals and what is the potential impact of patient navigation on screening adherence Purpose . Identify the influence of medical mistrust , fears , attitudes , and sociodemographic characteristics on unwillingness to participate in colorectal cancer ( CRC ) screening . Design . Cross-sectional , disproportionally allocated , stratified , r and om-digit-dial telephone question naire of noninstitutionalized households . Setting . New York City , New York ; Baltimore , Maryl and ; San Juan , Puerto Rico . Subjects . Ethnically diverse sample of 454 adults ≥50 years of age . Measures . Health status , cancer screening effectiveness , psychosocial factors ( e.g. , perceptions of pain , fear , trust ) , and CRC screening intentions using the Cancer Screening Question naire , which addresses a range of issues related to willingness of minorities to participate in cancer screening . Analysis . Multivariate logistic regression was used to model the probability of reporting unwillingness to participate in CRC screening . Results . Fear of embarrassment during screening ( odds ratio [ OR ] = 10.72 ; 95 % confidence interval [ CI ] , 2.15–53.39 ) , fear of getting AIDS ( OR = 8.75 ; 95 % CI , 2.48–30.86 ) , fear that exam might be painful ( OR = 3.43 ; 95 % CI , 1.03–11.35 ) , and older age ( OR = 1.10 ; 95 % CI , 1.04–1.17 ) were positively associated with unwillingness to participate in CRC screening . Fear of developing cancer ( OR = .12 ; 95 % CI , .03–.57 ) and medical mistrust ( OR = .19 ; 95 % CI , .06–.60 ) were negatively associated with unwillingness to screen . Conclusions . Findings suggest that CRC health initiatives should focus on increasing knowledge , addressing fears and mistrust , and normalizing CRC screening as a beneficial preventive practice , and should increase focus on older adults BACKGROUND Fecal occult blood testing ( FOBT ) can reduce colorectal cancer ( CRC ) mortality . Unfortunately , CRC screening is underutilized . Sociocultural mediators of FOBT adherence have not been extensively studied in lower income , minority population s. This study prospect ively studied FOBT return in a low-income , multiethnic population . METHODS Participants ( N = 298 ) , aged > or = 40 years , were surveyed and given FOBT kits with instructions . Those not returning kits within 30 days received a reminder telephone call . Bivariate and multivariate analyses assessed predictors of FOBT card return at 90 days . RESULTS Participants ( median age = 48 ) were predominately African American ( 69 % ) , without private insurance ( 88 % ) , and of low income . The largest group of participants preferred FOBT alone ( 46 % ) , followed by whatever my doctor recommends ( 19 % ) , endoscopy + annual FOBT ( 16 % ) , endoscopy alone ( 14 % ) , and no screening ( 5 % ) . In multivariate analyses , FOBT return was predicted by age ( OR = 1.05 ) and lack of reported FOBT barriers ( OR = 3.81 ) . Among those > or = 50 and not up-to- date with screening , FOBT return was predicted by cancer fatalism ( OR = 0.83 ) . FOBT barriers were associated with age ( OR = 0.96 ) , less than high school education ( OR = 2.05 ) , and less physician trust ( OR = 2.12 ) . Endoscopy barriers were associated with age ( OR = 0.93 ) , less physician trust ( OR = 1.95 ) , and female gender ( OR = 3.45 ) . CONCLUSIONS Younger individuals and those with less education , less trust in health care providers , and more fatalistic beliefs are at risk for CRC screening non-adherence . Strategies addressing common misconceptions should improve CRC screening rates in low-income , multiethnic population OBJECTIVE This study examined the effects ( affective reactions , cognitive reactions and processing , perceived benefits and barriers and intent to screen ) of targeted peripheral+evidential ( PE ) and peripheral+evidential+socio-cultural ( PE+SC ) colorectal cancer communications . METHODS This study was a two-arm r and omized control study of cancer communication effects on affective , cognitive processing , and behavioral outcomes over a 22-week intervention . There were 771 African American participants , 45 - 75 years , participating in the baseline survey related to CRC screening . Three follow-up interviews that assessed intervention effects on affective response to the publications , cognitive processing , and intent to obtain CRC screening were completed . RESULTS There were no statistically significant differences between PE and PE+SC intervention groups for affect , cognitive processing or intent to screen . However , there were significant interactions effects on outcome variables . CONCLUSIONS The advantages and disadvantages of PE+SC targeted cancer communications and implication s of sex differences are considered . PRACTICE IMPLICATION S While there do not appear to be significant differences in behavioral outcomes when using PE and PE+SC strategies , there appear to be subtle differences in affective and cognitive processing outcomes related to medical suspicion and ethnic identity , particularly as it relates to gender PURPOSE We report the validation of an instrument to measure mistrust of health care organizations and examine the relationship between mistrust and health care service underutilization . METHODS We conducted a telephone survey of a r and om sample of households in Baltimore City , MD . We surveyed 401 persons and followed up with 327 persons ( 81.5 percent ) 3 weeks after the baseline interview . We conducted tests of the validity and reliability of the Medical Mistrust Index ( MMI ) and then conducted multivariate modeling to examine the relationship between mistrust and five measures of underutilization of health services . RESULTS Using principle components analysis , we reduced the 17-item MMI to 7 items with a single dimension . Test-retest reliability was moderately strong , ranging from Pearson correlation of 0.346 - 0.697 . In multivariate modeling , the MMI was predictive of four of five measures of underutilization of health services : failure to take medical advice ( b=1.56 , p<.01 ) , failure to keep a follow-up appointment ( b=1.11 , p=.01 ) , postponing receiving needed care ( b=0.939 , p=.01 ) , and failure to fill a prescription ( b=1.48 , p=.002 ) . MMI was not significantly associated with failure to get needed medical care ( b=0.815 , p=.06 ) . CONCLUSIONS The MMI is a robust predictor of underutilization of health services . Greater attention should be devoted to building greater trust among patients BACKGROUND Colorectal cancer ( CRC ) screening is effective but underutilized . Although physician recommendation is an important predictor of screening , considerable variation in CRC screening completion remains . PURPOSE To characterize the influence of patient trust in care providers on CRC screening behavior . METHODS Data were collected as part of a cluster-r and omized CRC screening intervention trial performed in the San Francisco Community Health Network from March 2007 to January 2012 ( analysis , Spring 2012 ) . All study participants received a recommendation to complete CRC screening from their primary care provider ( PCP ) . Included participants were aged 50 - 79 years , not current with screening , and completed the Wake Forest Trust Scale ( WFTS ) measuring trust in PCPs and doctors in general . Primary outcome was CRC screening completion ( colonoscopy or fecal occult blood testing ) within 12 months following enrollment . Multivariable association adjusted for race/ethnicity , language , and other sociodemographics was estimated using generalized estimating equations with logit link and binomial distribution . RESULTS WFTS response was 70.3 % ( 701 ) . Most participants ( 83 % ) were Latino , Asian , or black . Most had income < $ 30,000 ( 96 % ) and public health insurance ( 86 % ) . Higher trust in PCP was associated with screening completion ( OR=1.11 , 95 % CI=1.03 , 1.17 ) , but trust in doctors was not ( OR=1.02 , 95 % CI=0.82 , 1.28 ) . Race , language , and other sociodemographic factors were not significant in multivariable analysis . CONCLUSIONS After controlling for traditional factors , trust in PCP remained the only significant driver of CRC screening completion in low-income patients . Interventions to promote CRC screening may be improved by including efforts to enhance patient trust in PCP |
13,718 | 22,824,564 | The most effective recruitment in primary care research requires practitioner involvement .
The active participation of primary care practitioners in both the design and conduct of research helps to identify strategies that are congruent with the context in which patient care is delivered .
This is reported to be the optimal recruitment strategy | BACKGROUND Patient recruitment in primary care research is often a protracted and frustrating process , affecting project timeframes , budget and the dissemination of research findings .
Yet , clear guidance on patient recruitment strategies in primary care research is limited .
This paper addresses this issue through a systematic review . | Background The success of a human intervention trial depends upon the ability to recruit eligible volunteers . Many trials fail because of unrealistic recruitment targets and flawed recruitment strategies . In order to predict recruitment rates accurately , research ers need information on the relative success of various recruitment strategies . Few published trials include such information and the number of participants screened or approached is not always cited . Methods This paper will describe in detail the recruitment strategies employed to identify older adults for recruitment to a 6-month r and omised controlled dietary intervention trial which aim ed to explore the relationship between diet and immune function ( The FIT study ) . The number of people approached and recruited , and the reasons for exclusion , will be discussed . Results Two hundred and seventeen participants were recruited to the trial . A total of 7,482 letters were sent to potential recruits using names and addresses that had been supplied by local Family ( General ) Practice s. Eight hundred and forty three potential recruits replied to all methods of recruitment ( 528 from GP letters and 315 from other methods ) . The eligibility of those who replied was determined using a screening telephone interview , 217 of whom were found to be suitable and agreed to take part in the study . Conclusion The study demonstrates the application of multiple recruitment methods to successfully recruit older people to a r and omised controlled trial . The most successful recruitment method was by contacting potential recruits by letter on NHS headed note paper using contacts provided from General Practice s. Ninety percent of recruitment was achieved using this method . Adequate recruitment is fundamental to the success of a research project , and appropriate strategies must therefore be adopted in order to identify eligible individuals and achieve recruitment targets . Trial registration numberIS RCT N45031464 Reports of cluster r and omised trials require additional information to allow readers to interpret them accurately The effective reporting of r and omised controlled trials has received useful attention in recent years . Many journals now require that reports conform to the guidelines in the Consoli date d St and ards of Reporting Trials ( CONSORT ) statement , first published in 1996 and revised in 2001 . The statement includes a checklist of items that should be included in the trial report . These items are evidence based whenever possible and are regularly review ed . The statement also recommends including a flow diagram to show the flow of participants from group assignment through to the final analysis . The CONSORT statement focused on reporting parallel group r and omised trials in which individual participants are r and omly assigned to study groups . However , in some situations it is preferable to r and omly assign groups of individuals ( such as families or medical practice s ) rather than individuals . Reasons include the threat of contamination of some interventions ( such as dietary interventions ) if individual r and omisation is used . 5 Also , in certain setting s r and omisation by group may be the only feasible method of conducting a trial . Trials with this design are variously known as field trials , community based trials , place based trials , or ( as in this paper ) cluster r and omised trials . In an earlier discussion paper we considered the implication s of the CONSORT statement for the reporting of cluster r and omised trials . Here we present up date d guidance , based on the 2001 revision of the CONSORT statement Background It is notoriously difficult to recruit patients to r and omised controlled trials in primary care . This is particularly true when the disease process under investigation occurs relatively infrequently and must be investigated during a brief time window . Bell 's palsy , an acute unilateral paralysis of the facial nerve is just such a relatively rare condition . In this case study we describe the organisational issues presented in setting up a large r and omised controlled trial of the management of Bell 's palsy across primary and secondary care in Scotl and and how we managed to successfully recruit and retain patients presenting in the community . Methods Where possible we used existing evidence on recruitment strategies to maximise recruitment and retention . We consider that the key issues in the success of this study were ; the fact that the research was seen as clinical ly important by the clinicians who had initial responsibility for recruitment ; employing an experienced trial co-ordinator and dedicated research ers willing to recruit participants seven days per week and to visit them at home at a time convenient to them , hence reducing missed patients and ensuring they were retained in the study ; national visibility and repeated publicity at a local level delivered by locally based principal investigators well known to their primary care community ; encouraging recruitment by payment to practice s and reducing the workload of the referring doctors by providing immediate access to specialist care ; good collaboration between primary and secondary care and basing local investigators in the otolarnygology trial centres Results Although the recruitment rate did not meet our initial expectations , enhanced retention meant that we exceeded our planned target of recruiting 550 patients within the planned time-scale . Conclusion While difficult , recruitment to and retention within multi-centre trials from primary care can be successfully achieved through the application of the best available evidence , establishing good relationships with practice s , minimising the workload of those involved in recruitment and offering enhanced care to all participants . Primary care trialists should describe their experiences of the methods used to persuade patients to participate in their trials when publishing their results Background Recruitment of patients by health professionals is reported as one of the most challenging steps when undertaking studies in primary care setting s. Numerous investigations of the barriers to patient recruitment in trials which recruit patients to receive an intervention have been published . However , we are not aware of any studies that have reported on the recruitment barriers as perceived by health professionals to recruiting patients into cluster r and omised trials where patients do not directly receive an intervention . This particular subtype of cluster trial is commonly termed a professional-cluster trial . The aim of this study was to investigate factors that contributed to general practitioners recruitment of patients in a professional-cluster trial which evaluated the effectiveness of an intervention to increase general practitioners adherence to a clinical practice guideline for acute low-back pain . Method General practitioners enrolled in the study were posted a question naire , consisting of quantitative items and an open-ended question , to assess possible reasons for poor patient recruitment . Descriptive statistics were used to summarise quantitative items and responses to the open-ended question were coded into categories . Results Seventy-nine general practitioners completed at least one item ( 79/94 = 84 % ) , representing 68 practice s ( 85 % practice response rate ) , and 44 provided a response to the open-ended question . General practitioners recalled inviting a median of two patients with acute low-back pain to participate in the trial over a seven-month period ; they reported that they intended to recruit patients , but forgot to approach patients to participate ; and they did not perceive that patients had a strong interest or disinterest in participating . Additional open-ended comments were generally consistent with the quantitative data . Conclusion A number of barriers to the recruitment of patients with acute low-back pain by general practitioners in a professional-cluster trial were identified . These barriers were similar to those that have been identified in the literature surrounding the recruitment of patients in individual patient r and omised trials . To advance the evidence base for patient recruitment strategies in primary care setting s , trialists undertaking professional-cluster trials need to develop and evaluate patient recruitment strategies that minimise the efforts required by practice staff to recruit patients , while also meeting privacy and ethical responsibilities and minimising the risk of selection bias . Trial registration Australian New Zeal and Clinical Trials Registry ACTRN012606000098538 ( date registered 14/03/2006 ) BACKGROUND Specialist National Health Service clinics for smoking cessation have increased in number , but most smokers prefer less intensive self-help and many smokers have no serious intentions to attempt to quit . Computer-tailored self-help material s can be adapted to provide advice to less motivated smokers , and can also take into account features such as level of education and socio-economic circumstance . OBJECTIVE To assess the feasibility of delivering tailored feedback to a large population by identifying smokers from general practice records , with the aim of informing a large-scale trial of effectiveness . METHOD Question naires were sent to a r and om sample of smokers ( n = 876 ) aged between 18 and 65 years , identified from records in four practice s. Smokers returning the question naire ( n = 78 ) were r and omized to receive st and ard information , or to receive st and ard information plus computer-tailored feedback reports . Follow-up question naires were sent 3 months after the return of the baseline question naire . RESULTS The recruitment strategy yielded a response rate of 8.9 % , and a 66.7 % follow-up rate . There were no significant differences in outcome between the two conditions , and no significant differences in outcome between practice s. In the Intervention group significantly more of those who remembered receiving the tailored advice letter had made a quit attempt ( 6[60%]/3[21.4 % ] , P < 0.05 ) . CONCLUSION This pilot study demonstrated the feasibility of carrying out such a trial to evaluate the effectiveness of delivering an intervention for smoking cessation in primary care , and highlighted issues that should be addressed in considering the design of a large-scale trial Background Financial incentives have been used for many years internationally to improve quality of care in general practice . The aim of this pilot study was to determine if offering general practitioners ( GP ) a small incentive payment per test would increase chlamydia testing in women aged 16 to 24 years , attending general practice . Methods General practice clinics ( n = 12 ) across Victoria , Australia , were cluster r and omized to receive either a $ AUD5 payment per chlamydia test or no payment for testing 16 to 24 year old women for chlamydia . Data were collected on the number of chlamydia tests and patient consultations undertaken by each GP over two time periods : 12 month pre-trial and 6 month trial period . The impact of the intervention was assessed using a mixed effects logistic regression model , accommodating for clustering at GP level . Results Testing increased from 6.2 % ( 95 % CI : 4.2 , 8.4 ) to 8.8 % ( 95 % CI : 4.8 , 13.0 ) ( p = 0.1 ) in the control group and from 11.5 % ( 95 % CI : 4.6 , 18.5 ) to 13.4 % ( 95 % CI : 9.5 , 17.5 ) ( p = 0.4 ) in the intervention group . Overall , the intervention did not result in a significant increase in chlamydia testing in general practice . The odds ratio for an increase in testing in the intervention group compared to the control group was 0.9 ( 95 % CI : 0.6 , 1.2 ) . Major barriers to increased chlamydia testing reported by GPs included a lack of time , difficulty in remembering to offer testing and a lack of patient awareness around testing . Conclusions A small financial incentive alone did not increase chlamydia testing among young women attending general practice . It is possible small incentive payments in conjunction with reminder and feedback systems may be effective , as may higher financial incentive payments . Further research is required to determine if financial incentives can increase testing in Australian general practice , the type and level of financial scheme required and whether incentives needs to be part of a multi-faceted package . Trial Registration Australian New Zeal and Clinical Trial Registry ACTRN12608000499381 BACKGROUND Recruiting adequate numbers of participants represents a major problem to the completion of r and omised clinical trials in primary care . Information on different recruitment strategies applied in one trial is scarce . AIM To evaluate the application of two recruitment strategies in one trial . DESIGN OF STUDY The study was performed within the framework of a r and omised clinical trial on the effectiveness of a behavioural treatment for patients with chronic shoulder complaints . SETTING Thirty-two general practice s in the Netherl and s. METHOD Patients recruited during a consultation with their GP for chronic shoulder complaints were compared with patients recruited by advertisement in a local newspaper as regards baseline characteristics , withdrawals ( drop-outs and losses to follow-up ) and post-treatment clinical outcomes . RESULTS Patients recruited by the GPs ( n = 83 ) were similar to those recruited by advertisement ( n = 83 ) in terms of demographic characteristics and clinical outcome measures at baseline , but differed slightly in disease characteristics and treatment preferences . Recruitment strategy was not related to reasons for or numbers of withdrawals . Improvements on outcome measures were greater in patients recruited by the GPs , irrespective of allocated treatment . Results on the clinical effectiveness of treatments at the end of the treatment period or during follow-up were neither modified by recruitment strategy , nor by differences between the two strategy groups in patient characteristics found at baseline . CONCLUSION Using two recruitment strategies did not influence the outcomes on clinical effectiveness in this trial . However , recruitment strategy should be considered as a putative modifying factor in the design of a study Recruitment methods heavily impact budget and outcomes in clinical trials . We conducted a post-hoc examination of the efficiency and cost of three different recruitment methods used in Journey for Control of Diabetes : the IDEA Study , a r and omized controlled trial evaluating outcomes of group and individual diabetes education in New Mexico and Minnesota . Electronic data bases were used to identify health plan members with diabetes and then one of the following three methods was used to recruit study participants : 1 . Minnesota Method 1 - -Mail only ( first half of recruitment period ) . Mailed invitations with return-response forms . 2 . Minnesota Method 2 - -Mail and selective phone calls ( second half of recruitment period ) . Mailed invitations with return-response forms and subsequent phone calls to nonresponders . 3 . New Mexico Method 3 - -Mail and non-selective phone calls ( full recruitment period ) : Mailed invitations with subsequent phone calls to all . The combined methods succeeded in meeting the recruitment goal of 623 subjects . There were 147 subjects recruited using Minnesota 's Method 1 , 190 using Minnesota 's Method 2 , and 286 using New Mexico 's Method 3 . Efficiency rates ( percentage of invited patients who enrolled ) were 4.2 % for Method 1 , 8.4 % for Method 2 , and 7.9 % for Method 3 . Calculated costs per enrolled subject were $ 71.58 ( Method 1 ) , $ 85.47 ( Method 2 ) , and $ 92.09 ( Method 3 ) . A mail-only method to assess study interest was relatively inexpensive but not efficient enough to sustain recruitment targets . Phone call follow-up after mailed invitations added to recruitment efficiency . Use of return-response forms with selective phone follow-up to non-responders was cost effective Background Guidelines recommend multifactorial intervention programmes to prevent falls in older adults but there are few r and omised controlled trials in a real life health care setting . We describe the rationale , intervention , study design , recruitment strategies and baseline characteristics of participants in a r and omised controlled trial of a multifactorial falls prevention programme in primary health care . Methods Participants are patients from 19 primary care practice s in Hutt Valley , New Zeal and aged 75 years and over who have fallen in the past year and live independently . Two recruitment strategies were used – waiting room screening and practice mail-out . Intervention participants receive a community based nurse assessment of falls and fracture risk factors , home hazards , referral to appropriate community interventions , and strength and balance exercise programme . Control participants receive usual care and social visits . Outcome measures include number of falls and injuries over 12 months , balance , strength , falls efficacy , activities of daily living , quality of life , and physical activity levels . Results 312 participants were recruited ( 69 % women ) . Of those who had fallen , 58 % of people screened in the practice waiting rooms and 40 % when screened by practice letter were willing to participate . Characteristics of participants recruited using the two methods are similar ( p > 0.05 ) . Mean age of all participants was 81 years ( SD 5 ) . On average participants have 7 medical conditions , take 5.5 medications ( 29 % on psychotropics ) with a median of 2 falls ( interquartile range 1 , 3 ) in the previous year . Conclusion The two recruitment strategies and the community based intervention delivery were feasible and successful , identifying a high risk group with multiple falls . Recruitment in the waiting room gave higher response rates but was less efficient than practice mail-out . Testing the effectiveness of an evidence based intervention in a ' real life ' setting is important . Trial registration Australian Clinical Trials Register ID 12605000054617 Background Recruitment and retention of patients and healthcare providers in r and omised controlled trials ( RCTs ) is important in order to determine the effectiveness of interventions . However , failure to achieve recruitment targets is common and reasons why a particular recruitment strategy works for one study and not another remain unclear . We sought to describe a strategy used in a multicentre RCT in primary care , to report research ers ' and participants ' experiences of its implementation and to inform future strategies to maximise recruitment and retention . Methods In total 48 general practice s and 903 patients were recruited from three different areas of Irel and to a RCT of an intervention design ed to optimise secondary prevention of coronary heart disease . The recruitment process involved telephoning practice s , posting information , visiting practice s , identifying potential participants , posting invitations and obtaining consent . Retention involved patients attending review s and responding to question naires and practice s facilitating data collection . Results We achieved high retention rates for practice s ( 100 % ) and for patients ( 85 % ) over an 18-month intervention period . Pilot work , knowledge of the setting , awareness of change in staff and organisation amongst participant sites , rapid responses to queries and acknowledgement of practitioners ' contributions were identified as being important . Minor variations in protocol and research support helped to meet varied , complex and changing individual needs of practitioners and patients and encouraged retention in the trial . A collaborative relationship between research er and practice staff which required time to develop was perceived as vital for both recruitment and retention . Conclusion Recruiting and retaining the numbers of practice s and patients estimated as required to provide findings with adequate power contributes to increased confidence in the validity and generalisability of RCT results . A continuous dynamic process of monitoring progress within trials and tailoring strategies to particular circumstances , whilst not compromising trial protocol s , should allow maximal recruitment and retention . Trial registration IS RCT BACKGROUND There is limited evidence regarding the factors that facilitate recruitment and retention of general practice s in clinical trials . It is therefore pertinent to consider the factors that facilitate research in primary care . AIM To formulate hypotheses about effective ways of recruiting and retaining practice s to clinical trials , based on a case study . DESIGN OF STUDY Case study of practice recruitment and retention to a trial of delivering antenatal sickle cell and thalassaemia screening . SETTING Two UK primary care trusts with 123 practice s , with a high incidence of sickle cell and thalassaemia , and high levels of social deprivation . METHOD Practice s were invited to take part in the trial using a research information sheet for practice s. Invitations were sent to all practice managers , GPs , practice nurses , and nurse practitioners . Expenses of approximately pound 3000 per practice were available . Practice s and the research team signed research activity agreements , detailing a payment schedule based on deliverables . Semi-structured interviews were completed with 20 GPs who participated in the trial . Outcome measures were the number of practice s recruited to , and completing , the trial . RESULTS Four practice s did not agree to r and omisation and were excluded . Of 119 eligible practice s , 29 expressed an interest in participation . Two practice s withdrew from the trial and 27 participated ( two hosted pilot studies and 25 completed the trial ) , giving a retention rate of 93 % ( 27/29 ) . The 27 participating practice s did not differ from non-participating practice s in list size , number of GPs , social deprivation , or minority ethnic group composition of the practice population . CONCLUSION Three factors appeared important in recruiting practice s : research topic , invitation method , and interest in research . Three factors appeared important in retaining practice s : good communication , easy data - collection methods , and payment upon meeting pre-agreed targets . The effectiveness of these factors at facilitating recruitment and retention requires assessment in experimental studies BACKGROUND Failure to recruit adequate numbers of participants represents a major barrier to the completion of r and omized controlled trials in primary care and is associated with substantial opportunity costs . However , uncertainty exists regarding the relative effectiveness of different methods to promote recruitment . OBJECTIVES The purpose of this study was to estimate the proportion of strategies used to promote patient recruitment to r and omized controlled trials in primary care that are evidence based . METHODS Investigators from seven primary care-based clinical trials of dyspepsia management aim ing to recruit a total of 6070 patients participated . Following a survey of trial organization , a Delphi technique was used to reach consensus on levels of evidence on the effectiveness of interventions or organizational characteristics in influencing recruitment . The main outcome measures were the proportions of interventions or organizational characteristics for influencing patient recruitment that are based upon r and omized controlled trials , on convincing non-experimental evidence or meeting neither of these criteria . RESULTS Out of a total of 56 interventions used across the trials , 35 ( 63 % ) were judged as evidence based . Out of a total of 29 organizational characteristics possessed by the trials , five ( 17 % ) were judged as evidence based . Across the seven dyspepsia trials , the presence of ' favourable ' organizational characteristics appeared to be important contributors towards successful recruitment . CONCLUSIONS A wide range of interventions and organizational characteristics with the potential to promote recruitment were used or possessed by seven primary care trials . Many were not evidence based . Our experience suggests that organizational characteristics could be more influential in trial recruitment than the use of specific interventions . Given the costs of primary care-based trials , research ers need more rigorous evidence to inform recruitment strategies Background Postal question naires are an economical and simple method of data collection for research purpose s but are subject to non-response bias . Several studies have explored the effect of monetary and non-monetary incentives on response . Recent meta-analyses conclude that financial incentives are an effective way of increasing response rates . However , large surveys rarely have the re sources to reward individual participants . Three previous papers report on the effectiveness of lottery incentives with contradictory results . This study aim ed to determine the effect of including a lottery-style incentive on response rates to a postal health survey . Methods R and omised controlled trial . Setting : North and West Birmingham . 8,645 patients aged 18 or over r and omly selected from registers of eight general practice s ( family physician practice s ) . Intervention : Inclusion of a flyer and letter with a health question naire informing patients that returned question naires would be entered into a lottery-style draw for £ 100 of gift vouchers . Control : Health question naire accompanied only by st and ard letter of explanation . Main outcome measures : Response rate and completion rate to question naire . Results 5,209 individuals responded with identical rates in both groups ( 62.1 % ) . Practice , patient age , sex and Townsend score ( a postcode based deprivation measure ) were identified as predictive of response , with higher response related to older age , being female and living in an area with a lower Townsend score ( less deprived ) . Conclusion This RCT , using a large community based sample , found that the offer of entry into a lottery style draw for £ 100 of High Street vouchers has no effect on response rates to a postal health question naire Background Trials frequently encounter difficulties in recruitment , but evidence on effective recruitment methods in primary care is sparse . A robust test of recruitment methods involves comparing alternative methods using a r and omized trial , ' nested ' in an ongoing ' host ' trial . There are potential scientific , logistical and ethical obstacles to such studies . Methods Telephone interviews were undertaken with four groups of stakeholders ( funders , principal investigators , trial managers and ethics committee chairs ) to explore their views on the practicality and acceptability of undertaking nested trials of recruitment methods . These semi-structured interviews were transcribed and analysed thematically . Results Twenty people were interviewed . Respondents were familiar with recruitment difficulties in primary care and recognised the case for ' nested ' studies to build an evidence base on effective recruitment strategies . However , enthusiasm for this global aim was tempered by the challenges of implementation . Challenges for host studies included increasing complexity and management burden ; compatibility between the host and nested study ; and the impact of the nested study on trial design and relationships with collaborators . For nested recruitment studies , there were concerns that host study investigators might have strong preferences , limiting the nested study investigators ' control over their research , and also concerns about sample size which might limit statistical power . Nested studies needed to be compatible with the main trial and should be planned from the outset . Good communication and adequate re sources were seen as important . Conclusions Although research on recruitment was welcomed in principle , the issue of which study had control of key decisions emerged as critical . To address this concern , it appeared important to align the interests of both host and nested studies and to reduce the burden of hosting a recruitment trial . These findings should prove useful in devising a programme of research involving nested studies of recruitment interventions OBJECTIVE To determine factors that facilitated or hindered recruitment of general practice s into a large New Zeal and primary care project that aim ed to determine general practice characteristics of immunization coverage . METHODS The project had a multi-level recruitment strategy requiring recruitment of r and omly selected practice s before r and omly selecting GPs , practice nurses and caregivers of children enrolled at those practice s. Detailed quantitative and qualitative recruitment data were recorded on an access data base . Post-recruitment , recruiters underwent semi-structured interviews . Analysis was mixed method , with triangulation of descriptive statistics of the number of calls and time course to recruitment and general inductive thematic analysis of qualitative data . RESULTS Identifying key decision makers and how individual practice processes work can save significant recruitment time . Factors identified as assisting practice recruitment included using a personal approach from doctor to doctor , getting buy-in from all practice staff , streamlining the research process to minimize disruption to the practice and flexibility to accommo date practice s. CONCLUSIONS The task of recruiting should not be underestimated . Adequate time and re source need to be allocated from the onset . Long periods where practice s have no added burdens such as audits , mass vaccination programmes or influenza season are unlikely , therefore there are always considerable challenges in recruiting practice s for research . Remaining flexible to individual practice styles and influences and acknowledging the commitment of participants is important PURPOSE " Physicians-recruiting-physicians " is the preferred recruitment approach for practice -based research . However , yields are variable ; and the approach can be costly and lead to biased , unrepresentative sample s. We sought to explore the potential efficiency of alternative methods . METHODS We conducted a retrospective analysis of the yield and cost of 10 recruitment strategies used to recruit primary care practice s to a r and omized trial to improve cardiovascular disease risk factor management . We measured response and recruitment yields and the re sources used to estimate the value of each strategy . Providers at recruited practice s were surveyed about motivation for participation . RESULTS Response to 6 opt-in marketing strategies was 0.40 % ( 53/13290 ) , ranging from 0 % to 2.86 % by strategy ; 33.96 % ( 18/53 ) of responders were recruited to the study . Of those recruited from opt-out strategies , 8.68 % joined the study , ranging from 5.35 % to 41.67 % per strategy . A strategy that combined both opt-in and opt-out approaches result ed in a 51.14 % ( 90/176 ) response and a 10.80 % ( 19/90 ) recruitment rate . Cost of recruitment was $ 613 per recruited practice . Recruitment approaches based on in-person meetings ( 41.67 % ) , previous relationships ( 33.33 % ) , and borrowing an Area Health Education Center 's established networks ( 10.80 % ) , yielded the most recruited practice s per effort and were most cost efficient . Individual providers who chose to participate were motivated by interest in improving their clinical practice ( 80.5 % ) ; contributing to CVD primary prevention ( 54.4 % ) ; and invigorating their practice with new ideas ( 42.1 % ) . CONCLUSIONS This analysis provides suggestions for future recruitment efforts and research . Translational studies with limited funds could consider multi-modal recruitment approaches including in-person presentations to practice groups and exploitation of previous relationships , which require the providers to opt-out , and interactive opt-in approaches which rely on borrowed networks . These approaches can be supplemented with non-relationship-based opt-out strategies such as cold calls strategically targeted to underrepresented provider groups The objective of this study was to identify factors associated with general practitioner ( GP ) participation and the recruitment of people to trials in primary care , based on data from two trials of interventions for treating chronic low back pain . The study was based on data from two r and omized controlled trials ( RCTs ) , one involving exercise , the other acupuncture , and subsequent reporting by GPs in a postal question naire . The exercise trial achieved 62 % recruitment whereas the acupuncture trial achieved 100 % recruitment . In both trials GPs most efficient at referring patients were those with a special interest in the subject area , and those known personally to the research team . A follow-up GP question naire found that both trials had maintained a high profile with over 80 % of GPs , and successful recruitment strategies included project reminder letters , up date s and personal contacts . Achieving target recruitment of patients in the acupuncture trial was aided by the deliberate application of lessons learned in the exercise trial , in particular the need to keep initial study entry criteria broad , with subsequent filtering undertaken by the study research er . In addition the use of effective methods of maintaining the trial profile , the involvement of a GP advisor , the decision to maximize the recruitment of GPs early in the trial and the direct recruitment of interested individual GPs . The successful recruitment of patients to trials in primary care requires careful planning and continuous monitoring from the outset . Prior to starting recruitment , it is useful to identify previous trials in a similar environment in order to learn from their experience and optimize patient recruitment A r and omised controlled trial was planned to compare two different treatment strategies -- structured problem solving and selective serotonin reuptake inhibitor ( SSRI ) medication -- for patients with mild to moderate major depression . The trial was to be conducted in the primary care setting with all treatment given by general practitioners . When no patients had been recruited into the study after six months , we performed an audit of all patients with depressive symptoms attending the doctors ' practice s over three weeks . Exclusion criteria were changed to ease entry into the trial , but still no patients were recruited over the following six months . What went wrong Studies show that it is difficult to recruit women of low socioeconomic status as clinical research participants . Such an objective was attained though as our results demonstrate in an evaluative study of a program implemented to lower the percentage of low birthweight in four CLSCs of the Isl and of Montreal between 1994 and 1996 . The global recruitment strategy enabled us to reach 56.2 % of our goal in 1994 and 77.4 % in 1996 . Two conclusions can be drawn from this result : the effectiveness of the three methods of recruitment varied according to each participating CLSC , and the global strategy , combined with the mobilization of community re sources , was successful in enrolling women of low socioeconomic status OBJECTIVE To test the effect of postal r and omization on recruitment of patients into a r and omized trial in primary care . STUDY DESIGN AND SETTING General practice s used a telephone service to r and omize patients in our trial . Delays in the start of recruitment at some sites led us to modify the r and omization procedure . When new practice s took part patients completed and posted baseline material s to the Trial Secretary in York who performed the r and omization and informed those concerned of the allocation . RESULTS Of the 647 practice s who were invited to take part , 130 ( 45 % ) of 288 agreed to participate using telephone r and omization and 155 ( 43 % ) of 359 using the postal method . These practice s recruited 553 patients from November 2002 to October 2004 across 11 sites in the United Kingdom . The postal method reduced the number of patients recruited by a factor of 0.86 ( 95 % confidence interval=0.62 - 1.20 ) , or 14 % . The number of general practitioners working in a practice significantly increased patient recruitment by a factor of 1.12 ( 1.05 - 1.20 ) , whereas practice distance from hospital significantly decreased recruitment by a factor of 0.98 ( 0.97 - 0.99 ) . CONCLUSION Postal r and omization had no significant effect on recruitment of patients into our trial OBJECTIVE To investigate the perceived barriers among GPs towards introducing participation in r and omized controlled trials ( RCTs ) to patients presenting with depression during consultations . METHODS Qualitative study using semi-structured interviews . Interviews were recorded using a digital voice recorder , transcribed verbatim and analysed using the Framework Approach . The participants were 41 GPs from five primary care trusts in the South West who were collaborating with the University of Bristol on an RCT recruiting patients with depression . RESULTS Three themes were identified : ( i ) concern about protecting the vulnerable patient and the impact on the doctor-patient relationship ; ( ii ) the perceived lack of skill and confidence of GPs to introduce a request for research participation within a potentially sensitive consultation ; and ( iii ) the priority given to clinical and administrative issues over research participation . These themes were underpinned by GPs ' observations that consultations with people about depression differed in content , style and perceived difficulty compared to other types of consultations . CONCLUSION Depressed patients were often viewed as vulnerable and in need of protection and it was seen as difficult and intrusive to introduce research . Patients were not always given the choice to participate in research in the same way that they are encouraged to participate in treatment decision making . A lack of skills in introducing research could be addressed with training through the new Primary Care Research Network . A more radical change in clinician attitudes and policy may be needed in order to give research a higher priority within primary care BACKGROUND Physical activity and dietary behavior changes are important to both the primary prevention and secondary management of the majority of our most prevalent chronic conditions ( i.e. , cardiovascular disease , hypertension , type 2 diabetes , breast and colon cancer ) . With over 85 % of Australian adults visiting a general practitioner each year , the general practice setting has enormous potential to facilitate wide scale delivery of health behaviour interventions . However , there are also many barriers to delivery in such setting s , including lack of time , training , re sources and remuneration . Thus there is an important need to evaluate other feasible and effective means of delivering evidence -based physical activity and dietary behaviour programs to patients in primary care , including telephone counseling interventions . METHODS Using a cluster r and omized design with practice as the unit of r and omization , this study evaluated a telephone-delivered intervention for physical activity and dietary change targeting patients with chronic conditions ( type 2 diabetes or hypertension ) recruited from primary care practice s in a socially disadvantaged community in Queensl and , Australia . Ten practice s were r and omly assigned to the telephone intervention or to usual care , and 434 patients were recruited . Patients in intervention practice s received a workbook and 18 calls over 12 months . Assessment at baseline , 4- , 12- and 18-months allows for assessment of initial change and maintenance of primary outcomes ( physical activity and dietary behavior change ) and secondary outcomes ( quality of life , cost-effectiveness , support for health behavior change ) . CONCLUSIONS This effectiveness trial adds to the currently limited number of telephone-delivered intervention studies targeting both physical activity and dietary change . It also addresses some of the shortcomings of previous trials by targeting patients from a disadvantaged community , and by including detailed reporting on participant representativeness , intervention implementation and cost-effectiveness , as well as an evaluation of maintenance of health behavior change BACKGROUND The study objective is to evaluate the effect of monetary incentives on response rates of adolescents to a smoking-related survey as the first step toward participation in an intervention trial . METHODS A sample of 4,200 adolescent members of a managed care organization were r and omized to one of four incentive groups : a $ 2 cash group , a $ 15 cash group , a $ 200 prize drawing group , or a no-incentive group . We compared group-specific response rates and willingness to be contacted about future study activities , as well as costs . RESULTS Incentives increased survey response rates ( 55 % response without incentive vs. a 69 % response with incentive ) , with response of 74 % in the $ 15 cash group , 69 % in the token group , and 63 % with a prize incentive . Incentives did not adversely affect willingness of adolescents to be contacted about a smoking intervention , ( 65 % willing with incentives vs. 60 % without , P = 0.03 ) . In terms of cost per additional survey completed , token and prize groups were marginally more expensive than the no-incentive group ( $ 0.40 and $ 1.42 , respectively ) while the large cash incentive was substantially more costly ( $ 11.37 ) . CONCLUSIONS Monetary incentives improve response rates to a mailed survey , without adverse impact on willingness to further participate in intervention activities . However , a variety of issues must be considered when using incentives for recruitment to intervention studies This study compares the efficiency of two methods of recruitment into a r and omised controlled trial examining the cost-effectiveness of water therapy for elderly people with lower limb osteoarthritis . The direct cost of recruiting patients via general practice was 27.66 Pounds per patient ( 1.1 personnel hours/patient ) . The cost per recruited patient from a local newspaper article was 2.72 Pounds ( 0.2 personnel hours/patient ) . The cost differential between the two recruitment methods was largely owing to poor administration practice s , difficulties in accessing patient information , and difficulties in contacting patients from the general practice computer data base OBJECTIVES To review UK guidelines regarding the use of financial incentives for healthcare professionals to become involved in clinical trials , and to survey perceptions and current practice . DATA SOURCES Electronic data bases were search ed from inception to June 2006 . Interviews were held with NHS healthcare professionals , research managers from the pharmaceutical industry and members of the public . REVIEW METHODS From the search es , 634 identified studies were assessed for inclusion in the systematic review , but only three met the criteria for data extraction . Fifty-eight individuals were interviewed : 38 chief investigators , six non- research active clinicians , eight public and six pharmaceutical managers . Investigators were selected from those funded by the HTA Programme , the other by ' snowballing ' and personal contact . RESULTS The evidence from the literature was limited and inconclusive . In UK guidelines , the issues around payments to clinicians or patients were implied rather than stated , usually linked to discussion of conflict of interest and disclosure of any such conflicts . Developments in NHS research governance had led to increased transparency in all payments for research participation and for payments to be made to NHS Trusts rather than individual clinicians . While reimbursement of costs incurred by research was strongly supported by the interviewees , payments to incentivise recruitment were not . A code of practice was suggested for payments in publicly funded trials , which was closely linked to the principles of Good Clinical Practice in research . Factors such as interest in the topic , scope for patient benefit and good communication were considered more important than payment . Interviews with the general public indicated low levels of awareness of the existence of payments to clinicians linked to patient recruitment in trials , and unanimous support for full disclosure . Interviews with managers in the pharmaceutical industry showed greater familiarity with payments for research involvement . GPs were seen as the only group for whom scope existed for individual payments . Concerns were expressed by the pharmaceutical company interviewees at the rising cost of research and unnecessary bureaucracy . CONCLUSIONS The ethical stances outlined in Good Clinical Practice in research were widely endorsed by the three groups interviewed . These allow reasonable payments to clinicians , subject to disclosure of any possible conflicts of interest . The potential for incentivising clinicians to recruit was limited as any payments should be based on the cost of inputs and should not be made to individuals but to their host organisation . NHS professionals were concerned that payments could damage the quality of research and also considered full disclosure to patients as challenging . Patients and members of the public favoured full disclosure and payment of expenses to patients involved in research . Pharmaceutical company interviewees viewed payment to the NHS for all research activities as normal and highly regulated . They complained that the prices charged were high and so variable that they required benchmarking . Considerable scope exists for compiling data on the factors that help and hinder the progress of clinical trials and also for experimenting with different incentives to encourage involvement in clinical research . Further research should focus on improved reporting of those organisational aspects of trials that are known to affect recruitment ; retrospective analysis of the factors associated with different levels of recruitment to RCTs ; prospect i ve comparative research on trial recruitment ; qualitative research on participants ' experiences of being involved in different kinds of trials , and proposals to include within trials experiments with payments methods This article examines different recruitment strategies for the VECAT Study , a 4-year , double-masked , placebo-controlled , r and omized clinical trial of vitamin E in the prevention of cataract and age-related maculopathy . Five recruitment methods were employed : newspaper advertising , radio advertising , approaches to community groups , approaches via general practice s , and an electoral roll mail-out . Participants ( 1204 ) from the community in Melbourne , Australia were recruited and enrolled within 15 months ( age range : 55 - 80 years , mean 66 years ; gender ratio : 57 % female , 43 % male ) . The electoral roll mail-out and newspaper advertising were the most efficient methods of recruitment in terms of absolute numbers of participants recruited and cost per participant . Recruitment for the VECAT study was successfully completed within the planned period . Although the electoral roll mail-out and newspaper advertising were the most efficient for this study , other methods may be of value for studies with different subject selection criteria BACKGROUND Regular physical activity has been shown to have many health benefits . However , many older people are physically inactive . OBJECTIVE To investigate why older people are reluctant to participate in leisure time physical activity and to identify strategies to encourage increased activity . DESIGN Cross-sectional survey . SETTING 16 general practice s in Dundee , Scotl and . METHODS 409 r and omly selected older people ( 65 - 84 years ) who lived independently were interviewed at home . Forty-six percent of those invited to take part were recruited into the study . RESULTS Levels of knowledge about the specific health benefits of physical activity were high . Almost all participants ( 95 % ) believed that physical activity was beneficial and 79 % believed that they did enough to keep healthy . However , 36 % did no leisure time physical activity and a further 17 % did less than 2 hours per week . Regression modelling identified 11 factors that exerted significant independent effects on levels of leisure time physical activity . The most powerful deterrent was lack of interest ( OR = 7.8 ) . Other factors included lack of daily access to a car , shortness of breath , joint pain , dislike of going out alone or in the evening , perceived lack of fitness , lack of energy , doubting that exercise can lengthen life , not belonging to a group and doubting that meeting new people is beneficial . CONCLUSIONS Increasing leisure time physical activities poses major challenges . Beliefs about desirable levels of activity in older people would need to be changed . Action would be needed to relieve physical symptoms and address fears about perceived ability to undertake physical activity . Finally , easily accessible facilities would be needed to encourage participation in physical activity Cluster r and omised controlled trials for health promotion , education , public health or organisational change interventions are becoming increasingly common to inform evidence -based policy . However , there is little published method ological evidence on recruitment strategies for primary care population clusters . In this paper , we discuss how choosing which population cluster to r and omise can impact on the practicalities of recruitment in primary care . We describe strategies developed through our experiences of recruiting primary care organisations to participate in a national r and omised controlled trial of a policy to provide community breastfeeding groups for pregnant and breastfeeding mothers , the BIG ( Breastfeeding in Groups ) trial . We propose an iterative qualitative approach to recruitment ; collecting data generated through the recruitment process , identifying themes and using the constant comparative method of analysis . This can assist in developing successful recruitment strategies and contrasts with the st and ardised approach commonly used when recruiting individuals to participate in r and omised controlled trials . Recruiting primary care population clusters to participate in trials is currently an uphill battle in Britain . It is a complex process , which can benefit from applying qualitative methods to inform trial design and recruitment strategy . Recruitment could be facilitated if health service managers were committed to supporting peer review ed , funded and ethics committee approved research at national level OBJECTIVE The aim of this study was to describe recruitment strategies for a single-visit cervical cancer prevention study . METHODS From January through December 1999 , low-income , predominantly Latino women were recruited to participate in a single-visit cervical cancer prevention study . For the first 6 months , all women who had ever visited one of two community-based study clinics were invited to participate ( clinic registry recruitment ) . For the remainder of the year , recruitment was modified to be primarily inclusive of advertisements in English- and Spanish- language community newspapers and fliers left in local businesses and organizations ( media campaign recruitment ) . Eligible volunteers were r and omized to one of two study arms , usual-care program or single-visit program . All study subjects completed demographic and medical question naires delivered by bilingual staff . Women who declined to participate in this study were asked to provide reasons for this preference . Statistical analyses included the use of chi-square , logistic regression , and Student 's t test . RESULTS The proportion of women who agreed to participate was higher in the media recruitment group than in the clinic registry group [ 51 % ( 535/1041 ) compared to 26 % ( 405/1542 ) , P < 0.001 ] . The no-show rate among participants solicited from the media strategy was significantly less than that from the clinic registry . There were no significant differences in the median age , number of months since the last Papanicolaou smear , incidence of abnormal Papanicolaou smear , education , or income of the subjects based on the recruitment strategy . CONCLUSION A media-based recruitment strategy was effective for this single-visit cervical prevention study . This approach may be effective for recruitment of other low-income groups to clinical trials Participant recruitment is considered the most difficult aspect of the research process . Despite the integral role of recruitment in r and omized clinical trials , publication of data defining the recruitment effort is not routine in rehabilitation initiatives . The recruitment process for the Extremity Constraint-Induced Therapy Evaluation ( EXCITE ) trial illustrates obstacles to and strategies for participant accrual and retention that are inherent in rehabilitation clinical trials . The purpose of this article is to increase awareness of the multiple facets of recruitment necessary for successful clinical trials , thus supporting the continued development of evidence -based practice in physical therapy . The Recruitment Index is presented as a variable to measure recruitment efficacy . In addition , ethical aspects of recruitment are explored , including informed consent and the concept of therapeutic misconception |
13,719 | 29,040,025 | The synergism between PUFA , MUFA , polyphenols and carotenoids present in pistachios can modulate specific miRNA , increasing insulin sensitivity through the PI3K-AKT signaling pathway . | ABSTRACT Pistachio is a nut with high polyunsaturated fatty acids ( PUFA ) , monounsaturated fatty acids ( MUFA ) , polyphenols and carotenoids content , and the synergism between these compounds appears to affect glucose metabolism .
In this systematic review we analyzed studies in which the effect of chronic consumption of pistachio on markers of glucose metabolism was evaluated in pre-diabetic and type 2 diabetics . | CONTEXT Diabetes is frequently diagnosed late , when the development of complications is almost inevitable , decreasing the quality of life of patients . However , early detection of affected individuals would allow the implementation of timely and effective therapies . OBJECTIVE Here we set to describe the profile of circulating microRNAs ( miRNAs ) in prediabetic patients with the intention of identifying novel diagnostic and therapeutic tools . DESIGN We used real-time RT-PCR to measure the abundance of 176 miRNAs in serum of a cohort of 92 control and prediabetic individuals with either impaired fasting glucose or impaired glucose tolerance , as well as newly diagnosed diabetic patients . We vali date d the results in a second cohort of control and prediabetic subjects undergoing a therapeutic exercise intervention , as well as in a mouse model of glucose intolerance . RESULTS We identified two miRNAs , miR-192 and miR-193b , whose abundance is significantly increased in the prediabetic state but not in diabetic patients . Strikingly , these miRNAs are also increased in plasma of glucose-intolerant mice . Moreover , circulating levels of miR-192 and miR-193b return to baseline in both prediabetic humans and glucose-intolerant mice undergoing a therapeutic intervention consisting in chronic exercise , which succeeded in normalizing metabolic parameters . CONCLUSIONS Our data show that the pattern of circulating miRNAs is modified by defects in glucose metabolism in a similar manner in mice and humans . This circulating miRNA signature for prediabetes could be used as a new diagnostic tool , as well as to monitor response to intervention Saturated fatty acids ( SFA ) and monounsaturated fatty acids ( MUFA ) show different effects on the development of insulin resistance . In this study , we compared the effect of dietary SFA and MUFA on the insulin signaling pathway in the skeletal muscle of a type 2 diabetic animal model . Twenty-nine-week-old male Otsuka Long-Evans Tokushima fatty ( OLETF ) rats were r and omly divided into three groups and fed one of the following diets for 3 weeks ; a normal chow diet , an SFA ( lard oil ) enriched or a MUFA ( olive oil ) enriched high-fat diet . The vastus lateralis muscle was used for analyses . Insulin tolerance test showed improved insulin sensitivity in rats fed the MUFA diet , as compared to those fed the SFA diet ( p < 0.001 ) . The SFA diet reduced IRS-1 expression and phosphorylated PI3 K levels in skeletal muscle , as compared with a chow diet ( p < 0.001 , respectively ) . On the contrary , muscle IRS-2 expression and phosphorylated ERK1/2 was significantly increased in rats fed the SFA diet ( p < 0.001 , respectively ) . Membrane translocation of glucose transporter type 4 decreased in the skeletal muscle of rats fed the SFA diet , as compared to those fed a chow diet ( p < 0.001 ) . These changes in insulin signaling pathway in skeletal muscle were not observed in rats fed the MUFA diet . In conclusion , the beneficial effect of dietary MUFA on insulin sensitivity is associated with a conserved IRS-1/PI3 K insulin signaling pathway which was altered by dietary SFA OBJECTIVE Fat intake , especially monounsaturated fatty acid ( MUFA ) , has been liberalized in diabetic diets to preserve HDL cholesterol and improve glycemic control , yet the exact sources have not been clearly defined . Therefore , we assessed the effect of mixed nut consumption as a source of vegetable fat on serum lipids and HbA1c in type 2 diabetes . RESEARCH DESIGN AND METHODS A total of 117 type 2 diabetic subjects were r and omized to one of three treatments for 3 months . Supplements were provided at 475 kcal per 2,000-kcal diet as mixed nuts ( 75 g/day ) , muffins , or half portions of both . The primary outcome was change in HbA1c . RESULTS The relative increase in MUFAs was 8.7 % energy on the full-nut dose compared with muffins . Using an intention-to-treat analysis ( n = 117 ) , full-nut dose ( mean intake 73 g/day ) reduced HbA1c ( −0.21 % absolute HbA1c units , 95 % CI −0.30 to −0.11 , P < 0.001 ) with no change after half-nut dose or muffin . Full-nut dose was significantly different from half-nut dose ( P = 0.004 ) and muffin ( P = 0.001 ) , but no difference was seen between half-nut dose and muffins . LDL cholesterol also decreased significantly after full-nut dose compared with muffin . The LDL cholesterol reduction after half-nut dose was intermediate and not significantly different from the other treatments . Apolipoprotein ( apo ) B and the apoB : apoA1 ratio behaved similarly . Nut intake related negatively to changes in HbA1c ( r = −0.20 , P = 0.033 ) and LDL cholesterol ( r = −0.24 , P = 0.011 ) . CONCLUSIONS Two ounces of nuts daily as a replacement for carbohydrate foods improved both glycemic control and serum lipids in type 2 diabetes Rationale : MicroRNAs ( miRNAs ) have been implicated in the epigenetic regulation of key metabolic , inflammatory , and antiangiogenic pathways in type 2 diabetes ( DM ) and may contribute to common disease complications . Objective : In this study , we explore plasma miRNA profiles in patients with DM . Methods and Results : Total RNA was extracted from plasma sample s of the prospect i ve population -based Bruneck study . A total of 13 c and i date miRNAs identified by microarray screening and miRNA network inference were quantified by quantitative PCR in all diabetic patients of the Bruneck study and age- and sex-matched controls ( 1995 evaluation , n=80 each ) . Quantitative PCR assessment revealed lower plasma levels of miR-20b , miR-21 , miR-24 , miR-15a , miR-126 , miR-191 , miR-197 , miR-223 , miR-320 , and miR-486 in prevalent DM , but a modest increase of miR-28 - 3p . Findings emerged as robust in multivariable analysis and were independent of the st and ardization procedure applied . For endothelial miR-126 , results were confirmed in the entire Bruneck cohort ( n=822 ) in univariate ( odds ratio [ 95 % confidence interval ] , 0.38 [ 0.26 to 0.55 ] ; P=2.72 × 10−7 ) and multivariate analyses ( 0.57 [ 0.37 to 0.86 ] ; P=0.0082 ) . Importantly , reduced miR-15a , miR-29b , miR-126 , miR-223 , and elevated miR-28 - 3p levels ante date d the manifestation of disease . Most differences in miRNA levels were replicated in plasma obtained from hyperglycemic Lepob mice . High glucose concentrations reduced the miR-126 content of endothelial apoptotic bodies . Similarly in patients with DM , the reduction of miR-126 was confined to circulating vesicles in plasma . Conclusions : We reveal a plasma miRNA signature for DM that includes loss of endothelial miR-126 . These findings might explain the impaired peripheral angiogenic signaling in patients with DM OBJECTIVE Recent studies have suggested that nuts have favorable effects beyond lipid lowering . We aim ed to investigate effect of the Antep pistachio ( Pistacia vera L. ) on blood glucose , lipid parameters , endothelial function , inflammation , and oxidation in healthy young men living in a controlled environment . METHODS A Mediterranean diet was administered to normolipidemic 32 healthy young men ( mean age 22 y , range 21 - 24 ) for 4 wk . After 4 wk , participants continued to receive the Mediterranean diet but pistachio was added for 4 wk by replacing the monounsaturated fat content constituting approximately 20 % of daily caloric intake . Fasting blood sample s and brachial endothelial function measurements were performed at baseline and after each diet . RESULTS Compared with the Mediterranean diet , the pistachio diet decreased glucose ( P<0.001 , -8.8+/-8.5 % ) , low-density lipoprotein ( P<0.001 , -23.2+/-11.9 % ) , total cholesterol ( P<0.001 , -21.2+/-9.9 % ) , and triacylglycerol ( P=0.008 , -13.8+/-33.8 % ) significantly and high-density lipoprotein ( P=0.069 , -3.1+/-11.7 % ) non-significantly . Total cholesterol/high-density lipoprotein and low-density lipoprotein/high-density lipoprotein ratios decreased significantly ( P<0.001 for both ) . The pistachio diet significantly improved endothelium-dependent vasodilation ( P=0.002 , 30 % relative increase ) , decreased serum interleukin-6 , total oxidant status , lipid hydroperoxide , and malondialdehyde and increased superoxide dismutase ( P<0.001 for all ) , whereas there was no significant change in C-reactive protein and tumor necrosis factor-alpha levels . CONCLUSION In this trial , we demonstrated that a pistachio diet improved blood glucose level , endothelial function , and some indices of inflammation and oxidative status in healthy young men . These findings are in accordance with the idea that nuts , in particular pistachio nuts , have favorable effects beyond lipid lowering that deserve to be evaluated with prospect i ve follow-up studies BACKGROUND AND AIMS Carotenoids may reduce diabetes risk , due to their antioxidant properties . However , the association between dietary carotenoids intake and type 2 diabetes risk is still unclear . Therefore , the objective of this study was to examine whether higher dietary carotenoid intakes associate with reduced type 2 diabetes risk . METHODS AND RESULTS Data from 37,846 participants of the European Prospect i ve Investigation into Cancer and Nutrition- Netherl and s study were analyzed . Dietary intakes of β-carotene , α-carotene , β-cryptoxanthin , lycopene , lutein & zeaxanthin and the sum of these carotenoids were assessed using a vali date d food frequency question naire . Incident type 2 diabetes was mainly self-reported , and verified against general practitioner information . Mean ±SD total carotenoid intake was 10 ± 4 mg/day . During a mean ±SD follow-up of 10 ± 2 years , 915 incident cases of type 2 diabetes were ascertained . After adjustment for age , sex , diabetes risk factors , dietary intake , waist circumference and BMI , higher β-carotene intakes associated inversely with diabetes risk [ Hazard Ratio quartile 4 versus quartile 1 ( HR(Q4 ) ) : 0.78 ( 95%CI:0.64,0.95 ) , P-linear trend 0.01 ] . For α-carotene , a borderline significant reduced risk was observed , with a HR(Q4 ) of 0.85 ( 95%CI:0.70,1.03 ) , and P-linear trend 0.05 . β-cryptoxanthin , lycopene , lutein & zeaxanthin , and the sum of all carotenoids did not associate with diabetes risk . CONCLUSIONS This study shows that diets high in β-carotene and α-carotene are associated with reduced type 2 diabetes in generally healthy men and women BACKGROUND Diabetes is a chronic , potentially debilitating , and often fatal disease . Dietary strategies to reduce postpr and ial glycemia are important in the prevention and treatment of diabetes . Nuts are rich in mono- and polyunsaturated fatty acids , which may reduce hyperglycemia and improve metabolism . OBJECTIVES To evaluate the effectiveness of pistachio nut supplementation on glycemic and inflammatory measures in patients with type 2 diabetes . METHODS In this double-blind , r and omized , placebo-controlled , crossover trial , 48 diabetic patients were equally assigned to groups A and B. Patients in group A received a snack of 25 g pistachio nuts twice a day for 12 weeks and group B received a control meal without nuts . After 12 weeks of intervention , the patients had an 8-week washout . Then the groups were displaced , and group B received the same amount of pistachios for 12 weeks . RESULTS With respect to the total change in variables over both phases , there was a marked decrease in HbA1c ( -0.4 % ) and fasting blood glucose ( FBG ) concentrations ( -16 mg/dl ) in the pistachio group compared with the control group ( p ≤ 0.001 for both ) . There was no overall significant change in BMI , blood pressure , HOMA-IR , and C-reactive protein ( CRP ) concentrations . Analysis of the two phases separately showed a decrease in FBG by 14 mg/dl and in HbA1c by 0.45 % in the treatment group ( A ) after 12 weeks , while no significant differences were seen in group B ( control group ) . In the second phase , FBG decreased from 151.36 ± 39.22 to 137.28 ± 28.65 mg/dl ( -14 mg/dl ) and HbA1c decreased from 7.42 ± 0.97 to 7.15 ± 0.68 mg/dl ( -0.28 % , p = 0.013 and p = 0.033 , respectively ) in the pistachio group ( B ) . Pistachio consumption reduced systolic blood pressure ( p = 0.007 ) , BMI ( p = 0.011 ) , and CRP ( p = 0.002 ) in patients from the treatment groups , but not insulin resistance . CONCLUSIONS Dietary consumption of pistachio nuts as a snack has beneficial effects on glycemic control , blood pressure , obesity , and inflammation markers in diabetic patients INTRODUCTION Diabetes mellitus is the most common metabolic disorder in humans , and its incidence is increasing rapidly worldwide . Although polyunsaturated fatty acids have beneficial effects on diabetes mellitus , previous data regarding the possible positive effects of n-3 fatty acids on glycaemic indices were inconclusive . We conducted a double-blind r and omised clinical trial to determine the effects of eicosapentaenoic acid ( EPA ) , an n-3 polyunsaturated fatty acid , on overweight patients with type 2 diabetes mellitus ( T2DM ) . METHODS This double-blind , placebo-controlled r and omised clinical trial was conducted on a total of 67 overweight patients with T2DM for a duration of three months . Of these 67 patients , 32 received 2 g purified EPA daily , while 35 received a placebo of 2 g corn oil daily . The patients ' fasting plasma glucose ( FPG ) , serum insulin , glycated haemoglobin ( HbA1c ) and insulin sensitivity indices were assessed . RESULTS After three months of EPA supplementation , the group that received EPA showed significant decreases in FPG ( p < 0.001 ) , HbA1c ( p = 0.01 ) and homeostasis model assessment of insulin resistance ( HOMA-IR ) ( p = 0.032 ) , when compared to the placebo group . EPA supplementation result ed in decreased serum insulin levels , with the levels between the EPA and placebo groups showing a significant difference ( p = 0.004 ) . CONCLUSION The results of our study indicate that EPA supplementation could improve insulin sensitivity . It was able to decrease serum insulin , FPG , HbA1c and HOMA-IR . EPA could have beneficial effects on glycaemic indices in patients with T2DM OBJECTIVES Previous studies have demonstrated beneficial effects of regular consumption of pistachio nuts on glycemic , lipid , and oxidative stress parameters . The aim of this study was to determine its effect on vascular health , which has not been adequately studied so far . METHODS In this open label , r and omized parallel-group study , 60 adults with mild dyslipidemia were r and omized to lifestyle modification ( LSM ) alone or LSM with consumption of 80 g ( in-shell ) pistachios ( equivalent to 40 g or 1.5 oz shelled pistachios ) daily for 3 mo . Biochemical parameters , brachial artery flow-mediated vasodilation ( BAFMD ) , and carotid-femoral and brachial-ankle pulse wave velocity ( cfPWV and baPWV , respectively ) were measured before and after the intervention . RESULTS At 3 mo , there was no change in any of the clinical or biochemical parameters in the LSM group . However , the patients in the pistachio group had a significant increase in high-density lipoprotein cholesterol ( HDL-C ; 35.7 ± 8.8 mg/dL versus 37.8 ± 10.1 mg/dL ; P = 0.04 ) and a reduction in low-density lipoprotein cholesterol ( 137.2 ± 32.6 mg/dL versus 127.6 ± 34.0 mg/dL ; P = 0.02 ) , total cholesterol (TC)-to-HDL-C ratio ( 5.8 ± 1.3 mg/dL versus 5.3 ± 1.1 mg/dL ; P = 0.001 ) , and fasting blood sugar ( 88.8 ± 7.1 mg/dL versus 86.6 ± 6.3 mg/dL ; P = 0.05 ) . Additionally , whereas LSM alone was associated with no improvement in BAFMD or PWV , individuals in the pistachio group had significant reduction in left baPWV ( 1261.7 ± 187.5 cm/sec versus 1192.4 ± 152.5 cm/sec ; P = 0.02 ) and statistically nonsignificant improvement in most other parameters , including BAFMD . As a result , at 3 mo the patients in the pistachio group had lower cfPWV ( 770.9 ± 96.5 cm/sec versus 846.4 ± 162.0 cm/sec ; P = 0.08 ) , lower left baPWV ( 1192.4 ± 152.5 cm/sec versus 1326.3 ± 253.7 cm/sec ; P = 0.05 ) , and lower average baPWV ( 1208.2 ± 118.4 cm/sec versus 1295.8 ± 194.1 cm/sec ; P = 0.08 ) compared with the LSM group . Two-way analysis of variance revealed significant treatment effect of pistachio consumption on cfPWV , left baPWV , average baPWV , and BAFMD ( P = 0.037 , 0.01 , 0.07 , and 0.046 , respectively ) . CONCLUSIONS The present study demonstrates that regular consumption of pistachio nuts not only improves glycemic and lipid parameters , but also results in improvements in vascular stiffness and endothelial function . Importantly , these improvements were seen in apparently healthy individuals and with a diet ( including pistachios ) and exercise regimen that every adult individual is expected to follow Objective : To study the effects of three weight-maintenance diets with different macronutrient composition on carbohydrate , lipid metabolism , insulin and incretin levels in insulin-resistant subjects . Methods : A prospect i ve study was performed in eleven ( 7 W , 4 M ) offspring of obese and type 2 diabetes patients . Subjects had a BMI > 25 Kg/m2 , waist circumference ( men/women ) > 102/88 , HBA1c < 6.5 % and were regarded as insulin-resistant after an OGTT ( Matsuda ISIm < 4 ) . They were r and omly divided into three groups and underwent three dietary periods each of 28 days in a crossover design : a ) diet high in saturated fat ( SAT ) , b ) diet rich in monounsaturated fat ( MUFA ; Mediterranean diet ) and c ) diet rich in carbohydrate ( CHO ) . Results : Body weight and resting energy expenditure did not changed during the three dietary periods . Fasting serum glucose concentrations fell during MUFA-rich and CHO-rich diets compared with high-SAT diets ( 5.02 ± 0.1 , 5.03 ± 0.1 , 5.50 ± 0.2 mmol/L , respectively . Anova < 0.05 ) . The MUFA-rich diet improved insulin sensitivity , as indicated by lower homeostasis model analysis -insulin resistance ( HOMA-ir ) , compared with CHO-rich and high-SAT diets ( 2.32 ± 0.3 , 2.52 ± 0.4 , 2.72 ± 0.4 , respectively , Anova < 0.01 ) . After a MUFA-rich and high-SAT breakfasts ( 443 kcal ) the postpr and ial integrated area under curve ( AUC ) of glucose and insulin were lowered compared with isocaloric CHO-rich breakfast ( 7.8 ± 1.3 , 5.84 ± 1.2 , 11.9 ± 2.7 mmol · 180 min/L , Anova < 0.05 ; and 1004 ± 147 , 1253 ± 140 , 2667 ± 329 pmol · 180 min/L , Anova < 0.01 , respectively ) ; while the integrated glucagon-like peptide-1 response increased with MUFA and SAT breakfasts compared with isocaloric CHO-rich meals ( 4.22 ± 0.7 , 4.34 ± 1.1 , 1.85 ± 1.1 , respectively , Anova < 0.05 ) . Fasting and postpr and ial HDL cholesterol concentrations rose with MUFA-rich diets , and the AUCs of triacylglycerol fell with the CHO-rich diet . Similarly fasting proinsulin ( PI ) concentration fell , while stimulated ratio PI/I was not changed by MUFA-rich diet . Conclusions : Weight maintenance with a MUFA-rich diet improves HOMA-ir and fasting proinsulin levels in insulin-resistant subjects . Ingestion of a virgin olive oil-based breakfast decreased postpr and ial glucose and insulin concentrations , and increased HDL-C and GLP-1 concentrations as compared with CHO-rich diet OBJECTIVE The health benefits of regular nut consumption have been well-documented ; however , effects on cardiovascular risk in diabetes are emerging . This study examined the effects of daily pistachio consumption on the lipid/lipoprotein profile , glycemic control , markers of inflammation , and endothelial function in adults with type 2 diabetes . MATERIAL S/ METHODS We enrolled 30 adults ( 40 - 74 years ) with well-controlled type 2 diabetes ( mean glycated hemoglobin 6.2 % ) in a r and omized , crossover , controlled feeding study . After a 2-week run-in period , participants consumed nutritionally-adequate diets with pistachios ( contributing 20 % of total energy ) or without pistachios for 4 weeks each , separated by a 2-week washout . We assessed fasting lipids/lipoproteins , glycemic measures ( while fasted and during a 75 g oral glucose tolerance test ) , inflammatory markers , and endothelial function after each diet period . RESULTS Total cholesterol and the ratio of total to HDL cholesterol were significantly lower ( p<0.05 ) following the pistachio diet ( 4.00 mmol/L and 4.06 mmol/L , respectively ) compared to the control diet ( 4.15 mmol/L and 4.37 mmol/L , respectively ) . Triglycerides were significantly lower ( p=0.003 ) following the pistachio diet ( 1.56 mmol/L ) compared to the control diet ( 1.84 mmol/L ) . There were no treatment differences in fasting glucose and insulin , but fructosamine was significantly lower ( p=0.03 ) following the pistachio diet ( 228.5 μmol/l ) compared to the control diet ( 233.5 μmol/l ) . Inflammatory markers and endothelial function were unchanged . CONCLUSION Daily pistachio consumption can improve some cardiometabolic risk factors in adults with well-controlled type 2 diabetes . Our findings support recommendations that individuals with diabetes follow healthy dietary patterns that include nuts OBJECTIVE This study sought to identify the profile of circulating microRNAs ( miRNAs ) in type 2 diabetes ( T2D ) and its response to changes in insulin sensitivity . RESEARCH DESIGN AND METHODS The circulating miRNA profile was assessed in a pilot study of 12 men : 6 with normal glucose tolerance ( NGT ) and 6 T2D patients . The association of 10 circulating miRNAs with T2D was cross-sectionally vali date d in an extended sample of 45 NGT vs. 48 T2D subjects ( 65 nonobese and 28 obese men ) and longitudinally in 35 T2D patients who were recruited in a r and omized , double-blinded , and placebo-controlled 3-month trial of metformin treatment . Circulating miRNAs were also measured in seven healthy volunteers before and after a 6-h hyperinsulinemic-euglycemic clamp and insulin plus intralipid/heparin infusion . RESULTS Cross-sectional studies disclosed a marked increase of miR-140 - 5p , miR-142 - 3p , and miR-222 and decreased miR-423 - 5p , miR-125b , miR-192 , miR-195 , miR-130b , miR-532 - 5p , and miR-126 in T2D patients . Multiple linear regression analyses revealed that miR-140 - 5p and miR-423 - 5p contributed independently to explain 49.5 % ( P < 0.0001 ) of fasting glucose variance after controlling for confounders . A discriminant function of four miRNAs ( miR-140 - 5p , miR-423 - 5p , miR-195 , and miR-126 ) was specific for T2D with an accuracy of 89.2 % ( P < 0.0001 ) . Metformin ( but not placebo ) led to significant changes in circulating miR-192 ( 49.5 % ; P = 0.022 ) , miR-140 - 5p ( −15.8 % ; P = 0.004 ) , and miR-222 ( −47.2 % ; P = 0.03 ) , in parallel to decreased fasting glucose and HbA1c . Furthermore , while insulin infusion during clamp decreased miR-222 ( −62 % ; P = 0.002 ) , the intralipid/heparin mixture increased circulating miR-222 ( 163 % ; P = 0.015 ) and miR-140 - 5p ( 67.5 % ; P = 0.05 ) . CONCLUSIONS This study depicts the close association between variations in circulating miRNAs and T2D and their potential relevance in insulin sensitivity Numerous studies have shown that resveratrol ( RES ) exerts anti-inflammatory effects but human trials evidencing these effects in vivo are limited . Furthermore , the molecular mechanisms triggered in humans following the oral intake of RES are not yet understood . Therefore , the purpose of this study was to investigate the molecular changes in peripheral blood mononuclear cells ( P BMC s ) associated to the one-year daily intake of a RES enriched ( 8 mg ) grape extract ( GE-RES ) in hypertensive male patients with type 2 diabetes mellitus ( T2DM ) . We used microarrays and RT-PCR to analyze expression changes in genes and microRNAs ( miRs ) involved in the inflammatory response modulated by the consumption of GE-RES in comparison to a placebo and GE lacking RES . We also examined the changes in several serobiochemical variables , inflammatory and fibrinolytic markers . Our results showed that supplementation with GE or GE-RES did not affect body weight , blood pressure , glucose , HbA1c or lipids , beyond the values regulated by gold st and ard medication in these patients . We did not find either any significant change on serum inflammatory markers except for a significant reduction of ALP and IL-6 levels . The expression of the pro-inflammatory cytokines CCL3 , IL-1β and TNF-α was significantly reduced and that of the transcriptional repressor LRRFIP-1 increased in P BMC s from patients taking the GE-RES extract . Also , a group of miRs involved in the regulation of the inflammatory response : miR-21 , miR-181b , miR-663 , miR-30c2 , miR-155 and miR-34a were found to be highly correlated and altered in the group consuming the GE-RES for 12 months . Our results provide preliminary evidence that long-term supplementation with a grape extract containing RES downregulates the expression of key pro-inflammatory cytokines with the involvement of inflammation-related miRs in circulating immune cells of T2DM hypertensive medicated patients and support a beneficial immunomodulatory effect in these patients |
13,720 | 19,687,765 | However , VEGFC and vascular endothelial growth factor receptor 3 (VEGFR3)/flt-1 overexpression did not significantly correlate with survival in patients with NSCLC .
The data collected were not sufficient to determine the prognostic value of VEGF in patients with squamous cell lung carcinomas .
CONCLUSION VEGF overexpression indicates a poor prognosis for patients with NSCLC and SCLC ; VEGFC and VEGFR3/flt-1 overexpression was not significantly correlated with survival for patients with NSCLC | BACKGROUND Vascular endothelial growth factor ( VEGF ) has been implicated in tumorigenesis and metastasis , and it presumably mediates the proliferation of endothelial cells and promotes vascular permeability .
However , the prognostic value of VEGF overexpression in patients with lung cancer remains controversial . | We performed a clinical study to identify biological markers useful for the treatment of resectable non-small-cell lung cancers ( NSCLCs ) . In all , 173 patients were studied . By immunohistochemistry , we evaluated the Ki-67 proliferation index , tumour vascularity , thymidylate synthase ( TS ) , vascular endothelial growth factor (VEGF)-A , VEGF-C , and E (epithelial)-cadherin . Concerning the survival of NSCLC patients , tumour vascularity ( P<0.01 ) , VEGF-A status ( P=0.03 ) , VEGF-C status ( P=0.03 ) , and E-cadherin status ( P=0.03 ) were significant prognostic factors in patients with stage I NSCLCs . The Ki-67 proliferation index ( P=0.02 ) and TS status ( P<0.01 ) were significant prognostic factors in patients with stage II – III NSCLCs . In patients with stage II – III NSCLCs , furthermore , the survival of UFT ( a combination of tegafur and uracil)-treated patients with TS-negative tumours was significantly better than those of any other patients . Biological markers associated with tumour angiogenesis or metastasis are useful for the detection of aggressive tumours among early-stage NSCLCs . Postoperative chemotherapy might be necessary in such tumours even in stage I. In contrast , tumour proliferation rate and TS status are useful markers for identifying less aggressive tumours in locally advanced NSCLCs . Thymidylate synthase expression is also a useful marker to evaluate responsiveness of UFT-based chemotherapy for these tumours PURPOSE This study attempted to determine the prognostic value for survival of various pretreatment characteristics in patients with nonresectable non-small-cell lung cancer in the context of more than 10 years of experience of a European Cooperative Group . PATIENTS AND METHODS We included in the analysis all eligible patients ( N = 1,052 ) with advanced non-small-cell lung cancer registered onto one of seven trials conducted by the European Lung Cancer Working Party ( ELCWP ) during one decade . The patients were treated by chemotherapy regimens based on platinum derivatives . We prospect ively collected 23 variables and analyzed them by univariate and multivariate methods . RESULTS The global estimated median survival time was 29 weeks , with a 95 % confidence interval of 27 to 30 weeks . After univariate analysis , we applied two multivariate statistical techniques . In a Cox regression model , the selected explanatory variables were disease extent , Karnofsky performance status , WBC and neutrophil counts , metastatic involvement of skin , serum calcium level , age , and sex . These results were confirmed by application of recursive partitioning and amalgamation algorithms ( RECPAM ) , which led to classification of the patients into four homogeneous subgroups . CONCLUSION We confirmed by our analysis the role of well-known independent prognostic factors for survival , but also identified the effect of the neutrophil count , rarely studied , with the use of two methods : a classical Cox regression model and a RECPAM analysis . The classification of patients into the four subgroups we obtained needs to be vali date d in other series BACKGROUND Bevacizumab , a monoclonal antibody against vascular endothelial growth factor , has been shown to benefit patients with a variety of cancers . METHODS Between July 2001 and April 2004 , the Eastern Cooperative Oncology Group ( ECOG ) conducted a r and omized study in which 878 patients with recurrent or advanced non-small-cell lung cancer ( stage IIIB or IV ) were assigned to chemotherapy with paclitaxel and carboplatin alone ( 444 ) or paclitaxel and carboplatin plus bevacizumab ( 434 ) . Chemotherapy was administered every 3 weeks for six cycles , and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable . Patients with squamous-cell tumors , brain metastases , clinical ly significant hemoptysis , or inadequate organ function or performance status ( ECOG performance status , > 1 ) were excluded . The primary end point was overall survival . RESULTS The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab , as compared with 10.3 months in the chemotherapy-alone group ( hazard ratio for death , 0.79 ; P=0.003 ) . The median progression-free survival in the two groups was 6.2 and 4.5 months , respectively ( hazard ratio for disease progression , 0.66 ; P<0.001 ) , with corresponding response rates of 35 % and 15 % ( P<0.001 ) . Rates of clinical ly significant bleeding were 4.4 % and 0.7 % , respectively ( P<0.001 ) . There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group , including 5 from pulmonary hemorrhage . CONCLUSIONS The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths . ( Clinical Trials.gov number , NCT00021060 . Vascular endothelial growth factor ( VEGF ) is an important regulator of angiogenesis and vascular permeability . Increased serum VEGF concentrations ( S-VEGF ) have been found in patients with various types of human cancer , including cancer of the lung . However , the clinical and prognostic significance of S-VEGF in cancer is unknown . We measured S-VEGF , using enzyme-linked immunosorbent assay , in sera taken from 68 untreated patients with small-cell lung cancer ( SCLC ) at the time of diagnosis . The patients were treated with 6 cycles of cisplatin and etoposide , and were r and omly assigned to receive recombinant interferon , leukocyte interferon or neither . S-VEGF ranged from 70 to 1738 pg/ml ( mean , 527 pg/ml ) . The patients who achieved partial or complete response to treatment had lower pre-treatment S-VEGF than the non-responding patients ( p = 0.0083 , Mann-Whitney test ) . High ( > 527 pg/ml ) S-VEGF was associated with poor survival ( p = 0.012 , Log Rank Test ) , and all 3-year survivors had lower than mean pre-treatment S-VEGF . In a multivariate analysis , S-VEGF and stage were the only independent prognostic factors , and the estimated 3-year survival of the patients with limited stage disease and low pretreatment S-VEGF ( n = 17 , 25 % of all patients ) was 41 % ( p = 0.0055 , log rank test ) . These data show that high pretreatment S-VEGF is associated with poor response to treatment and unfavourable survival in patients with SCLC treated with combination chemotherapy with or without interferon 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 |
13,721 | 29,954,828 | There was no evidence of inconsistency detected between direct and indirect treatment comparisons in the networks , but sparse data led to frequently wide CIs .
Available evidence does not suggest that any of the commonly used treatments for the management of PHP are better than any other , although corticosteroid injections , alone or in combination with exercise , and ESWT were ranked most likely to be effective for the management of short-term , medium-term and long-term pain or function ; placebo/sham/control appeared least likely to be effective ; and exercise appeared to only be beneficial for long-term pain or function .
Conclusions Current evidence is equivocal regarding which treatment is the most effective for the management of PHP . | Objective To evaluate the comparative effectiveness of current treatment options for plantar heel pain ( PHP ) . | Technological change in general orthopaedics and its multiple subspecialisations is continual . These changes are regulated , to varying degrees , by delegated authorities within appropriately m and ated concepts . One relatively recent technology , since approximately 1990 , has been the revision of treating relatively deep seated urolithiasis , whether in the renal parenchyma or the ureter , to more superficial musculoskeletal indications . Although originally conceived to dissipate calcifications in rotator cuff tendinopathy and to alter osseous biology , the technology rapidly spread to other common disorders that affect the musculoskeletal system . Unfortunately many of these applications were not tested through appropriate r and omised clinical trials or practical clinical trials , which could adequately assess clinical efficacy and significant modification of the natural history of a given musculoskeletal disorder . Such studies are obviously in dem and by clinicians and healthcare provider organisations to justify the application of both a given treatment modality and the efficiency of a new drug or device to accomplish an end result that is personally satisfactory to the patient and doctor and economically justifiable to the healthcare insurer/provider . Background Plantar heel pain is one of the most common musculoskeletal disorders of the foot and ankle . Treatment of the condition is usually conservative , however the effectiveness of many treatments frequently used in clinical practice , including stretching , has not been established . We performed a participant-blinded r and omised trial to assess the effectiveness of calf muscle stretching , a commonly used short-term treatment for plantar heel pain . Methods Ninety-two participants with plantar heel pain were recruited from the general public between April and June 2005 . Participants were r and omly allocated to an intervention group that were prescribed calf muscle stretches and sham ultrasound ( n = 46 ) or a control group who received sham ultrasound alone ( n = 46 ) . The intervention period was two weeks . No participants were lost to follow-up . Primary outcome measures were ' first-step ' pain ( measured on a 100 mm Visual Analogue Scale ) and the Foot Health Status Question naire domains of foot pain , foot function and general foot health . Results Both treatment groups improved over the two week period of follow-up but there were no statistically significant differences in improvement between groups for any of the measured outcomes . For example , the mean improvement for ' first-step ' pain ( 0–100 mm ) was -19.8 mm in the stretching group and -13.2 mm in the control group ( adjusted mean difference between groups -7.9 mm ; 95 % CI -18.3 to 2.6 ) . For foot function ( 0–100 scale ) , the stretching group improved 16.2 points and the control group improved 8.3 points ( adjusted mean difference between groups 7.3 ; 95 % CI -0.1 to 14.8 ) . Ten participants in the stretching group experienced an adverse event , however most events were mild to moderate and short-lived . Conclusion When used for the short-term treatment of plantar heel pain , a two-week stretching program provides no statistically significant benefit in ' first-step ' pain , foot pain , foot function or general foot health compared to not stretching Plantar fasciitis is one of the most common causes of foot pain in adults . In this prospect i ve study , the outcomes of local tenoxicam injection and corticosteroid therapy for the treatment of plantar fasciitis were compared . Patients were r and omly assigned to either the tenoxicam or corticosteroid group . The tenoxicam group ( n=31 ) was treated using a local injection of 1 mL of tenoxicam ( 20 mg/2 mL ) and 1 mL of 2 % lidocaine , whereas the steroid group ( n=30 ) was treated with a local 1-mL injection containing 40 mg of methylprednisolone acetate and 1 mL of 2 % lidocaine . Clinical evaluations , which were performed before the injection and 6 and 12 months after the injection , consisted of patient-assessed pain using a visual analog scale . In addition , patient satisfaction was measured using the Roles and Maudsley score . Comparison of pre- and posttreatment visual analog scale scores demonstrated a statistically significant difference in both groups ( P<.05 ) . Furthermore , no significant difference was found between the steroid and tenoxicam groups in terms of visual analog scale scores measured 12 months after injection ( P>.05 ) . The tenoxicam injection was not significantly more effective than the corticosteroid injection . However , both methods were effective and successful in treating patients with plantar fasciitis . Tenoxicam therapy appears to provide pain relief , but its effectiveness in the long term should be explored in additional studies Background Plantar heel pain is a commonly occurring foot complaint . Stretching is frequently utilised as a treatment , yet a systematic review focusing only on its effectiveness has not been published . This review aim ed to assess the effectiveness of stretching on pain and function in people with plantar heel pain . Methods Medline , EMBASE , CINAHL , AMED , and The Cochrane Library were search ed from inception to July 2010 . Studies fulfilling the inclusion criteria were independently assessed , and their quality evaluated using the modified PEDro scale . Results Six studies including 365 symptomatic participants were included . Two compared stretching with a control , one study compared stretching to an alternative intervention , one study compared stretching to both alternative and control interventions , and two compared different stretching techniques and duration s. Quality rating on the modified Pedro scale varied from two to eight out of a maximum of ten points . The method ologies and interventions varied significantly between studies , making meta- analysis inappropriate . Most participants improved over the course of the studies , but when stretching was compared to alternative or control interventions , the changes only reached statistical significance in one study that used a combination of calf muscle stretches and plantar fascia stretches in their stretching programme . Another study comparing different stretching techniques , showed a statistically significant reduction in some aspects of pain in favour of plantar fascia stretching over calf stretches in the short term . Conclusions There were too few studies to assess whether stretching is effective compared to control or other interventions , for either pain or function . However , there is some evidence that plantar fascia stretching may be more effective than Achilles tendon stretching alone in the short-term . Appropriately powered r and omised controlled trials , utilizing vali date d outcome measures , blinded assessors and long-term follow up are needed to assess the efficacy of stretching Plantar fasciitis is a common cause of heel pain . It is a disabling disease in its chronic form . It is a degenerative tissue condition of the plantar fascia rather than an inflammation . Various treatment options are available , including nonsteroidal anti-inflammatory drugs , corticosteroid injections , orthosis , and physiotherapy . This study compared the effects of local platelet-rich plasma , corticosteroid , and placebo injections in the treatment of chronic plantar fasciitis . In this double-blind study , patients were divided r and omly into 3 groups . Local injections of platelet-rich plasma , corticosteroid , or normal saline were given . Patients were assessed with the visual analog scale for pain and with the American Orthopaedic Foot and Ankle Society ( AOFAS ) Ankle and Hindfoot score before injection , at 3 weeks , and at 3-month follow-up . Mean visual analog scale score in the platelet-rich plasma and corticosteroid groups decreased from 7.44 and 7.72 preinjection to 2.52 and 3.64 at final follow-up , respectively . Mean AOFAS score in the platelet-rich plasma and corticosteroid groups improved from 51.56 and 55.72 preinjection to 88.24 and 81.32 at final follow-up , respectively . There was a significant improvement in visual analog scale score and AOFAS score in the platelet-rich plasma and corticosteroid groups at 3 weeks and at 3-month follow-up . There was no significant improvement in visual analog scale score or AOFAS score in the placebo group at any stage of the study . The authors concluded that local injection of platelet-rich plasma or corticosteroid is an effective treatment option for chronic plantar fasciitis . Platelet-rich plasma injection is as effective as or more effective than corticosteroid injection in treating chronic plantar fasciitis Dear Editor-in-ChiefThe treatment of Plantar Fasciitis ( PF ) is primarily conservative , initially with rest and icing to give pain relief . In about 10 % of the cases who do not respond to such treatments , surgical intervention is suggested . An alternative to the surgical treatment of PF is Extracorporeal Shockwave Therapy - ESWT ( 1 , 2 ) . The aim of the study was to compare analgesic effects of ESWT and P-ESWT in males with chronic PF.Thirty patients were included in the study from September 2012 to October 2014 . The study was conducted in Military Hospital in Busko-Zdroj . Exclusion criteria were local soft-tissue infection , skin ulcerations , malignant disease , pacemaker , epileptic disorders , local arthritis , rheumatoid arthritis , ankylosing spondylitis , and Reiter syndrome , previous operation on the heel , patients who had received local corticosteroid injection within 12 weeks , age under 18 years . Patients were r and omized into the ESWT or PESWT group . R and omization was done before the first treatment by means of a computer-generated r and omization list ( MedCalc 11.4.3.0 , Kielce ) . In the ESWT group , patients received either 1000 or 2000 shock waves per treatment of energy levels varying between 0.02 mJ/mm2 and 0.33 mJ/mm2 , pulse frequency gradually increased to 240 per minute . In the P-ESWT , treatment consisted of 100 shock waves per treatment , energy level of 0.02 mJ/mm2 , frequency 60 per minute . Both groups took a series of 5 ESWT . Apparatus used for the treatment was BTL-5000 SWT . The procedure was performed in the area of most intense pain - calcaneal tubercle . The basic method of research was to evaluate pain after normal daily activity according to VAS . The patients of the two groups were tested pretreatment , and 12 months post treatment . In various combinations , the value of the function t was observed . The statistical significant of differences in the intensity of pain assessed was noticed ( PCalculations were performed at the Department of Computer Science at Holy Cross College in Kielce with the use of MedCalc software - version 11.4.3.0 . The research project was authorized by the Bioethics Committee at Holy Cross College in Kielce - resolutions of 1/10/KB on 20.06.2012.In the ESWT group and P-ESWT group , a significant decrease of VAS was seen 12 months post treatment after normal daily activity ( Table 1 ) . The analgesic efficacy of ESWT was confirmed by the analysis of differences in the frequency of occurrence of pain intensity between groups 12 months post treatment ( Table 2).Metzner et al. ( 3 ) used ESWT in patients with chronic PF.Each patient received 1000 impulses of shock wave ; the density of energy stream was 0.35 mJ/mm2 . It turned out that pain was reduced in 81 % of patients after 6 weeks , in 88 % of patients - after 16 months , and in 96 % of patients - after 72 months post ESWT . Objective : To investigate the effectiveness of a physiotherapy-based exercise program versus dexamethasone injection for chronic plantar fasciopathy in workers st and ing for prolonged periods of time . Design : A parallel group nonblinded r and omized controlled trial with 12-week follow-up . Setting : An outpatient sports medicine clinic in Vancouver , British Columbia , Canada . Participants : Fifty-six workers required to st and for greater than 5 h/d with chronic plantar fasciopathy took part . Diagnosis from a physiotherapist must include signs of structural changes to the plantar fascia seen on ultrasound . Interventions : The PHYSIO group included 7 physiotherapy-led exercises performed daily over a 12-week period . The INJECTION group received 1 palpation-guided dexamethasone injection followed by a daily routine of calf stretching . Main Outcome Measures : The Foot and Ankle Disability Index ( FADI ) scores 12-weeks postintervention and ultrasound-based measures of ligament appearance . Results : At follow-up , both groups reported significant improvements in FADI and visual analog scales for pain at work and with activities of daily living at 6 and 12 weeks compared with baseline scores ( P < 0.001 ) . There were no significant between-group differences . There were no significant changes to plantar fascia thickness reported at the 6- and 12-week follow-up point . Both the number of cases with focal anechoic areas and the size of these anechoic areas improved significantly in the PHYSIO ( P = 0.003 ) and INJECTION ( P < 0.001 ) groups at 12-week follow-up . Conclusions : Workers st and ing for prolonged periods experienced the same short-term therapeutic effectiveness with a physiotherapy-led exercise program compared with an injection of corticosteroid with stretching OBJECTIVE To explore the effect of extracorporeal shock wave therapy in patients with chronic plantar faciitis . METHODS The prospect i ve study was conducted at Department of Orhopaedic , Regional Hospital , Limerick , Irel and from January to December 2004 and comprised 70 heels in 62 patients with chronic plantar fasciitis in whom conventional conservative treatment consisting of non-steroidal anti-inflammatory drugs , heel cup , orthoses and /or shoe modifications , local steroid injections had failed , and they were treated with low energy extracorporeal shock wave therapy . Patients were review ed at 6 , 12 and 24 weeks post treatment . RESULTS At follow-up there was significant decrease in pain on the visual analogue scale ( p < 0.027 ) , with significant improvement in pain score ( p < 0.009 ) and in functional score ( p < 0.001 ) . The comfortable walking distance had increased significantly and there were no reported side effects . CONCLUSION Extracorporeal shock wave therapy is a new modality providing good pain relief and a satisfactory clinical outcome in patients with chronic plantar fasciitis Objective : To compare the effectiveness of different energy densities of extracorporeal shock wave therapy ( ESWT ) for managing chronic heel pain . Design : A r and omized clinical trial . Setting : Hospital-based practice . Subjects : Fifty-seven patients with chronic heel pain were recruited ; eight patients withdrew from the study . Interventions : Subjects were r and omized into three groups receiving : ( 1 ) a ‘ fixed ’ energy density , ( 2 ) ‘ maximum tolerable ’ energy density , or ( 3 ) control treatment once a week for three weeks . Outcome measures : Pain on palpation , pain on tension , maximum tolerable walking/st and ing duration and Foot Function Index were assessed before treatment in each treatment session and at the three-week follow-up . Results : By week 3 , the ‘ maximum tolerable ’ energy density group experienced a 66 % cumulative reduction in pain from tension , a 65 % reduction on palpation and a 112 % cumulative increase in maximum tolerable walking/st and ing duration . The ‘ fixed ’ energy density group experienced a 45 % cumulative reduction in pain from tension , a 32 % reduction in pain on palpation , and a 45 % increase in walking/st and ing tolerance . The ‘ maximum tolerable ’ energy density group also showed a significantly greater reduction in Foot Function Index scores than the other two groups . Therapeutic effects were maintained at least up to the three-week follow-up period . The control group had no significant changes in any outcome measures across time periods . Conclusion : The delivery of ESWT with a maximum tolerable energy density is a more effective treatment protocol than a fixed energy density in terms of relieving pain and restoring the functional activity of people suffering from chronic heel pain . The analgesic effects were maintained at least up to the three-week follow-up 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 We compared the long-term clinical and ultrasonographic effects of radial extracorporeal shockwave therapy ( rESWT ) versus ultrasound-guided corticosteroid injection treatment in patients with plantar fasciitis unresponsive to conservative therapy . METHODS Seventy-two patients with unilateral plantar fasciitis were r and omized to receive either rESWT ( three times once per week ) ( n = 36 ) or corticosteroid treatment ( a single 1-mL dose of betamethasone sodium plus 0.5 mL of prilocaine under ultrasound guidance by injection into the plantar fascia ) ( n = 36 ) . The primary outcome measures were visual analog scale ( VAS ) and Foot Function Index ( FFI ) scores . Secondary outcome measures included the heel tenderness index ( HTI ) score and plantar fascia thickness ( PFT ) as obtained by ultrasound examination . All of the assessment s were performed at baseline and 1 , 3 , and 6 months after treatment . RESULTS Significant improvements were observed in the rESWT group in VAS , HTI , and FFI scores and PFT at the end of treatment and were maintained during follow-up . Posttreatment improvements in VAS , HTI , and FFI scores and PFT were also seen in the corticosteroid group but were not maintained for VAS and FFI scores after the completion of therapy and were lost at 1 and 6 months , respectively . No serious treatment-related complications occurred . CONCLUSIONS Both rESWT and corticosteroid injection therapy are effective modalities for treatment of chronic plantar fasciitis . However , rESWT seems to be superior to corticosteroid injection therapy due to its longer duration of action OBJECTIVE To investigate the effectiveness of ultrasound guided corticosteroid injection in the treatment of plantar fasciitis . DESIGN R and omised , investigator and participant blinded , placebo controlled trial . SETTING University clinic in Melbourne , Australia . PARTICIPANTS 82 people with a clinical and ultrasound diagnosis of plantar fasciitis unrelated to systemic inflammatory disease . INTERVENTIONS Participants were r and omly allocated to ultrasound guided injection of the plantar fascia with either 1 mL of 4 mg/mL dexamethasone sodium phosphate ( experimental group ) or 1 mL normal saline ( placebo ) . Before injection the participants were given an ultrasound guided posterior tibial nerve block with 2 % lidocaine ( lignocaine ) . MAIN OUTCOME MEASURES Primary outcomes were pain , as measured by the foot health status question naire ( 0 - 100 point scale ) , and plantar fascia thickness , measured by ultrasound at 4 , 8 , and 12 weeks . RESULTS Reduction in pain at four weeks favoured the dexamethasone group by 10.9 points ( 95 % confidence interval 1.4 to 20.4 , P=0.03 ) . Between group differences for pain scores at eight and 12 weeks were not statistically significant . Plantar fascia thickness measured at four weeks favoured the dexamethasone group by -0.35 mm ( 95 % confidence interval -0.67 to -0.03 , P=0.03 ) . At eight and 12 weeks , between group differences for plantar fascia thickness also favoured dexamethasone , at -0.39 mm ( -0.73 to -0.05 , P=0.02 ) and -0.43 mm ( -0.85 to -0.01 , P=0.04 ) , respectively . The number needed to treat with dexamethasone for one successful outcome for pain at four weeks was 2.93 ( 95 % confidence interval 2.76 to 3.12 ) . There were no reported adverse events associated with the intervention . CONCLUSION A single ultrasound guided dexamethasone injection is a safe and effective short term treatment for plantar fasciitis . It provides greater pain relief than placebo at four weeks and reduces abnormal swelling of the plantar fascia for up to three months . However , clinicians offering this treatment should also note that significant pain relief did not continue beyond four weeks . TRIAL REGISTRATION Australian New Zeal and Clinical Trials Registry ACTRN12610000239066 OBJECTIVES To compare the effectiveness of a steroid injection ( 25 mg/ml prednisolone acetate ) with a local anaesthetic control in the treatment of heel pain and to determine any advantage for patients ' comfort of using a posterior tibial nerve block to anesthetize the heel prior to infiltration . METHODS A double-blind r and omized controlled trial using a 2 x 2 design in a hospital-based rheumatology clinic . Subjects comprised 106 patients with heel pain referred by general practitioners and other rheumatologists working in Camden and Islington Health Authority . MAIN OUTCOME MEASURES heel pain reduction at 1 , 3 and 6 months , and patient comfort at the time of injection . All outcomes were measured using a 10 cm visual analogue scale . RESULTS A statistically significant reduction in pain was detected at 1 month ( P=0.02 ) in favour of steroid injection , but thereafter no differences could be detected . Patient comfort was not significantly affected by anaesthesia of the heel ( P=0.5 ) . CONCLUSIONS A steroid injection can provide relief from heel pain in the short term . There appears to be no increase in patient comfort from anaesthetizing the heel prior to infiltration OBJECTIVE : To compare radial shockwave treatment with conventional physiotherapy for plantar fasciitis after 12 months of follow-up . METHOD : This was a r and omized , prospect i ve , comparative clinical study . Forty patients with a diagnosis of plantar fasciitis were divided r and omly into two treatment groups : group 1 , with 20 patients who underwent ten physiotherapy sessions comprising ultrasound , kinesiotherapy and guidance for home-based stretching ; and group 2 , with 20 patients who underwent three applications of radial shockwaves , once a week , and guidance for home-based stretching . All patients were assessed regarding pain and functional abilities before treatment , immediately after and 12 months after treatment . The mean age was 49.6±11.8 years ( range : 25 - 68 years ) , 85 % were female , 88 % were overweight , 63 % were affected bilaterally , and 83 % used analgesics regularly . RESULTS : At the 12-month follow-up , both treatments were effective for improving pain and functional ability among the patients with plantar fasciitis . The improvement with shockwaves was faster . CONCLUSION : Shockwave treatment was not more effective than conventional physiotherapy treatment 12 months after the end of the treatment The outcome of corticosteroid injection ( CSI ) and extracorporeal shock wave therapy ( ESWT ) as primary treatment of acute plantar fasciitis has been debated . The purpose of the present study was to evaluate and compare the therapeutic effects of CSI and ESWT in patients with acute ( < 6-week duration ) symptomatic plantar fasciitis . Of the 116 eligible patients , 68 were r and omized to 2 equal groups of 34 patients , each undergoing either ESWT or CSI . The ESWT method included 2000 impulses with energy of 0.15 mJ/mm(2 ) and a total energy flux density of 900 mJ/mm(2 ) for 3 consecutive sessions at 1-week intervals . In the CSI group , 40 mg of methyl prednisolone acetate plus 1 mL of lidocaine 2 % was injected into the maximal tenderness point at the inframedial calcaneal tuberosity . The success and recurrence rates and pain intensity measured using the visual analog scale , were recorded and compared at the 3-month follow-up visit . The pain intensity had reduced significantly in all patients undergoing either technique . However , the value and trend of pain reduction in the CSI group was significantly greater than those in the ESWT group ( p < .0001 ) . In the ESWT and CSI groups , 19 ( 55.9 % ) and 5 ( 14.7 % ) patients experienced treatment failure , respectively . Age , gender , body mass index , and recurrence rate were similar between the 2 groups ( p > .05 ) . Both ESWT and CSI can be used as the primary and /or initial treatment option for treating patients with acute plantar fasciitis ; however , the CSI technique had better therapeutic outcomes Background : This study compared the effectiveness of joint mobilization combined with stretching exercises ( JM&Str ) vs steroid injection ( SI ) in the treatment of plantar fasciitis ( PF ) . Methods : A total of 43 patients ( mean age , 45.5 ± 8.5 years ; range , 30 - 60 years ; 23 females ) with PF were r and omly assigned to receive either JM&Str ( n = 22 ) or SIs ( n = 21 ) . JM&Str was applied 3 times per week for 3 weeks for a total of 9 visits . The SI group received 1 injection at baseline . The patients ’ functional scores were assessed using the Foot and Ankle Ability Measure ( FAAM ) , and pain was evaluated using the Visual Analog Scale ( VAS ) . Outcomes of interest were captured at baseline and at 3-week , 6-week , 12-week , and 1-year follow-ups . The primary aim was examined using a mixed-model analysis of variance ( ANOVA ) . Pairwise comparisons were performed to examine differences between the baseline and follow-up periods using Bonferroni e quality at an alpha level of 0.05 . Results : Age , sex , body mass index , and dorsiflexion range of motion did not significantly impact pain relief or functional outcome ( P > .05 ) at the 3- , 6- or 12-week follow-ups compared to baseline . Planned pairwise comparisons demonstrated significant improvements in pain relief and functional outcomes in both groups ( P < .05 ) at the 3- , 6- , and 12-week follow-ups compared to baseline . However , at the 12-week and 1-year follow-ups , pain and functional outcomes were significantly improved in only the JM&Str group ( P = .002 ) . The overall group-by-time interaction was statistically significant for both FAAM ( P = .001 ; F = 7.0 ) and VAS ( P = .001 ; F = 8.3 ) scores . Between-group differences favored the SI group at the 3-week ( P = .001 , P = .001 ) , 6-week ( P = .002 , P = .001 ) , and 12-week ( P = .008 , P = .001 ) follow-ups for pain relief and functional outcomes . However , no significant differences ( P = .62 , P = .57 ) were detected in the measured outcomes at the 1-year follow-up . Conclusion : Our study demonstrated that while both groups achieved significant improvements at the 3- , 6- , and 12-week follow-ups , the SI group exhibited better outcomes at all 3 time points . The noted improvements continued in only the JM&Str group for a period of time ranging from 12 weeks to 1 year . Level of Evidence : Level II , comparative study BACKGROUND Plantar fasciitis is one of the most common foot complaints . It is often treated with foot orthoses ; however , studies of the effects of orthoses are generally of poor quality , and to our knowledge , no trials have investigated long-term effectiveness . The aim of this trial was to evaluate the short- and long-term effectiveness of foot orthoses in the treatment of plantar fasciitis . METHODS A pragmatic , participant-blinded , r and omized trial was conducted from April 1999 to July 2001 . The duration of follow-up for each participant was 12 months . One hundred and thirty-five participants with plantar fasciitis from the local community were recruited to a university-based clinic and were r and omly allocated to receive a sham orthosis ( soft , thin foam ) , a prefabricated orthosis ( firm foam ) , or a customized orthosis ( semirigid plastic ) . RESULTS After 3 months of treatment , estimates of effects on pain and function favored the prefabricated and customized orthoses over the sham orthoses , although only the effects on function were statistically significant . Compared with sham orthoses , the mean pain score ( scale , 0 - 100 ) was 8.7 points better for the prefabricated orthoses ( 95 % confidence interval , -0.1 to 17.6 ; P = .05 ) and 7.4 points better for the customized orthoses ( 95 % confidence interval , -1.4 to 16.2 ; P = .10 ) . Compared with sham orthoses , the mean function score ( scale , 0 - 100 ) was 8.4 points better for the prefabricated orthoses ( 95 % confidence interval , 1.0 - 15.8 ; P = .03 ) and 7.5 points better for the customized orthoses ( 95 % confidence interval , 0.3 - 14.7 ; P = .04 ) . There were no significant effects on primary outcomes at the 12-month review . CONCLUSIONS Foot orthoses produce small short-term benefits in function and may also produce small reductions in pain for people with plantar fasciitis , but they do not have long-term beneficial effects compared with a sham device . The customized and prefabricated orthoses used in this trial have similar effectiveness in the treatment of plantar fasciitis Background and Aim : Results of previous studies have been conflicting on the efficacy of extracorporeal shock wave therapy ( ESWT ) in the treatment of plantar fasciitis . We evaluated the effects of ESWT on plantar fasciitis in terms of ultrasonographic and subjective evaluations . Material s and Methods : In this r and omized placebo-controlled trial , patients with plantar fasciitis were assigned to receive ESWT ( 4000 shock waves/session of 0.2 mJ/mm2 ) in 3 sessions at weekly intervals ) or sham therapy ( n = 20 in each group ) . Outcomes were documented by the ultrasonographic appearance of the aponeurosis and by patients ’ pain scores , performed at baseline and 12 weeks after completion of the therapy . Results : The two groups were similar in baseline characteristics . Over the study period , plantar fascia thickness significantly reduced in the ESWT group ( 4.1 ± 1.3 to 3.6 ± 1.2 mm , P < 0.001 ) , but slightly increased in the sham group ( 4.1 ± 0.8 to 4.5 ± 0.9 mm , P = 0.03 ) . Both groups showed significant pain improvement over the course of the study ( P < 0.001 ) , though pain scores were significantly more reduced in the ESWT than the sham group ( -4.2 ± 2.9 vs. -2.7 ± 1.8 , P = 0.049 ) . Conclusions : Extracorporeal shock wave therapy contributes to healing and pain reduction in plantar fasciitis and ultrasound imaging is able to depict the morphologic changes related to plantar fasciitis as a result of this therapy Numerous r and omized controlled trials ( RCTs ) demonstrated efficacy and safety of extracorporeal shock wave therapy ( ESWT ) for chronic plantar fasciopathy ( cPF ) . However , only two such RCTs investigated a follow-up period of more than 1 year , both applying focused ESWT . Corresponding data for radial ESWT ( rESWT ) have not yet been reported . We therefore tested the hypothesis that rESWT is effective and safe for the management of cPF with long-term follow-up of 2 years . To this end n = 50 patients with cPF were r and omly allocated to either two sessions of rESWT ( one session per week ; 2,000 shock waves with energy flux density of 0.16 mJ/mm2 per session ) ( n = 25 ) or to placebo treatment ( n = 25 ) . Evaluation was by change in Visual Analog Scale ( VAS ) score and Roles and Maudsley ( RM ) score . Mean pretreatment VAS scores for the rESWT and placebo groups were 8.5 and 8.9 , respectively . 1 , 3 , 6 , 12 , and 24 months after treatment , the mean VAS scores for the rESWT and placebo groups were 0.6 , 1.1 , 0.5 , 2.3 , and 1.4 and 7.6 , 7.7 , 7.4 , 6.9 , and 5.6 ( p < 0.001 ) , respectively . Differences in mean RM scores were statistically significant between groups at 1 , 3 , 6 , 12 , and 24 months post treatment , but not at baseline . There were no significant complications . These data indicate that rESWT is effective and safe for the management of cPF with long-term follow-up of 2 years . © 2016 Orthopaedic Research Society . Published by Wiley Periodicals , Inc. J Orthop Res 35:1532 - 1538 , 2017 CONTEXT Extracorporeal shock wave therapy ( ESWT ) is increasingly used for plantar fasciitis , but limited evidence supports its use . OBJECTIVE To determine whether ultrasound-guided ESWT reduces pain and improves function in patients with plantar fasciitis . DESIGN Double-blind , r and omized , placebo-controlled trial conducted between April 1999 and June 2001 . SETTING Participants were recruited from the community-based referring physicians ( primary care physicians , rheumatologists , orthopedic surgeons , and sports physicians ) of a radiology group in Melbourne , Australia . PARTICIPANTS We screened 178 patients and enrolled 166 ; 160 completed the 15-week protocol . Entry criteria included age at least 18 years with plantar fasciitis , defined as heel pain maximal over the plantar aspect of the foot of at least 6 weeks ' duration , and an ultrasound-confirmed lesion , defined as thickening of the origin of the plantar fascia of at least 4 mm , hypoechogenicity , and alterations in the normal fibrillary pattern . INTERVENTIONS Patients were r and omly assigned to receive either ultrasound-guided ESWT given weekly for 3 weeks to a total dose of at least 1000 mJ/mm(2 ) ( n = 81 ) , or identical placebo to a total dose of 6.0 mJ/mm(2 ) ( n = 85 ) . MAIN OUTCOME MEASURES Overall , morning , and activity pain , measured on a visual analog scale ; Maryl and Foot Score ; walking ability ; Short-Form-36 Health Survey ( SF-36 ) score ; and Problem Elicitation Technique score , measured at 6 and 12 weeks after treatment completion . RESULTS At 6 and 12 weeks , there were significant improvements in overall pain in both the active group and placebo group ( mean [ SD ] improvement , 18.1 [ 30.6 ] and 19.8 [ 33.7 ] at 6 weeks [ P = .74 for between-group difference ] , and 26.3 [ 34.8 ] and 25.7 [ 34.9 ] at 12 weeks [ P = .99 ] , respectively ) . Similar improvements in both groups were also observed for morning and activity pain , walking ability , Maryl and Foot Score , Problem Elicitation Technique , and SF-36 . There were no statistically significant differences in the degree of improvement between treatment groups for any measured outcomes . CONCLUSION We found no evidence to support a beneficial effect on pain , function , and quality of life of ultrasound-guided ESWT over placebo in patients with ultrasound-proven plantar fasciitis 6 and 12 weeks following treatment BACKGROUND Evaluation of the effectiveness of three different types of prefabricated foot orthotics in the treatment of plantar fasciitis . METHODS Prospect i ve , r and omized head-to-head trial in 30 adults ( 21 women , 9 men ) with plantar fasciitis without any anatomic alterations . Three different prefabricated orthotics were tested ( thin , non supportive orthotic ( NO ) ; soft supportive foam orthotic ( FO ) ; foam covered rigid self-supporting plastic orthotic ( PO ) ) . The follow up was 3 weeks . Main outcome measures were maximum and average pain ( VAS ) , duration of pain per day , walking distance and subjective comfort . RESULTS There was no significant effect of NO on maximal pain and average pain . FO and PO had a significant effect on pain levels ( p<0.05 ) whereas PO was superior concerning pain reduction and the time until the onset of effect ( p<0.05 ) . CONCLUSIONS PO are superior regarding pain reduction and pain free time when compared to FO . NO did not demonstrate a significant effect in the test setup used Despite numerous publications and clinical trials , the results of treatment of recalcitrant chronic plantar fasciitis with extracorporeal shockwave therapy ( ESWT ) still remain equivocal as to whether or not this treatment provides relief from the pain associated with this condition . The objective of this study was to determine whether extracorporeal shock wave therapy can safely and effectively relieve the pain associated with chronic plantar fasciitis compared to placebo treatment , as demonstrated by pain with walking in the morning . This was set in a multicenter , r and omized , placebo-controlled , double-blind , confirmatory clinical study undertaken in four outpatient orthopedic clinics . The patients , 114 adult subjects with chronic plantar fasciitis , recalcitrant to conservative therapies for at least 6 months , were r and omized to two groups . Treatment consisted of approximately 3,800 total shock waves ( + /-10 ) reaching an approximated total energy delivery of 1,300 mJ/mm(2 ) ( ED+ ) in a single session versus placebo treatment . This study demonstrated a statistically significant difference between treatment groups in the change from baseline to 3 months in the primary efficacy outcome of pain during the first few minutes of walking measured by a visual analog scale . There was also a statistically significant difference between treatments in the number of participants whose changes in Visual Analog Scale scores met the study definition of success at both 6 weeks and 3 months posttreatment ; and between treatment groups in the change from baseline to 3 months posttreatment in the Roles and Maudsley Score . The results of this study confirm that ESWT administered with the Dornier Epos Ultra is a safe and effective treatment for recalcitrant plantar fasciitis Background Plantar fasciitis is a common cause of heel pain . The aim of this study was twofold : to compare steroid injection with placebo injection and to compare ultrasound guided with unguided steroid injection in the management of this condition . Methods 65 patients with inferior heel pain were recruited between November 2008 and June 2011 . Heel pain was measured using a visual analogue scale ( VAS ) at baseline and follow-up 6 and 12 weeks after injection . Results 22 patients were r and omised to ultrasound guided steroid injection , 21 patients to palpation guided steroid injection and 22 to ultrasound guided placebo injection . There was a significant difference in VAS scores between the groups at 6 and 12 weeks ( p=0.018 and p=0.004 , respectively ) . There was a 19.7 ( 95 % CI 2.5 to 37.0 ) difference in mean VAS scores at 6 weeks between the ultrasound guided steroid group and the placebo group and a 24.0 ( 95 % CI 6.6 to 41.3 ) difference between the unguided steroid group and the placebo group at 6 weeks . At 12 weeks , the mean difference was 25.1 ( 95 % CI 6.5 to 43.6 ) and 28.4 ( 95 % CI 11.1 to 45.7 ) respectively between both steroid injection groups and the placebo group . There was no difference in VAS scores following steroid injection between the ultrasound guided and the unguided groups at either time point . Plantar fascia thickness was significantly reduced after injection in both active treatment groups ( p=0.00 ) . Conclusions In this study , steroid injection showed a clear benefit over placebo at 6 weeks and this difference was maintained at 12 weeks . Trial Registration No IS RCT N79628180 ( www.controlled-trials.com ) OBJECTIVE To observe the therapeutic effect of extracorporeal shock wave combined with orthopaedic insole on plantar fasciitis . METHODS A total of 153 plantar with plantar fasciitis were r and omly divided into a combined group ( n=51 ) , an extracorporeal shock wave group ( n=53 ) and an orthopaedic group ( n=49 ) . The combined group received treatment of both extracorporeal shock wave and orthopaedic insole while the extracorporeal shock wave or the orthopaedic group only received the treatment of extracorporeal shock wave or orthopaedic insole . The therapeutic parameters such as visual analogue scale ( VAS ) scores , continued walking time and thickness of the plantar fascia were monitored before and aft er the treatment for 2 weeks , 1 month and 3 months , respectively . RESULTS The VAS scores in the 3 groups were all reduced after the treatment compared with the corresponding scores before the therapy ( P < 0.05 ) . The VAS score in the extracorporeal shock wave group was greater than that in the orthopedic group after the treatment for 2 weeks . The VAS score in the combined group was smaller than that in the orthopedic group after the treatment for 2 weeks and 3 months ( P < 0.05 ) . The VAS scores in the orthopedic group and the combined group were smaller than those in the extracorporeal shock wave group after the treatment for 1 month or 3 months ( P < 0.05 ) . The continued walking time and thickness of the plantar fascia was improved after the treatment ( P < 0.05 ) . The cure rate and total effective rate in the combination group were obviously greater than those in the two other groups . The cure rate in the orthopedic group was greater than that in the extracorporeal shock wave group ( P < 0.05 ) . CONCLUSION Extracorporeal shock wave combined with orthopaedic insole therapy is an effective method to treat plantar fasciitis . It is recommended to spread in clinic Background : Recent articles have reported success with repeated low-energy shock wave application for treatment of chronic plantar fasciitis in runners . Hypothesis : Shock wave treatment for chronic plantar fasciitis is safe and effective . Study Design : Prospect i ve , r and omized , placebo-controlled trial . Methods : Forty-five running athletes with intractable plantar heel pain for more than 12 months were enrolled ; half were assigned to a treatment group that received three applications of 2100 impulses of low-energy shock waves , and half received sham treatment . Follow-up examinations were performed at 6 months and at 1 year by a blinded observer . Results : After 6 months , self- assessment of pain on first walking in the morning was significantly reduced from an average of 6.9 to 2.1 points on a visual analog scale in the treatment group and from an average of 7.0 to 4.7 points in the sham group . The mean difference between groups was 2.6 points . After 12 months , there was a further reduction of pain in both groups , to an average 1.5 points in the treatment group , and to 4.4 points in the sham group . Conclusion : Three treatments with 2100 impulses of low-energy shock waves were a safe and effective method for treatment of chronic plantar fasciitis in long-distance runners Background : Radial extracorporeal shock wave therapy ( RSWT ) has been previously demonstrated as an efficient treatment option for chronic plantar fasciitis ( PF ) when administered in three sessions . The present study tested the hypothesis that chronic PF can also be treated successfully with RSWT when only two treatment sessions are performed . Material s and Methods : A total of 50 patients with unilateral , chronic PF were r and omly assigned to either RSWT ( n = 25 ) or placebo treatment ( n = 25 ) . RSWT was applied in two sessions 1 week apart ( 2,000 impulses with energy flux density = 0.16 mJ/mm2 per session ) . Placebo treatment was performed with a clasp on the heel . Endpoints were changes in the Visual Analog Scale ( VAS ) score and the modified Roles & Maudsley ( RM ) score from baseline to 4 weeks , 12 weeks and 24 weeks followup . Results : Mean VAS scores were reduced after RSWT from 8.5 ± 0.3 ( mean ± SEM ) at baseline to 0.6 ± 1.5 at 4 weeks , 1.1 ± 0.3 at 12 weeks and 0.5 ± 0.1 at 24 weeks from baseline . Similar changes were found for mean RM scores from baseline after RSWT but were not observed after placebo treatment . Statistical analysis demonstrated that RSWT result ed in significantly reduced mean VAS scores and mean RM scores at all followup intervals compared to placebo treatment ( each with p < 0.001 ) . No serious adverse events of RSWT were observed . Conclusion : RSWT was successful in the treatment of chronic PF even when only two sessions with 2,000 impulses each were performed 1 week apart . Level of Evidence : I , Prospect i ve R and omized In order to evaluate the long-term results of patients treated conservatively for plantar heel pain , a telephone follow-up survey was conducted . After eliminating those patients with worker 's compensation-related complaints and those with documented inflammatory arthritides , data on 100 patients ( 58 females and 42 males ) were available for review . The average patient was 48 years old ( range 20–85 years ) . The average follow-up was 47 months ( 24–132 months ) . Clinical results were classified as good ( resolution of symptoms ) for 82 patients , fair ( continued symptoms but no limitation of activity or work ) for 15 patients , and poor ( continued symptoms limiting activity or changing work status ) in 3 patients . The average duration of symptoms before medical attention was sought was 6.1 , 18.9 , and 10 months for the three groups , respectively . The three patients with poor results all had bilateral complaints , but had no other obvious risk factors predictive of their poor result . Thirty-one patients stated that , even with the underst and ing that surgical treatment carries significant risk , they would have seriously considered it at the time medical attention was sought ; twenty-two of these patients eventually had resolution of symptoms . Although the treatment of heel pain can be frustrating due to its indolent course , a given patient with plantar fasciitis has a very good chance of complete resolution of symptoms . There is a higher risk for continued symptoms in overweight patients , patients with bilateral symptoms , and those who have symptoms for a prolonged period before seeking medical attention Background : Plantar fasciitis often leads to disability . Optimal treatment for this clinical condition is still unknown . Objective : To compare the effectiveness of wearing a full-length silicone insole with ultrasound-guided corticosteroid injection in the management of plantar fasciitis . Study design : R and omized clinical trial . Methods : Forty-two patients with chronic unilateral plantar fasciitis were allocated r and omly to have an ultrasound-guided corticosteroid injection or wear a full-length silicone insole . Data were collected before the procedure and 1 month after . The primary outcome measures included first-step heel pain via Visual Analogue Scale and Heel Tenderness Index . Other outcome measures were the Foot and Ankle Outcome Score and ultrasonographic thickness of the plantar fascia . Results : After 1 month , a significant improvement was shown in Visual Analogue Scale , Heel Tenderness Index , Foot and Ankle Outcome Score , and ultrasonographic thickness of plantar fascia in both groups . Visual Analogue Scale scores , Foot and Ankle Outcome Score pain , Foot and Ankle Outcome Score for activities of daily living , Foot and Ankle Outcome Score for sport and recreation function , and plantar fascia thickness were better in injection group than in insole group ( p < 0.05 ) . Conclusions : Although both ultrasound-guided corticosteroid injection and wearing a full-length silicone insole were effective in the conservative treatment of plantar fasciitis , we recommend the use of silicone insoles as a first line of treatment for persons with plantar fasciitis . Clinical relevance Silicone insole may be considered as a first-line treatment option in patients with plantar fasciitis Objective : To compare the efficacy of low-energy extracorporeal shock wave therapy ( ESWT ) and intralesional corticosteroid injection ( CSI ) for the treatment of plantar fasciopathy present for at least 6 weeks . Design : A prospect i ve , r and omized , controlled , observer-blinded study over a period of 12 months . Setting : Primary care and hospital setting . Patients : A total of 132 patients were enrolled in the study , and 125 completed the study . Nineteen nonr and omized patients acted as a surrogate control group . Interventions : All patients performed a st and ardized Achilles tendon and plantar fascia stretching program . The patients were r and omly allocated to either treatment group A or B. Group A received a single CSI , while group B were referred for a course of low-dose ESWT comprising 3 treatments over a period of 3 weeks . Group C consisted of 19 nonr and omized patients who performed the st and ardized stretching program only . Main Outcome Measurements : The worst daily pain recorded on a visual analogue scale ( VAS ) , and the tenderness at the plantar fascia insertion as determined by an algometer . These measures were recorded immediately prior to the commencement of treatment and 3 months and 12 months posttreatment . Results : With regard to VAS pain scores , values for the CSI ( 1.48 ; 0 - 7 ) were significantly lower than both ESWT ( 3.69 ; 0 - 8 ) , and controls ( 3.58 ; 2 - 5 ) at 3 months . At 12 months , VAS scores for CSI ( 0.84 ; 0 - 7 ) and ESWT ( 0.84 ; 0 - 4 ) were both significantly lower than controls ( 2.42 ; 1 - 4 ) . The tenderness values at 3 months were significantly higher for CSI ( 9.42 ; 7 - 11 ) than both ESWT ( 6.72 ; 4 - 11 ) and controls ( 7.63 ; 6 - 9 ) . P < 0.05 was used throughout . Conclusions : Corticosteroid injection is more efficacious and multiple times more cost-effective than ESWT in the treatment of plantar fasciopathy that has been symptomatic for more than 6 weeks OBJECTIVES Plantar fasciitis is a self-limiting condition , but can be painful and disabling . Among the different treatments which exist , corticosteroid injections are effective and popular . Extracorporeal shock wave therapy ( ESWT ) is another treatment modality used for resistant conditions . In this study , the authors evaluated the efficacy of radial ESWT versus corticosteroid injections in the treatment of chronic plantar fasciitis . DESIGN R and omized clinical trial . SETTING Physical medicine and rehabilitation research center in a university hospital . SUBJECTS Forty patients with plantar fasciitis who did not respond to conservative treatment . METHODS Patients were allocated to radial ESWT with 2000 shock waves/session of 0.2 mJ/mm(2 ) ( n = 20 ) or local methylprednisolone injections ( n = 20 ) . Pain in the morning and during the day based on a visual analog scale ( VAS ) , functional abilities using the foot function index ( FFI ) , and satisfaction were evaluated before treatment and at 4 and 8 weeks after treatment . RESULTS Patients ( average age : 42.1± 8.20 ) received five sessions of ESWT or single steroid injection . Changes in the VAS in morning and during the day and the FFI throughout the study period were significant in both groups ( P < 0.001 ) . ESWT group had a higher reduction in VAS in morning and better function in FFI , but these changes were insignificant statistically [ FFI decreased to 19.65 ± 21.26 points ( 67.4 % improvement ) in ESWT vs 31.50 ± 20.53 points ( 47.7 % ) in injection group at week 8 , P = 0.072 ) ] . Good or excellent results in the opinions of patients were achieved in 55 % of ESWT and 30 % of corticosteroid injection groups ( P = 0.11 ) . CONCLUSION Both interventions caused improvement in pain and functional ability 2 months after treatment . Although inter-group differences were not significant , the FFI was improved more with ESWT and patients were more satisfied with ESWT , thus shockwave therapy seems a safe alternative for management of chronic plantar fasciitis Objectives : To compare the effectiveness of oral nonsteroidal antiinflammatory drugs ( NSAIDs ) and locally injectable steroid ( methylprednisolone ) in the treatment of plantar fasciitis . Material s and Methods : One hundred and twenty subjects with unilateral plantar fasciitis were recruited and r and omly allocated to two study groups . Group I ( NSAIDs group ) ( n=60 ) received oral tablet diclofenac ( 50 mg ) and paracetamol ( 500 mg ) twice a day ( BD ) along with tab . ranitidine 150 mg BD . Group II ( injectable steroid group ) ( n=60 ) received injection of 1 ml of methylprednisolone ( Depomedrol ) ( 40 mg ) and 2 ml of 0.5 % bupivacaine into the inflammed plantar fascia . Pain intensity was measured using 10 cm visual analog scale ( VAS ) . Subjects were evaluated clinical ly before , and 1 week , 2 weeks , 4 weeks , and 8 weeks ( 2 months ) after the initiation of treatment in both the groups . The outcome was assessed in terms of VAS score and recurrence of the heel pain . Statistical Analysis Used : “ Z ” test and Chi-square test were used wherever applicable . Results : Pain relief was significant after steroid injection ( P<0.001 ) and the improvement was sustained . The recurrence of heel pain was significantly higher in the oral NSAIDS group ( P<0.001 ) . Conclusion : Local injection of steroid is more effective in the treatment of plantar fasciitis than oral NSAIDs Objective . To assess the effectiveness of total contact insoles ( TCI ) in patients with plantar fasciitis ( PF ) . Methods . A double-blind r and omized controlled trial was carried out with intention-to-treat analysis . Seventy-four patients were r and omly allocated to use a TCI made of ethylene vinyl acetate ( study group , n = 37 ) or a flat insole ( control group , n = 37 ) . The following assessment tools were used : visual analog scale for pain while walking and at rest , Medical Outcomes Study Short Form-36 ( SF-36 ) for quality of life , Foot Function Index and Foot Health Status Question naire for foot function , 6-min walk test ( 6MWT ) , and baropodometer FootWalk Pro for plantar pressure analysis . The groups were evaluated by a blinded assessor at baseline and after 45 , 90 , and 180 days . Results . The groups were homogeneous for the majority of variables at baseline . The over-time comparisons show a statistical difference between the groups for pain while walking ( p = 0.008 ) and the 6MWT ( p = 0.010 ) . Both groups showed significant improvements in pain at rest , foot function , and some quality of life variables ( physical functioning , bodily pain , vitality , and social functioning ) , with no significant statistical differences between them . The baropodometer recorded no changes from the use of the insoles . Conclusion . A TCI can be used to reduce pain while walking and to increase walking distance in individuals with PF |
13,722 | 29,205,264 | AUTHORS ' CONCLUSIONS There is no firm evidence that diet alone or physical activity alone compared to st and ard treatment influences the risk of T2DM and especially its associated complications in people at increased risk of developing T2DM .
However , diet plus physical activity reduces or delays the incidence of T2DM in people with IGT .
Data are lacking for the effect of diet plus physical activity for people with intermediate hyperglycaemia defined by other glycaemic variables . | BACKGROUND The projected rise in the incidence of type 2 diabetes mellitus ( T2DM ) could develop into a substantial health problem worldwide .
Whether diet , physical activity or both can prevent or delay T2DM and its associated complications in at-risk people is unknown .
OBJECTIVES To assess the effects of diet , physical activity or both on the prevention or delay of T2DM and its associated complications in people at increased risk of developing T2DM .
SEARCH METHODS This is an up date of the Cochrane Review published in 2008 . | Background Prevalence of type 2 diabetes ( T2D ) is increasing worldwide . T2D prevention by lifestyle intervention is effective . Pragmatic scalable interventions are needed , with evidence to efficiently target and monitor such interventions . We report pooled analyses of data from three European trial cohorts : to analyse T2D incidence , sustained weight loss and utility of risk predictors . Methods We analysed data on 749 adults with impaired glucose tolerance ( 278 men and 471 women , mean age 56 years , mean BMI 31 kgm−2 ) recruited between 1993 and 2003 , and r and omised to intensive lifestyle intervention ( I ) or lifestyle advice control ( C ) . The intervention aim ed to increase physical activity , modify diet , and promote weight loss≥5 % . Using Cox-regression survival analysis , we assessed T2D incidence and the impact on T2D incidence of sustained weight loss , and of baseline cut-point values of FINDRISC score , fasting plasma glucose ( FPG ) , and HbA1c . Results Mean follow-up duration was 3.1 years . T2D was diagnosed in 139 participants ( I = 45/379 , C = 94/370 ) . Cumulative T2D incidence was 57 % lower in the intervention compared with the control group ( HR 0.42 ( 95 % CI 0.29 to 0.60 ) P<0.001 ) . Participants with ≥5 % weight loss at one year had 65 % lower T2D incidence ( HR 0.35 ( 95 % CI 0.22 to 0.56 ) P<0.001 ) ; maintaining ≥5 % weight loss for two and three years further reduced T2D incidence . Recommended cut-points to identify those at high risk for T2D would have identified different proportions of European Diabetes Prevention Study ( EDIPS ) participants with similar hazard-ratios for intervention effect . Conclusions Pooled analysis of EDIPS trial data reinforces evidence for T2D prevention by lifestyle intervention . Analysis showed the preventive effect of ≥5 % weight loss , especially if maintained long term , which has utility for intervention monitoring . Analysis of proposed cut-points demonstrates difficulties in balancing risk and benefit , to efficiently target interventions and suggests evidence is needed to define clinical policy . Trial registration s The Finnish Diabetes Prevention study , Helsinki , Finl and : Clinical Trials.gov ; NCT00518167 The SLIM diabetes prevention study , Maastricht , The Netherl and s : Clinical Trials.gov ; NCT00381186 The EDIPS-Newcastle diabetes prevention study , Newcastle upon Tyne , UK : International St and ard R and omised Controlled Trial Number ; IS RCT N15670600 We examined self-determination theory ( SDT ) and weight loss , and hypothesized that the Diabetes Prevention Program ’s ( DPP ) intervention would result in an increase in autonomous regulation of motivation ( AR ) in participants . Further , that those with higher AR , and those who perceived educators as supporting SDT-defined needs , would lose more weight . Support , Health Information , Nutrition and Exercise ( SHINE ) Study data ( N = 257 ) were analyzed . SHINE was a r and omized , controlled DPP translation trial ( 2-years , telephonic , primary care staff ) . Autonomous motivation in males increased significantly , while females showed no change . Males with high AR , but not females , lost more weight . However , the significance of these relationships varied over time . Participants who perceived educators as more supportive of psychological needs lost more weight ( especially males ) . However , effect of support on weight loss was not mediated by AR change . Autonomous motivation and educator support are relevant to male weight loss . Future research might develop interventions to enhance autonomous motivation and educator support , and underst and change pathways Background The prevention of type 2 diabetes is a recognised health care priority globally . Within the United Kingdom , there is a lack of research investigating optimal methods of translating diabetes prevention programmes , based on the promotion of a healthy lifestyle , into routine primary care . This study aims to establish the behavioural and clinical effectiveness of a structured educational programme design ed to target perceptions and knowledge of diabetes risk and promote a healthily lifestyle , particularly increased walking activity , in a multi-ethnic population at a high risk of developing type 2 diabetes . Design Cluster r and omised controlled trial undertaken at the level of primary care practice s. Follow-up will be conducted at 12 , 24 and 36 months . The primary outcome is change in objective ly measured ambulatory activity . Secondary outcomes include progression to type 2 diabetes , biochemical variables ( including fasting glucose , 2-h glucose , HbA1c and lipids ) , anthropometric variables , quality of life and depression . Methods 10 primary care practice s will be recruited to the study ( 5 intervention , 5 control ) . Within each practice , individuals at high risk of impaired glucose regulation will be identified using an automated version of the Leicester Risk Assessment tool . Individuals scoring within the 90th percentile in each practice will be invited to take part in the study . Practice s will be assigned to either the control group ( advice leaflet ) or the intervention group , in which participants will be invited to attend a 3 hour structured educational programme design ed to promote physical activity and a healthy lifestyle . Participants in the intervention practice s will also be invited to attend annual group-based maintenance workshops and will receive telephone contact halfway between annual sessions . The study will run from 2010–2014 . Discussion This study will provide new evidence surrounding the long-term effectiveness of a diabetes prevention programme run within routine primary care in the United Kingdom . Trial Registration Clinical Trials . Gov identifier : Abstract Background Diabetes prevalence is increasing . The Finnish Diabetes Prevention Study ( DPS ) showed a 58 % reduction in Type 2 Diabetes ( T2D ) incidence in adults with impaired glucose tolerance ( IGT ) . The European Diabetes Prevention Study ( EDIPS ) extends the DPS to different European population s , using the same study design . In the Newcastle arm of this study ( EDIPS-Newcastle ) , we tested the hypothesis that T2D can be prevented by lifestyle intervention and explored secondary outcomes in relation to diabetes incidence . Methods We recruited 102 participants ( 42 men and 60 women , mean age 57 years , mean BMI 34 kgm-2 ) with IGT to EDIPS-Newcastle and r and omised to Intervention and usual care Control groups . The intervention included individual motivational interviewing aim ed at : weight reduction , increase in physical activity , fibre and carbohydrate intake and reduction of fat intake ( secondary outcomes ) . The primary outcome was diagnosis of T2D . Results Mean duration of follow-up was 3.1 years . T2D was diagnosed in 16 participants ( I = 5 , C = 11 ) . Absolute incidence of T2D was 32.7 per 1000 person-years in the Intervention-group and 67.1 per 1000 person-years in the Control-group . The overall incidence of diabetes was reduced by 55 % in the Intervention-group , compared with the Control-group : RR 0.45 ( 95%CI 0.2 to 1.2).Explanatory survival analysis of secondary outcomes showed that those who sustained beneficial changes for two or more years reduced their risk of developing T2D . Conclusion Our results are consistent with other diabetes prevention trials . This study was design ed as part of a larger study and although the sample size limits statistical significance , the results contribute to the evidence that T2D can be prevented by lifestyle changes in adults with IGT . In explanatory analysis small sustained beneficial changes in weight , physical activity or dietary factors were associated with reduction in T2D incidence . Trial Registration International St and ard R and omised Controlled Trial Number registry ( IS RCT N)Registry number : IS RCT N 15670600 http://www.controlled-trials.com/is rct n/ search .html?srch=15670600%26sort=3%26dir = OBJECTIVE —In participants of the Diabetes Prevention Program ( DPP ) r and omized to intensive lifestyle modification ( ILS ) , meeting ILS goals strongly correlated with prevention of diabetes in the group as a whole . Men met significantly more ILS goals than women but had a similar incidence of diabetes . Therefore , we explored sex differences in risk factors for diabetes and the effect of ILS on risk factors . RESEARCH DESIGN AND METHODS —Baseline risk factors for diabetes and percent change in risk factors over the first year in men versus women were compared using Wilcoxon 's rank-sum tests . RESULTS —At baseline , men were older and had a larger waist circumference ; higher fasting plasma glucose concentration , caloric intake , and blood pressure ; and lower HDL cholesterol and corrected insulin response than women , who were less physically active and had a higher BMI ( P < 0.01 for all comparisons ) . Over the first year of the DPP , no sex difference in risk factors for diabetes was observed for those who lost <3 % body weight . Weight loss of 3–7 % body weight yielded greater decreases in 2-h glucose ( P < 0.01 ) , insulin concentration ( P < 0.04 ) , and insulin resistance ( P < 0.03 ) in men than in women . Weight loss of > 7 % body weight result ed in greater decreases in 2-h glucose ( P < 0.01 ) , triglyceride level ( P < 0.01 ) , and A1C ( P < 0.03 ) in men than in women . CONCLUSIONS —Weight loss > 3 % body weight yielded greater reduction in risk factors for diabetes in men than in women . Despite the more favorable effects of ILS in men , baseline risk factors were more numerous in men and likely obscured any sex difference in incident diabetes Background Mobile technologies for health ( mHealth ) represent a promising strategy for reducing type 2 diabetes ( T2DM ) risk . The PROPELS trial investigates whether structured group-based education alone or supplemented with a follow-on support program combining self-monitoring with pedometers and tailored text-messaging is effective in promoting and maintaining physical activity among people at high risk of T2DM . Objective This paper describes the iterative development of the PROPELS follow-on support program and presents evidence on its acceptability and feasibility . Methods We used a modified mHealth development framework with four phases : ( 1 ) conceptualization of the follow-on support program using theory and evidence , ( 2 ) formative research including focus groups ( n=15 , ages 39 - 79 years ) , ( 3 ) pre-testing focus groups using a think aloud protocol ( n=20 , ages 52 - 78 years ) , and ( 4 ) piloting ( n=11 ) . Analysis was informed by the constant comparative approach , with findings from each phase informing subsequent phases . Results The first three phases informed the structure , nature , and content of the follow-on support program , including the frequency of text messages , the need for tailored content and two-way interaction , the importance of motivational messages based on encouragement and reinforcement of affective benefits ( eg , enjoyment ) with minimal messages about weight and T2DM risk , and the need for appropriate language . The refined program is personalized and tailored to the individual ’s perceived confidence , previous activity levels , and physical activity goals . The pilot phase indicated that the program appeared to fit well with everyday routines and was easy to use by older adults . Conclusions We developed a feasible and innovative text messaging and pedometer program based on evidence and behavior change theory and grounded in the experiences , views , and needs of people at high diabetes risk . A large scale trial is testing the effectiveness of this 4-year program over and above structured group education alone . Trial Registration International St and ard R and omized Controlled Trial Number ( IS RCT N ) : 83465245 ; http://www.controlled-trials.com/IS RCT N83465245/83465245 ( Archived by WebCite at http://www.webcitation.org/6dfSmrVAe Background Lifestyle modifications are considered the most effective means of delaying or preventing the development of type 2 diabetes ( T2DM ) . To contain the growing population of T2DM , it is critical to clarify effective and efficient setting s for intervention and modalities for intervention delivery with a wide population reach . The Japan Diabetes Outcome Intervention Trial-1 ( J-DOIT1 ) is a cluster r and omized controlled trial to test whether goal -focused lifestyle coaching delivered by telephone can prevent the development of T2DM in high-risk individuals in a real-world setting . This paper describes the study design and recruitment of the study subjects . Methods For the recruitment of study subjects and their follow-up annually over 3 years , we employed health checkups conducted annually at communities and worksites . Health care divisions recruited from communities and companies across Japan formed groups as a cluster r and omization unit . C and i date s for the study , aged 20 - 65 years with fasting plasma glucose ( FPG ) of 5.6 - 6.9 mmol/l , were recruited from each group using health checkups results in 2006 . Goal -focused lifestyle support is delivered by healthcare providers via telephone over a one-year period . Study subjects will be followed-up for three years by annual health checkups . Primary outcome is the development of diabetes defined as FPG≥7.0 mmol/l on annual health checkup or based on self-report , which is confirmed by referring to medical cards . Results Forty-three groups ( clusters ) , formed from 17 health care divisions , were r and omly assigned to an intervention arm ( 22 groups ) or control arm ( 21 clusters ) between March 2007 and February 2008 . A total of 2840 participants , 1336 from the intervention and 1504 from the control arm , were recruited . Consent rate was about 20 % , with no difference between the intervention and control arms . There were no differences in cluster size and characteristics of cluster between the groups . There were no differences in individual characteristics between the study arms . Conclusion We have launched J-DOIT1 , a nation-wide trial to prevent the development of T2DM in high-risk individuals using telephone-delivered intervention . This trial is expected to contribute to evidence -based real-world preventive practice s . Trial registration UMIN000000662 Background The prevention of type 2 diabetes is recognised as a health care priority . Lifestyle change has proven effective at reducing the risk of type 2 diabetes , but limitations in the current evidence have been identified in : the promotion of physical activity ; availability of interventions that are suitable for commissioning and implementation ; availability of evidence -based interventions using new technologies ; and physical activity promotion among ethnic minorities . We aim to investigate whether a structured education programme with differing levels of ongoing support , including text-messaging , can increase physical activity over a 4 year period in a multi-ethnic population at high risk of diabetes . Methods / Design A multi-centre r and omised controlled trial , with follow-up at 12 and 48 months . The primary outcome is change in ambulatory activity at 48 months . Secondary outcomes include changes to markers of metabolic , cardiovascular , anthropometric and psychological health along with cost-effectiveness . Participants aged 40–74 years for White European , or 25–74 years for South Asians , with an HbA1c value of between 6.0 and < 6.4 % ( 42 and 47 mmol/mol ) or with a previously recorded plasma glucose level or HbA1c value within the high risk ( prediabetes ) range within the last five years , are invited to take part in the trial . Participants are identified through primary care , using an automated diabetes risk score within their practice data base , or from a data base of previous research participants . Participants are r and omly assigned to either : 1 ) the control group who receive a detailed advice leaflet ; 2 ) the Walking Away group , who receive the same leaflet and attend a 3 hour structured education programme with annual maintenance sessions delivered in groups ; or 3 ) the Walking Away Plus group , who receive the leaflet , attend the structured education programme with annual maintenance sessions , plus receive follow-on support through highly-tailored text-messaging and telephone calls to help to aid pedometer use and behaviour change . Discussion This study will provide new evidence for the long-term effectiveness of a structured education programme focused on physical activity , conducted within routine care in a multi-ethnic population in the UK . It will also investigate the impact of different levels of ongoing support and the cost-effectiveness of each intervention . Trial registration IS RCT N83465245 Trial registration date : OBJECTIVE Changing dietary and physical activity habits has the potential to postpone or prevent the development of type 2 diabetes . However , it needs to be assessed whether moderate interventions , in agreement with current guidelines for the general population , are effective . We evaluated the impact of a 2-year combined diet and physical activity intervention program on glucose tolerance in Dutch subjects at increased risk for developing diabetes . RESEARCH METHODS AND PROCEDURES Subjects with glucose intolerance were r and omly assigned to either the lifestyle intervention group ( INT ) or control group ( CON ) . The INT received regular dietary advice and was stimulated to increase their physical activity . The CON received a brief leaflet about healthy diet and increased physical activity . Primary outcome measure was the change in glucose tolerance . RESULTS In total , 88 subjects completed 2 years of intervention ( 40 subjects in the INT , 48 subjects in the CON , mean BMI 29.4 kg/m2 ) . Subjects in the INT reduced their body weight , waist circumference , and ( saturated ) fat intake and improved their aerobic capacity . Two-hour plasma glucose concentration declined from 8.7 to 8.0 mM in the INT and rose from 8.6 to 9.4 mM in the CON ( p < 0.01 ) . Subjects adherent to both the diet and exercise intervention showed the largest reduction in 2-hour glucose levels . DISCUSSION Our results showed that a lifestyle intervention program according to general recommendations improves glucose tolerance , even in a less obese and more physical active population . Furthermore , our results underscore the importance of combining diet and physical activity to improve glucose tolerance and insulin resistance Objective To examine the prevalence of outcome reporting bias — the selection for publication of a subset of the original recorded outcome variables on the basis of the results — and its impact on Cochrane review s. Design A nine point classification system for missing outcome data in r and omised trials was developed and applied to the trials assessed in a large , unselected cohort of Cochrane systematic review s. Research ers who conducted the trials were contacted and the reason sought for the non-reporting of data . A sensitivity analysis was undertaken to assess the impact of outcome reporting bias on review s that included a single meta- analysis of the review primary outcome . Results More than half ( 157/283 ( 55 % ) ) the review s did not include full data for the review primary outcome of interest from all eligible trials . The median amount of review outcome data missing for any reason was 10 % , whereas 50 % or more of the potential data were missing in 70 ( 25 % ) review s. It was clear from the publications for 155 ( 6 % ) of the 2486 assessable trials that the research ers had measured and analysed the review primary outcome but did not report or only partially reported the results . For reports that did not mention the review primary outcome , our classification regarding the presence of outcome reporting bias was shown to have a sensitivity of 88 % ( 95 % CI 65 % to 100 % ) and specificity of 80 % ( 95 % CI 69 % to 90 % ) on the basis of responses from 62 trialists . A third of Cochrane review s ( 96/283 ( 34 % ) ) contained at least one trial with high suspicion of outcome reporting bias for the review primary outcome . In a sensitivity analysis undertaken for 81 review s with a single meta- analysis of the primary outcome of interest , the treatment effect estimate was reduced by 20 % or more in 19 ( 23 % ) . Of the 42 meta-analyses with a statistically significant result only , eight ( 19 % ) became non-significant after adjustment for outcome reporting bias and 11 ( 26 % ) would have overestimated the treatment effect by 20 % or more . Conclusions Outcome reporting bias is an under-recognised problem that affects the conclusions in a substantial proportion of Cochrane review s. Individuals conducting systematic review s need to address explicitly the issue of missing outcome data for their review to be considered a reliable source of evidence . Extra care is required during data extraction , review ers should identify when a trial reports that an outcome was measured but no results were reported or events observed , and contact with trialists should be encouraged Purpose The purpose of this study is to assess if diagnosis of type 2 diabetes affected health-related quality of life ( HRQoL ) among participants in the Diabetes Prevention Program/Diabetes Prevention Program Outcome Study and changes with treatment or diabetes duration . Methods 3,210 participants with pre-diabetes were r and omized to metformin ( MET ) , intensive lifestyle intervention ( ILS ) , or placebo ( PLB ) . HRQoL was assessed using the SF-36 including : ( 1 ) 8 SF-36 subscales ; ( 2 ) the physical component ( PCS ) and mental component summary ( MCS ) scores ; and ( 3 ) the SF-6D . The sample was categorized by diabetes free versus diagnosed . For diagnosed subgroup , mean scores in the diabetes-free period , at 6 months , 2 , 4 and 6 years post-diagnosis , were compared . Results PCS and SF-6D scores declined in all participants in all treatment arms ( P < .001 ) . MCS scores did not change significantly in any treatment arm regardless of diagnosis . ILS participants reported a greater decrease in PCS scores at 6 months post-diagnosis ( P < .001 ) and a more rapid decline immediately post-diagnosis in SF-6D scores ( P = .003 ) than the MET or PLB arms . ILS participants reported a significant decrease in the social functioning subscale at 6 months ( P < .001 ) and two years ( P < .001 ) post-diagnosis . Conclusions Participants reported a decline in measures of overall health state ( SF-6D ) and overall physical HRQoL , whether or not they were diagnosed with diabetes during the study . There was no change in overall mental HRQoL. Participants in the ILS arm with diabetes reported a more significant decline in some HRQoL measures than those in the MET and PLB arms that developed diabetes AIM To determine the efficacy of delivering short-message service ( SMS ) to provide diabetes-related information in reducing the risk of developing diabetes in Chinese professional drivers with pre-diabetes . METHODS A pilot single-blinded r and omized controlled trial was conducted in Hong Kong between 05/2009 and 04/2012 . Professional drivers with impaired glucose tolerance ( IGT ) were r and omly allocated to either a SMS group receiving messages comprising knowledge and lifestyle modification on diabetes or to a control group with usual care . Primary outcomes were the incidence rate of diabetes mellitus over 12 and 24 months period . RESULTS Fifty-four , out of 104 professional drivers recruited , were r and omly allocated to intervention group . Fewer subjects developed diabetes at 12 months in intervention group ( 5.56 % ) compared to control group ( 16.00 % ) . Relative risk ( RR ) of diabetes onset was 0.35 ( 95%CI : 0.10–1.24 ) and the number needed to treat ( NNT ) for preventing one diabetes was 9.57 . At 24 months , RR increased to 0.62 ( 95%CI : 0.24–1.61 ) with a NNT of 10.58 . Logistic regression showed a significant odds ratio of 0.04 ( P = 0.021 ) for intervention group compared to control group at 12-month follow-up for completers and a non-significant odds ratio of 0.34 ( P = 0.303 ) at 24-month follow-up . CONCLUSIONS The SMS program proved to have potential to reduce the risk of developing diabetes at 12 months but additional measures should be integrated to prevent or delay disease progression A number of research studies have attempted to translate the behavioral lifestyle intervention delivered in the Diabetes Prevention Program ( DPP ) . To compare the active interventions of two trials , Diabetes Prevention Program DPP and Healthy Living Partnerships to Prevent Diabetes ( HELP PD ) , after 1 and 2 years of intervention . DPP included 3234 adults with prediabetes r and omized to intensive lifestyle intervention , metformin , troglitazone , or placebo . The lifestyle intervention , professionally delivered to individuals in a clinical setting , focused on diet and increased physical activity . HELP PD , a community-based translation of DPP , included 301 adults r and omized to receive intensive lifestyle intervention or enhanced usual care . Mean weight-losses at 1 year ( 6.9 kg in DPP , 6.4 kg in HELP PD ) and 2 years ( 5.5 kg in DPP , 4.4 kg in HELP PD ) were similar across studies . Reductions in glucose were also similar across studies at both time points ( 5.2 mg/dL in DPP and 4.1 mg/dL in HELP PD at 1 year ; 1.8 mg/dL and 1.6 mg/dL at 2 years ) . HELP PD participants achieved larger reductions in triglycerides at 1 and 2 years ( 38.4 mg/dL and 34.9 mg/dL , respectively ) than DPP participants ( 24.8 mg/dL and 22.4 mg/dL ) . High-density lipoprotein decreased in HELP PD participants at year 1 ( −0.6 mg/dL ) and increased in DPP ( 1.2 mg/dL ) but there were no significant differences in year 2 . HELP PD , a community model for diabetes prevention , was similar to DPP in reducing body weight and lowering blood glucose , both important risk factors that should be controlled to reduce risk for developing type 2 diabetes Background Gestational diabetes mellitus ( GDM ) , a hyperglycemic state detected during pregnancy , is an established risk factor for diabetes . However , treatment during pregnancy in and of itself is not able to eliminate this risk , and a considerable fraction of women with GDM will develop frank diabetes in the decade following pregnancy . Our aim is to conduct a multicenter r and omized controlled trial to investigate the effectiveness of a lifestyle intervention program implemented after a pregnancy complicated by GDM in delaying or preventing the development of type 2 diabetes . Methods Women aged 18 or older identified as having recent GDM are recruited and followed by telephone to assess eligibility for the trial . To be eligible , women must have used insulin during pregnancy or present intermediate hyperglycemia postpartum . Women are encouraged to enter the trial as early as 10 weeks , and are permitted to do so up to 2 years after a pregnancy with GDM . An estimated 740 women will be r and omized to either conventional care or to coach-based interventions focused on breastfeeding , weight loss , healthy eating , and increased physical activity , and predominantly delivered by telephone . Women are followed annually to detect new onset diabetes , the primary outcome , and additional secondary outcomes which include reversion to normoglycemia , weight loss , physical activity and fitness , and insulin resistance . Discussion Though previous studies have demonstrated that type 2 diabetes can be delayed or prevented , no study has yet demonstrated the feasibility and effectiveness of similar interventions implemented in the postpartum period for women with recent GDM . If shown to be successful , this approach could become an important means of preventing diabetes in primary care setting s . Trial registration Clinical Trials.gov Identifier : NCT02327286 ; Registered 23 December 2014 OBJECTIVE To explore the impact of lifestyle and quantitative nutrition intervention on individuals with prediabetes . METHODS A total of 214 prediabetic patients from epidemiologic survey in Ximazhuang and Guangrunmen community centers in Nanchang from January 2011 to January 2012 were enrolled in the study . All the participants were r and omly divided into two groups : the intervention group and the control group , with 107 patients in each group . Intensified lifestyle and quantitative nutrition interventions were carried out in the intervention group , and routine lifestyle intervention was carried out in control group . Height and weight were measured , and the body mass index ( BMI ) was calculated . Blood glucose was tested by glucose oxidase method , and glycosylated hemoglobin ( HbA1c ) was detected by high performance liquid chromatography . Various parameter changes were compared between two groups after two year 's follow-up , and the outcome data of patients was collected . The study was approved by the Ethics Committee of the Third Hospital of Nanchang . RESULTS There were no significant differences in each parameter between two groups before intervention ( all P>0.05 ) . No obvious change was found for the parameters in the control group after two year 's follow-up ( all P>0.05 ) , but weight , BMI , fasting blood glucose , postpr and ial two-hour blood glucose and HbA1c decreased in the intervention group ( P<0.05 ) . There were 11 ( 13.1 % ) diabetic cases and 1 ( 1.2 % ) participant with normal glucose tolerance in the control group , and 3 ( 3.4 % ) diabetic cases and 7 ( 8.0 % ) participants with normal glucose tolerance in the intervention group ( P<0.05 ) . The risk of diabetes in two groups was performed using cox regression model analysis , and the primary end-point was the incidence of diabetes . The risk of diabetes in the control group was significantly higher than that in the intervention group [ HR=3.903 , 95 % CI : 1.089 - 13.992 , P=0.037 ] . CONCLUSION The lifestyle and quantitative nutrition interventions may improve the blood glucose control and delay the progression of diabetes in prediabetes patients Background South Asian migrants are at particularly high risk of type 2 diabetes . Previous studies have shown that intensive lifestyle interventions may prevent the onset of diabetes . Such interventions have not been culturally adapted and evaluated among South Asians in industrialized countries . Therefore , we have set up a r and omized controlled trial to study the effectiveness of a targeted lifestyle intervention for the risk of type 2 diabetes and cardiovascular risk factors among 18 to 60-year-old Hindustani Surinamese ( South Asians ) in The Hague , the Netherl and s. Here we present the study design and describe the characteristics of those recruited . Methods Between May 18 , 2009 and October 11 , 2010 , we screened 2307 Hindustani Surinamese ( 18–60 years old ) living in The Hague . We sent invitations to participate to those who had an impaired fasting glucose of 5.6 - 6.9 mmol/l , an impaired glucose tolerance of 7.8 - 11.0 mmol/L , a glycated hemoglobin level of 6.0 % or more and /or a value of 2.39 or more for the homeostasis model assessment of estimated insulin resistance . In total , 536 people ( 56.1 % of those eligible ) participated . People with a higher level of education and a family history of type 2 diabetes were more likely to participate . The control and intervention groups were similar with regard to important background characteristics . The intervention group will receive a culturally targeted intervention consisting of dietary counseling using motivational interviewing and a supervised physical activity program . The control group will receive generic lifestyle advice . To determine the effectiveness , a physical examination ( anthropometrics , cardiorespiratory test , lipid profile , and measures of oral glucose tolerance , glycated hemoglobin , and insulin ) and interview ( physical activity , diet , quality of life , and intermediate outcomes ) were carried out at baseline and will be repeated at 1 year and 2 years . The process and the costs will be evaluated . Discussion This trial will provide insight into the feasibility and effectiveness of a targeted , intensive , lifestyle intervention for the risk of type 2 diabetes and cardiovascular risk factors among 18 to 60-year-old South Asians . Trial registration Dutch Trial Register : OBJECTIVES To determine if a widely available weight-management program ( Weight Watchers ) could achieve sufficient weight loss in persons with prediabetes compared with a Diabetes Prevention Program-based individual counseling program supported by National Diabetes Education Program material s. METHODS We conducted an individual , r and omized intervention trial in Indianapolis , Indiana , in 2013 to 2014 , in 225 persons with prediabetes . We compared the Weight Watchers weight-management program ( n = 112 ) with Your Game Plan to Prevent Type 2 Diabetes , a program developed by the National Diabetes Education Program . Outcomes were weight and metabolic markers measured at baseline , 6 months , and 12 months . RESULTS Intervention participants lost significantly more weight than controls at 6 months ( 5.5 % vs 0.8 % ) and 12 months ( 5.5 % vs 0.2 % ; both P < .001 ) . The intervention group also had significantly greater improvements in hemoglobin A1c and high-density lipoprotein cholesterol level than did controls . CONCLUSIONS A large weight-management program is effective for achieving lifestyle changes associated with diabetes prevention . Such programs could significantly increase the availability of diabetes prevention programs worldwide making an immediate and significant public health impact Lifestyle modification reduces the risk of developing type 2 diabetes and may have its effect through improving insulin sensitivity , beta-cell function , or both . To determine whether diet and exercise improve insulin sensitivity and /or beta-cell function and to evaluate these effects over time , we quantified insulin sensitivity and the acute insulin response to glucose ( AIRg ) in 62 Japanese Americans ( age 56.5 + /- 1.3 years ; mean + /- SE ) with impaired glucose tolerance ( IGT ) who were r and omized to the American Heart Association ( AHA ) Step 2 diet plus endurance exercise ( n = 30 ) versus the AHA Step 1 diet plus stretching ( n = 32 ) for 24 months . beta-Cell function ( disposition index [ DI ] ) was calculated as S(i ) x AIRg , where S(i ) is the insulin sensitivity index . The incremental area under the curve for glucose ( incAUCg ) was calculated from a 75-g oral glucose tolerance test . Intra-abdominal fat ( IAF ) and subcutaneous fat ( SCF ) areas were measured by computed tomography . At 24 months , the Step 2/endurance group had lower weight ( 63.1 + /- 2.4 vs. 71.3 + /- 2.9 kg ; P = 0.004 ) and IAF ( 75.0 + /- 7.9 vs. 112.7 + /- 10.4 cm(2 ) ; P = 0.03 ) and SCF ( 196.5 + /- 18.0 vs. 227.7 + /- 19.9 cm(2 ) ; P < 0.001 ) areas , greater S(i ) ( 4.7 + /- 0.5 vs. 3.3 + /- 0.3 x 10(-5 ) min . pmol(-1 ) . l(-1 ) ; P = 0.01 ) , and a trend toward lower AIRg ( 294.9 + /- 50.0 vs. 305.4 + /- 30.0 pmol/l ; P = 0.06 ) and incAUCg ( 8,217.3 + /- 350.7 vs. 8,902.0 + /- 367.2 mg . dl(-1 ) . 2 h(-1 ) ; P = 0.08 ) compared with the Step 1/stretching group after adjusting for baseline values . There was no difference in the DI ( P = 0.7 ) between the groups . S(i ) was associated with changes in weight ( r = -0.426 , P = 0.001 ) and IAF ( r = -0.395 , P = 0.003 ) and SCF ( r = -0.341 , P = 0.01 ) areas . Thus , the lifestyle modifications decreased weight and central adiposity and improved insulin sensitivity in Japanese Americans with IGT . However , such changes did not improve beta-cell function , suggesting that this degree of lifestyle modifications may be limited in preventing type 2 diabetes over the long term AIMS To evaluate the efficacy of interventions to promote a healthy diet and physical activity in people with impaired glucose tolerance ( IGT ) . METHODS A r and omised controlled trial in Newcastle upon Tyne , UK , 1995 - 98 . Participants included 67 adults ( 38 men ; 29 women ) aged 24 - 75 years with IGT . The intervention consisted of regular diet and physical activity counselling based on the stages of change model . Main outcome measures were changes between baseline and 6 months in nutrient intake ; physical activity ; anthropometric and physiological measurements including serum lipids ; glucose tolerance ; insulin sensitivity . RESULTS The difference in change in total fat consumption was significant between intervention and control groups ( difference -21.8 ( 95 % confidence interval ( CI ) -37.8 to -5.8 ) g/day , P=0.008 ) . A significantly larger proportion of intervention participants reported taking up vigorous activity than controls ( difference 30.1 , ( 95 % CI 4.3 - -52.7)% , P=0.021 ) . The change in body mass index was significantly different between groups ( difference -0.95 ( 95 % CI -1.5 to -0.4 ) kg/m(2 ) , P=0.001 ) . There was no significant difference in change in mean 2-h plasma glucose between groups ( difference -0.19 ( 95 % CI -1.1 to 0.71 ) mmol/l , NS ) or in serum cholesterol ( difference 0.02 ( 95 % CI -0.26 to 0.31 ) mmol/l , NS ) . The difference in change in fasting serum insulin between groups was significant ( difference -3.4 ( 95 % CI -5.8 to -1.1 ) mU/l , P=0.005 ) . CONCLUSIONS After 6 months of intensive lifestyle intervention in participants with IGT , there were changes in diet and physical activity , some cardiovascular risk factors and insulin sensitivity , but not glucose tolerance . Further follow-up is in progress to investigate whether these changes are sustained or augmented over 2 years OBJECTIVE Glycated hemoglobin ( HbA1c ) , a st and ard measure of chronic glycemia for managing diabetes , has been proposed to diagnose diabetes and identify people at risk . The Diabetes Prevention Program ( DPP ) was a 3.2-year r and omized clinical trial of preventing type 2 diabetes with a 10-year follow-up study , the DPP Outcomes Study ( DPPOS ) . We evaluated baseline HbA1c as a predictor of diabetes and determined the effects of treatments on diabetes defined by an HbA1c ≥6.5 % ( 48 mmol/mol ) . RESEARCH DESIGN AND METHODS We r and omized 3,234 nondiabetic adults at high risk of diabetes to placebo , metformin , or intensive lifestyle intervention and followed them for the development of diabetes as diagnosed by fasting plasma glucose ( FPG ) and 2-h postload glucose ( 2hPG ) concentrations ( 1997 American Diabetes Association [ ADA ] criteria ) . HbA1c was measured but not used for study eligibility or outcomes . We now evaluate treatment effects in the 2,765 participants who did not have diabetes at baseline according to FPG , 2hPG , or HbA1c ( 2010 ADA criteria ) . RESULTS Baseline HbA1c predicted incident diabetes in all treatment groups . Diabetes incidence defined by HbA1c ≥6.5 % was reduced by 44 % by metformin and 49 % by lifestyle during the DPP and by 38 % by metformin and 29 % by lifestyle throughout follow-up . Unlike the primary DPP and DPPOS findings based on glucose criteria , metformin and lifestyle were similarly effective in preventing diabetes defined by HbA1c . CONCLUSIONS HbA1c predicted incident diabetes . In contrast to the superiority of the lifestyle intervention on glucose-defined diabetes , metformin and lifestyle interventions had similar effects in preventing HbA1c-defined diabetes . The long-term implication s for other health outcomes remain to be determined Aims /hypothesisWe determined the effects of 6 years of lifestyle intervention in persons with impaired glucose tolerance ( IGT ) on the development of retinopathy , nephropathy and neuropathy over a 20 year period . Methods In 1986 , 577 adults with IGT from 33 clinics in Da Qing , China were r and omly assigned by clinic to a control group or one of three lifestyle intervention groups ( diet , exercise , and diet plus exercise ) . Active intervention was carried out from 1986 to 1992 . In 2006 we conducted a 20 year follow-up study of the original participants to compare the incidence of microvascular complications in the combined intervention group vs the control group . Results Follow-up information was obtained on 542 ( 94 % ) of the 577 original participants . The cumulative incidence of severe retinopathy was 9.2 % in the combined intervention group and 16.2 % in the control group ( p = 0.03 , log-rank test ) . After adjusting for clinic and age , the incidence of severe retinopathy was 47 % lower in the intervention group than the control group ( hazard rate ratio 0.53 , 95 % CI 0.29–0.99 , p = 0.048 ) . No significant differences were found in the incidence of severe nephropathy ( hazard rate ratio 1.05 , 95 % CI 0.16–7.05 , intervention vs control , p = 0.96 ) or in the prevalence of neuropathy ( 8.6 % vs 9.1 % , p = 0.89 ) among the 20 year survivors . Conclusions /interpretationLifestyle intervention for 6 years in IGT was associated with a 47 % reduction in the incidence of severe , vision-threatening retinopathy over a 20 year interval , primarily due to the reduced incidence of diabetes in the intervention group . However , similar benefits were not seen for nephropathy or neuropathy OBJECTIVE The study aims to provide information about variance components of psychosocial outcomes : within and between-participant variance , within-participant correlation and for cluster r and omised trials , the intra-cluster correlation ( ICC ) and , also , to demonstrate how estimates of these variance components and ICCs can be used to design r and omised trials and cluster r and omised trials . METHOD Data from 15 longitudinal multi-centre psycho-oncology studies were analysed , and variance components including ICCs were estimated . Studies with psychosocial outcomes that had at least one measurement post-baseline including individual r and omised controlled trials , cluster r and omised trials and observational studies were included . RESULTS Variance components and ICCs from 87 outcome measures were estimated . The unadjusted , single timepoint ( first post-baseline ) ICCs ranged from 0 to 0.16 , with a median value of 0.022 and inter-quartile range 0 to 0.0605 . The longitudinal ICCs ranged from 0 to 0.09 with a median value of 0.0007 and inter-quartile range 0 to 0.018 . CONCLUSIONS Although the magnitude of variance components and ICCs used for sample -size calculation can not be known in advance of the study , published estimates can help reduce the uncertainty in sample -size calculations . Psycho-oncology research ers should be conservative in their sample -size calculations and use approaches that improve efficiency in their design and analysis Prevention of type 2 diabetes by intensive lifestyle intervention design ed to achieve and maintain ideal body weight was assessed in subjects with impaired glucose tolerance ( IGT ) . Male subjects with IGT recruited from health-screening examinees were r and omly assigned in a 4:1 ratio to a st and ard intervention group ( control group ) and intensive intervention group ( intervention group ) . The final numbers of subjects were 356 and 102 , respectively . The subjects in the control group and in the intervention group were advised to maintain body mass index ( BMI ) of < 24.0 kg/m2 and of < 22.0 kg/m2 , respectively , by diet and exercise . In the intervention group , detailed instructions on lifestyle were repeated every 3 - 4 months during hospital visits . Diabetes was judged to have developed when two or more consecutive fasting plasma glucose ( FPG ) values exceeded 140 mg/dl . A 100 g oral glucose tolerance test was performed every 6 months to detect improvement of glucose tolerance . The subjects were seen in an ordinary outpatient clinic . The cumulative 4-year incidence of diabetes was 9.3 % in the control group , versus 3.0 % in the intervention group , and the reduction in risk of diabetes was 67.4 % ( P < 0.001 ) . Body weight decreased by 0.39 kg in the control group and by 2.18 kg in the intervention group ( P < 0.001 ) . The control group was subclassified according to increase and decrease in body weight . The incidence of diabetes was positively correlated with the changes in body weight , and the improvement in glucose tolerance was negatively correlated . Subjects with higher FPG at baseline developed diabetes at a higher rate than those with lower FPG . Higher 2h plasma glucose values and higher BMI values at baseline were also associated with a higher incidence of diabetes , but the differences were not significant . Subjects with a low insulinogenic index ( DeltaIRI/DeltaPG 30 min after an oral glucose load ) developed diabetes at a significantly higher rate than those with a normal insulinogenic index . Comparison of the BMI data and incidence of diabetes in five diabetes prevention studies by lifestyle intervention revealed a linear correlation between the incidence of diabetes and the BMI values , with the exception of the DaQing Study . However , the slope of the reduction in incidence of diabetes in the intensive intervention groups was steeper than expected simply on the basis of the reduction of BMI , suggesting that the effect of lifestyle intervention can not be solely ascribed to the body weight reduction . We conclude that lifestyle intervention aim ed at achieving ideal body weight in men with IGT is effective and can be conducted in an outpatient clinic setting Aims : We hypothesised that the expected increase in insulin resistance over three years ’ time in individuals with impaired glucose tolerance ( IGT ) and /or impaired fasting glucose could be attenuated by an intervention with focus on physical activity in ordinary primary care . Methods : We conducted a r and omised controlled trial with 96 participants over three years . Examination of the participants included anthropometric measures , blood pressure , body weight and height , blood sample s , an oral glucose tolerance test , and question naires about diet and lifestyle . The study subjects were r and omised to either an intense intervention with information , group sessions , referral to physical activity and a step-counter ( n = 31 ) , a less intense intervention without the group sessions ( n = 35 ) , or care as usual group ( CAUG ) ( n = 30 ) . Differences between the groups were analysed with general linear models adjusted for age , gender , baseline values and time in the intervention . Results : Individual insulin resistance increased in the CAUG . Due to having a similar effect , we combined the two intervention groups into a combined intervention group ( CIG ; n = 66 ) in the analyses . In individuals with IGT , the increase in the homeostatic model assessment -insulin resistance differed significantly between those in the CAUG and the CIG ( Δ = 0.8 ; CI : 0.1–1.6 ; p = 0.034 ) . Likewise , diastolic blood pressure decreased more in the CIG than in the CAUG ( Δ = 5.1 ; CI : 0.1–10.0 ; p = 0.047 ) . A total of 17 individuals developed Type 2 diabetes , 23 % were in the CIG and 33 % in the CAUG ; so there was a 32 % reduced risk in the intervention group . Conclusions : A lifestyle intervention focused on physical activity is feasible in ordinary primary care and prevents deterioration in insulin sensitivity in individuals with IGT over a three-year period OBJECTIVE Objectives of this ancillary analysis of a prospect i ve , prevention study among Asian Indians with impaired glucose tolerance ( IGT ) were a ) to quantify the reduction in incident diabetes at 24 months in participants who achieved normal glucose tolerance ( NGT ) at 6 months ( NGT-6 m ) compared with the other participants , b ) the factors influencing the reversal to NGT at the end of the study at 24 months ( NGT-24 m ) , and c ) to assess changes in cardiometabolic risk factors in different categories of dysglycemia at 24 months . RESEARCH DESIGN AND METHODS Data from a 2-year primary prevention trial were used . Effect of reversion to NGT-6 m on incidence of type 2 diabetes mellitus ( T2DM ) was analyzed using the Cox proportional hazards model . Predictive variables for reversal to NGT were identified using multiple logistic regression analysis . Changes in cardiometabolic risk factors were estimated according to the final glycemic status using fixed-effect , mixed-linear regression modeling . RESULTS The risk of T2DM in 2 years was lower by 75 % in NGT-6 m group ( hazard ratio 0.25 [ 95 % CI 0.12–0.52 ] ) . Predictive variables for reversal to NGT-24 m were good baseline β-cell function ( odds ratio [ OR ] 2.79 [ 95 % CI 2.30–3.40 ] ) and its further improvement ( OR 5.70 [ 95 % CI 4.58–7.08 ] ) , and NGT-6 m ( OR 2.10 [ 95 % CI 1.14–3.83 ] ) . BMI decreased in those who reverted to NGT . Deterioration to T2DM was associated with an increase in the levels of cardiometabolic risk factors . CONCLUSIONS Early reversion to NGT by lifestyle intervention in prediabetic men was associated with a significant reduction in subsequent incidence of diabetes . Good baseline β-cell function and its further improvement and NGT-6 m were associated with reversion to NGT-24 months . Reversion to NGT was associated with modest improvements , whereas conversion to T2DM was associated with significant worsening of the cardiometabolic risk profile In a diabetes detection survey carried out between 1962 and 1965 , 2477 ( 1.1 % ) of 228,883 subjects had Clinistix-positive glucosuria after a carbohydrate-rich luncheon meal . Of these 2477 , 578 displayed impaired tolerance to oral glucose without having manifest diabetes . From this group , 267 men were divided into five groups and subjected to the following treatments and controls : ( a ) diet regulation and 0.5 g tolbutamide t.i.d . ( N = 49 ) , annual oral glucose tolerance test ( OGTT ) ; ( b ) diet regulation and one placebo tablet t.i.d . ( N = 48 ) , annual OGTT ; ( c ) diet regulation only ( N = 50 ) , annual OGTT ; ( d ) no treatment ( N = 61 ) , annual OGTT ; and ( e ) no treatment , OGTT at follow-up ( N = 59 at follow-up ) . In addition , a control group was included comprised of men with normal OGTT ( N = 52 ) . At follow-up , 29 % of those without diet regulation and medication ( group e ; N = 59 ) had developed diabetes . Of those on diet regulation , but without active medication ( group b plus group c , N = 98 ) , 13 % had diabetes . No individual maintaining tolbutamide and diet regulation ( N = 23 ) had progressed to diabetes . In this group , 80 % of those later examined ( N = 11 ) had serum tolbutamide concentrations in the therapeutic range . No individual with initially normal OGTT developed diabetes or impaired OGTT . The findings suggest that normal oral glucose tolerance signifies little risk of progress to impaired glucose tolerance and manifest diabetes , whereas impaired glucose tolerance is associated with a high risk of progression to diabetes . In addition , it seems possible that treatment with diet regulation , in combination with tolbutamide , may prevent or postpone progression from impaired glucose tolerance to manifest diabetes OBJECTIVE The Diabetes Prevention Program demonstrated the ability to delay or prevent type 2 diabetes in participants with impaired glucose tolerance ( IGT ) . Participants with IGT are at high risk for cardiovascular disease ( CVD ) , with a marked increase in the number and severity of CVD risk factors . We prospect ively assessed the impact of our interventions on hypertension , dyslipidemia , and CVD events . RESEARCH DESIGN AND METHODS The study group consisted of 3,234 individuals with IGT r and omly assigned to receive intensive lifestyle intervention , metformin , or placebo . Annual assessment of blood pressure , lipids , electrocardiogram , and CVD events was undertaken . RESULTS Hypertension was present in 30 % of participants at study entry and then increased in the placebo and metformin groups , although it significantly decreased with intensive lifestyle intervention . Triglyceride levels fell in all treatment groups , but fell significantly more with intensive lifestyle intervention . Total cholesterol and LDL cholesterol levels were similar among treatment groups . Intensive lifestyle intervention significantly increased the HDL cholesterol level and reduced the cumulative incidence of the proatherogenic LDL phenotype B. At 3 years of follow-up , the use for pharmacologic therapy to achieve established goals in the intensive lifestyle group was 27 - 28 % less for hypertension and 25 % less for hyperlipidemia compared with placebo and metformin groups . Over an average of 3 years , 89 CVD events from 64 participants were positively adjudicated study wide , with no differences among treatment groups . CONCLUSIONS Lifestyle intervention improves CVD risk factor status compared with placebo and metformin therapy . Although no differences in CVD events were noted after 3 years , achieved risk factor modifications suggest that longer intervention may reduce CVD event rates Aims /hypothesis . The aim of the Diabetes Prevention Study is to assess the efficacy of an intensive diet-exercise programme in preventing or delaying Type II ( non-insulin-dependent ) diabetes mellitus in subjects with impaired glucose tolerance , to evaluate the effects of the intervention programme on cardiovascular risk factors and to assess the determinants for the progression to diabetes in persons with impaired glucose tolerance . Methods . A total of 523 overweight subjects with impaired glucose tolerance ascertained by two oral glucose tolerance tests were r and omised to either a control or intervention group . The control subjects received general information at the start of the trial about the lifestyle changes necessary to prevent diabetes and about annual follow-up visits . The intervention subjects had seven sessions with a nutritionist during the first year and a visit every 3 months thereafter aim ed at reducing weight , the intake of saturated fat and increasing the intake of dietary fibre . Intervention subjects were also guided individually to increase their physical activity . Results . During the first year , weight loss in the first 212 study subjects was 4.7 ± 5.5 vs 0.9 ± 4.1 kg in the intervention and control group , respectively ( p < 0.001 ) . The plasma glucose concentrations ( fasting : 5.9 ± 0.7 vs 6.4 ± 0.8 mmol/l , p < 0.001 ; and 2-h 7.8 ± 1.8 vs 8.5 ± 2.3 mmol/l , p < 0.05 ) were significantly lower in the intervention group after the first year of intervention . Favourable changes were also found in blood pressure , serum lipids and anthropometric indices in the intervention group . Conclusion /interpretation . The interim results show the efficacy and feasibility of the lifestyle intervention programme . [ Diabetologia ( 1999 ) 42 : 793–801 OBJECTIVE —We investigated whether circulating adipokine concentrations can be altered by lifestyle intervention according to general recommendations in subjects at risk for diabetes as well as the potential of leptin , adiponectin , and resistin as biomarkers for lifestyle-induced improvements in glucose metabolism and insulin resistance . RESEARCH DESIGN AND METHODS —In the Study on Lifestyle intervention and Impaired glucose tolerance Maastricht , 147 men and women with impaired glucose tolerance ( IGT ) were r and omized to either a combined diet- and -exercise intervention or a control program . At baseline and after 1 year , an oral glucose tolerance test , an exercise test , and anthropometric measurements were performed . After 1 year , complete data of 103 subjects ( 50 intervention and 53 control subjects ) were obtained . RESULTS —Lifestyle intervention reduced plasma leptin concentrations ( −14.2 % ) in IGT subjects but did not alter plasma adiponectin ( −0.3 % ) or resistin ( −6.5 % ) concentrations despite marked improvements in glucose tolerance and insulin resistance . CONCLUSIONS —Changes in leptin concentration were related to improvements in insulin sensitivity independent of changes in body composition Objectives To determine the effects of a lifestyle intervention on the development of type 2 diabetes mellitus ( T2DM ) among participants with impaired glucose tolerance ( IGT ) , in particular in the subgroup with baseline glycated hemoglobin ( HbA1c ) levels ≥5.7 % , in primary healthcare setting s. Design R and omized controlled trial . Setting 32 healthcare centers in Japan . Participants Participants with IGT , aged 30–60 years , were r and omly assigned to either an intensive lifestyle intervention group ( ILG ) or a usual care group ( UCG ) . Interventions During the initial 6 months , participants in the ILG received four group sessions on healthy lifestyles by public health providers . An individual session was further conducted biannually during the 3 years . Participants in the UCG received usual care such as one group session on healthy lifestyles . Outcome measures The primary endpoint was the development of T2DM based on an oral glucose tolerance test . Results The mean follow-up period was 2.3 years . The annual incidence of T2DM were 2.7 and 5.1/100 person-years of follow-up in the ILG ( n=145 ) and UCG ( n=149 ) , respectively . The cumulative incidence of T2DM was significantly lower in the ILG than in the UCG among participants with HbA1c levels ≥5.7 % ( log-rank=3.52 , p=0.06 ; Breslow=4.05 , p=0.04 ; Tarone-Ware=3.79 , p=0.05 ) , while this was not found among participants with HbA1c levels < 5.7 % . Conclusions Intensive lifestyle intervention in primary healthcare setting is effective in preventing the development of T2DM in IGT participants with HbA1c levels ≥5.7 % , relative to those with HbA1c levels < 5.7 % . Trial registration number UMIN000003136 OBJECTIVE Although the Diabetes Prevention Program ( DPP ) and the Finnish Diabetes Prevention Study ( FDPS ) demonstrated that weight loss from lifestyle change reduces type 2 diabetes incidence in patients with prediabetes , the translation into community setting s has been difficult . The objective of this study is to report the first-year results of a community-based translation of the DPP lifestyle weight loss ( LWL ) intervention on fasting glucose , insulin resistance , and adiposity . RESEARCH DESIGN AND METHODS We r and omly assigned 301 overweight and obese volunteers ( BMI 25–40 kg/m2 ) with fasting blood glucose values between 95 and 125 mg/dL to a group-based translation of the DPP LWL intervention administered through a diabetes education program ( DEP ) and delivered by community health workers ( CHWs ) or to an enhanced usual-care condition . CHWs were volunteers with well-controlled type 2 diabetes . A total of 42.5 % of participants were male , mean age was 57.9 years , 26 % were of a race/ethnicity other than white , and 80 % reported having an education beyond high school . The primary outcome is mean fasting glucose over 12 months of follow-up , adjusting for baseline glucose . RESULTS Compared with usual-care participants , LWL intervention participants experienced significantly greater decreases in blood glucose ( −4.3 vs. −0.4 mg/dL ; P < 0.001 ) , insulin ( −6.5 vs. −2.7 μU/mL ; P < 0.001 ) , homeostasis model assessment of insulin resistance ( −1.9 vs. −0.8 ; P < 0.001 ) , weight ( −7.1 vs. −1.4 kg ; P < 0.001 ) , BMI ( −2.1 vs. −0.3 kg/m2 ; P < 0.001 ) , and waist circumference ( −5.9 vs. −0.8 cm ; P < 0.001 ) . CONCLUSIONS This translation of the DPP intervention conducted in community setting s , administered through a DEP , and delivered by CHWs holds great promise for the prevention of diabetes by significantly decreasing glucose , insulin , and adiposity The aim of the Finnish Diabetes Prevention Study is to assess the efficacy of an intensive diet-exercise programme in preventing or delaying type 2 diabetes in individuals with impaired glucose tolerance ( IGT ) and to evaluate the effect of the programme on the risk factors of atherosclerotic vascular diseases and the incidence of cardiovascular events . In this ongoing study , a total of 523 overweight subjects with IGT based on two oral glucose tolerance tests were r and omized to either an intervention group or a control group . The main measure in the intervention group is individual dietary advice aim ed at reducing weight and intake of saturated fat and increasing intake of dietary fibre . The intervention subjects are individually guided to increase their level of physical activity . The control group receives general information about the benefits of weight reduction , physical activity and healthy diet in the prevention of diabetes . A pilot study began in 1993 , and recruitment ended in 1998 . By the end of April 1999 there were 65 new cases of diabetes , 34 drop-outs and one death . The weight reduction was greater ( -4.6 kg ) at 1 year in the intervention group ( n = 152 ) than in the control group ( n = 143 , -0.9 kg , P < 0.0001 ) , and this difference was sustained in the second year of follow-up . At 1 year 43.4 % and at 2 years 41.8 % of the intervention subjects had achieved a weight reduction of at least 5 kg , while the corresponding figures for the control subjects were 14.0 and 12.0 % ( P < 0.001 between the groups ) . At 1 year the intervention group showed significantly greater reductions in 2 h glucose , fasting and 2 h insulin , systolic and diastolic blood pressure , and serum triglycerides . Most of the beneficial changes in cardiovascular risk factors were sustained for 2 years . These interim results of the ongoing Finnish Diabetes Prevention Study demonstrate the efficacy and feasibility of the lifestyle intervention programme AIMS To assess the beneficial effects of the components of lifestyle intervention in reducing incidence of diabetes in Asian Indian men with impaired glucose tolerance ( IGT ) in India . METHODS This analysis was based on a 2 year prospect i ve , r and omized controlled primary prevention trial in a cohort of Asian Indian men with IGT ( n=537 ) ( Clinical Trial No : NCT00819455 ) . Intervention and control groups were given st and ard care advice at baseline . Additionally , the intervention group received frequent , mobile phone based text message reminders on healthy lifestyle principles . Dietary intake and physical activity habits were recorded by vali date d question naires . The lifestyle goals were : reductions in consumption of carbohydrates , oil , portion size and body mass index of at least 1 unit ( 1 kg/m(2 ) ) from baseline and maintenance of good physical activity . The association between diabetes and lifestyle goals achieved was assessed using multiple logistic regression analyses . Changes in insulin sensitivity ( Matsuda 's insulin sensitivity index ) and oral disposition index during the follow-up were assessed . RESULTS At the end of the study , 123 ( 23.8 % ) participants developed diabetes . The mean lifestyle score was higher in the intervention group compared with control ( 2.59 ± 1.13 vs. 2.28 ± 1.17 ; P=0.002 ) . Among the 5 lifestyle variables , significant improvements in the 3 dietary goal were seen with intervention . Concomitant improvement in insulin sensitivity and oral disposition index was noted . Higher lifestyle score was associated with lower risk of developing diabetes ( odds ratio : 0.54 [ 95 % CI : 0.44 - 0.70 ] ; P<0.0001 ) . CONCLUSIONS Beneficial effects of intervention were associated with increased compliance to lifestyle goals . The plausible mechanism is through improvement in insulin sensitivity and beta cell preservation Aims : To evaluate the effects of a lifestyle intervention programme in primary healthcare , targeted to patients with moderate to high risk of cardiovascular disease in terms of cardiovascular risk factors , physical activity , and quality of life . Method : R and omized controlled trial with one-year follow-up , carried out in a primary healthcare centre in Northern Sweden . A total of 151 middle-aged men and women , with hypertension , dyslipidemia , type 2 diabetes , or obesity were enrolled . The subjects were r and omized to either the intervention ( n=75 ) or the control group ( n=76 ) . A total of 123 subjects completed the one-year follow-up . Interventions : Exercise : supervised endurance and circuit training in groups three times a week for three months . Diet : five group sessions of diet counselling with a dietitian . Follow- up meetings with a physiotherapist were conducted monthly thereafter . Primary outcomes were changes in anthropometry , maximal oxygen uptake , health-related quality of life , and self-reported physical activity . The secondary outcomes were changes in blood pressure and metabolic variables . Results : After one year the intervention group significantly increased maximal oxygen uptake , physical activity , and quality of life and significantly decreased body weight , waist and hip circumference , body mass index , waist — hip ratio , systolic and diastolic blood pressure , triglycerides , and glycosylated haemoglobin . There were significant differences between groups , mean changes ( and their 95 % confidence intervals , CI ) in waist circumference -1.9 cm ( -2.80 to -0.90 ; p<0.001 ) , in waist — hip ratio -0.01 ( -.02 to -0.004 ; p<0.01 ) and in diastolic blood pressure -2.3 mmHg ( -4.04 to -0.51 ; p<0.05 ) . Conclusion : A prevention programme in primary healthcare with a focus on physical activity and diet counselling followed by structured follow-up meetings can favourably influence several risk factors for cardiovascular diseases and quality of life in high-risk subjects for at least one year Lifestyle interventions reduce the incidence of type 2 diabetes among individuals with impaired glucose tolerance ( IGT ) . However , it is unknown whether this is due to improved insulin sensitivity or insulin secretion . We investigated at baseline insulin sensitivity and insulin secretion applying frequently sample d intravenous glucose tolerance test ( FSIGT ) in 87 of 101 obese middle-aged subjects with IGT r and omized into an intervention or a control group in the Finnish Diabetes Prevention Study . FSIGT was repeated after 4 years in 52 people . There were no significant differences in any of the baseline anthropometric or metabolic characteristics between the groups . The 4-year weight and waist circumference decreases were greater in the intervention than in the control group ( P = 0.043 and P = 0.025 , respectively ) . At 4-year examination , insulin sensitivity ( Si ) tended to be higher in the intervention group ( the difference between the mean values 36 % ; P = 0.067 , and P = 0.136 after adjustment for age , sex , BMI , and baseline Si value ) . There was strong correlation between the 4-year changes in Si and weight ( r = -0.628 and r = -0.710 , for intervention and control groups ; P < 0.001 for both ) . In the entire group , Si improved by 64 % in the highest tertile of weight loss but deteriorated by 24 % in those who gained weight ( lowest tertile ) . Acute insulin response declined significantly in the control group . In conclusion , Si markedly improved by weight reduction during the 4-year follow-up of individuals with IGT . Insulin secretion remained constant for years in individuals with IGT who were able to lose weight OBJECTIVE —We assessed the effects of a 2-day in-hospital diabetes educational program in preventing or delaying progression of impaired glucose tolerance ( IGT ) to type 2 diabetes , including analysis of changes in serum lipids , body weight , and blood pressure after the program . RESEARCH DESIGN AND METHODS —A total of 426 subjects ( 51 ± 9 years , BMI 24.6 ± 3.9 kg/m2 ) with newly diagnosed IGT were r and omly assigned to three groups , 143 as the short-term hospitalization with diabetes education and support ( STH ) group , 141 as the nonhospitalization but diabetes education and support ( DES ) group , and 142 as the neither hospitalization nor education ( control ) group . RESULTS —The average follow-up was 3.1 years . The incidence of diabetes was 8.0 , 10.7 , and 13.2 cases per 100 person-years for STH , DES , and control groups , respectively . The incidence of diabetes was 42 % lower ( 95 % CI 33–51 % ) in the STH group and 27 % lower ( 15–37 % ) in the DES group than in the control group . The incidence of diabetes was 21 % lower ( 10–31 % ) in the STH group than in the DES group . CONCLUSIONS —The 2-day in-hospital program with diabetes education and support every 3 months was more effective in preventing or delaying the progression from IGT to diabetes than only diabetes education and support every 3 months ABSTRACT BACKGROUND Adults at high risk for diabetes may have reduced health-related quality of life ( HRQoL ) . OBJECTIVE To assess changes in HRQoL after interventions aim ed at diabetes risk reduction . DESIGN , SETTING , AND PARTICIPANTS A r and omized clinical trial , the Diabetes Prevention Program , was conducted in 27 centers in the United States , in 3,234 non-diabetic persons with elevated fasting and post-load plasma glucose , mean age 51 years , mean BMI 34 Kg/m² ; 68 % women , and 45 % members of minority groups . INTERVENTIONS Intensive lifestyle ( ILS ) program with the goals of at least 7 % weight loss and 150 min of physical activity per week , metformin ( MET ) 850 mg twice daily , or placebo ( PLB ) . MEASUREMENTS HRQoL using the 36-Item Short-Form ( SF-36 ) health survey to evaluate health utility index ( SF-6D ) , physical component summaries ( PCS ) and mental component summaries ( MCS ) . A minimally important difference ( MID ) was met when the mean of HRQoL scores between groups differed by at least 3 % . RESULTS After a mean follow-up of 3.2 years , there were significant improvements in the SF-6D ( + 0.008 , p = 0.04 ) and PCS ( + 1.57 , p < 0.0001 ) scores in ILS but not in MET participants ( + 0.002 and + 0.15 , respectively , p = 0.6 ) compared to the PLB group . ILS participants showed improvements in general health ( + 3.2 , p < 0.001 ) , physical function ( + 3.6 , p < 0.001 ) , bodily pain ( + 1.9 , p = 0.01 ) , and vitality ( + 2.1 , p = 0.01 ) domain scores . Treatment effects remained significant after adjusting sequentially for baseline demographic factors , and for medical and psychological comorbidities . Increased physical activity and weight reduction mediated these ILS treatment effects . Participants who experienced weight gain had significant worsening on the same HRQoL specific domains when compared to those that had treatment-related ( ILS or MET ) weight loss . No benefits with ILS or MET were observed in the MCS score . CONCLUSION Overweight/obese adults at high risk for diabetes show small improvement in most physical HRQoL and vitality scores through the weight loss and increased physical activity achieved with an ILS intervention BACKGROUND In the 2.8 years of the Diabetes Prevention Program ( DPP ) r and omised clinical trial , diabetes incidence in high-risk adults was reduced by 58 % with intensive lifestyle intervention and by 31 % with metformin , compared with placebo . We investigated the persistence of these effects in the long term . METHODS All active DPP participants were eligible for continued follow-up . 2766 of 3150 ( 88 % ) enrolled for a median additional follow-up of 5.7 years ( IQR 5.5 - 5.8 ) . 910 participants were from the lifestyle , 924 from the metformin , and 932 were from the original placebo groups . On the basis of the benefits from the intensive lifestyle intervention in the DPP , all three groups were offered group-implemented lifestyle intervention . Metformin treatment was continued in the original metformin group ( 850 mg twice daily as tolerated ) , with participants unmasked to assignment , and the original lifestyle intervention group was offered additional lifestyle support . The primary outcome was development of diabetes according to American Diabetes Association criteria . Analysis was by intention-to-treat . This study is registered with Clinical Trials.gov , number NCT00038727 . FINDINGS During the 10.0-year ( IQR 9.0 - 10.5 ) follow-up since r and omisation to DPP , the original lifestyle group lost , then partly regained weight . The modest weight loss with metformin was maintained . Diabetes incidence rates during the DPP were 4.8 cases per 100 person-years ( 95 % CI 4.1 - 5.7 ) in the intensive lifestyle intervention group , 7.8 ( 6.8 - 8.8 ) in the metformin group , and 11.0 ( 9.8 - 12.3 ) in the placebo group . Diabetes incidence rates in this follow-up study were similar between treatment groups : 5.9 per 100 person-years ( 5.1 - 6.8 ) for lifestyle , 4.9 ( 4.2 - 5.7 ) for metformin , and 5.6 ( 4.8 - 6.5 ) for placebo . Diabetes incidence in the 10 years since DPP r and omisation was reduced by 34 % ( 24 - 42 ) in the lifestyle group and 18 % ( 7 - 28 ) in the metformin group compared with placebo . INTERPRETATION During follow-up after DPP , incidences in the former placebo and metformin groups fell to equal those in the former lifestyle group , but the cumulative incidence of diabetes remained lowest in the lifestyle group . Prevention or delay of diabetes with lifestyle intervention or metformin can persist for at least 10 years . FUNDING National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK ) OBJECTIVE The Diabetes Prevention Program ( DPP ) and its Outcomes Study ( DPPOS ) demonstrated that either intensive lifestyle intervention or metformin could prevent type 2 diabetes in high-risk adults for at least 10 years after r and omization . We report the 10-year within-trial cost-effectiveness of the interventions . RESEARCH DESIGN AND METHODS Data on re source utilization , cost , and quality of life were collected prospect ively . Economic analyses were performed from health system and societal perspectives . RESULTS Over 10 years , the cumulative , undiscounted per capita direct medical costs of the interventions , as implemented during the DPP , were greater for lifestyle ( $ 4,572 ) than metformin ( $ 2,281 ) or placebo ( $ 752 ) . The cumulative direct medical costs of care outside the DPP/DPPOS were least for lifestyle ( $ 26,810 lifestyle vs. $ 27,384 metformin vs. $ 29,007 placebo ) . The cumulative , combined total direct medical costs were greatest for lifestyle and least for metformin ( $ 31,382 lifestyle vs. $ 29,665 metformin vs. $ 29,759 placebo ) . The cumulative quality -adjusted life-years ( QALYs ) accrued over 10 years were greater for lifestyle ( 6.89 ) than metformin ( 6.79 ) or placebo ( 6.74 ) . When costs and outcomes were discounted at 3 % and adjusted for survival , lifestyle cost $ 12,878 per QALY , and metformin had slightly lower costs and nearly the same QALYs as placebo . CONCLUSIONS Over 10 years , from a payer perspective , lifestyle was cost-effective and metformin was marginally cost-saving compared with placebo . Investment in lifestyle and metformin interventions for diabetes prevention in high-risk adults provides good value for the money spent Objectives To describe the design and baseline population characteristics of an adapted lifestyle intervention trial aim ed at reducing weight and increasing physical activity in people of Indian and Pakistani origin at high risk of developing type 2 diabetes . Design Cluster , r and omised controlled trial . Setting Community-based in Edinburgh and Glasgow , Scotl and , UK . Participants 156 families , comprising 171 people with impaired glycaemia , and waist sizes ≥90 cm ( men ) and ≥80 cm ( women ) , plus 124 family volunteers . Interventions Families were r and omised into either an intensive intervention of 15 dietitian visits providing lifestyle advice , or a light ( control ) intervention of four visits , over a period of 3 years . Outcome measures The primary outcome is a change in mean weight between baseline and 3 years . Secondary outcomes are changes in waist , hip , body mass index , plasma blood glucose and physical activity . The cost of the intervention will be measured . Qualitative work will seek to underst and factors that motivated participation and retention in the trial and families ’ experience of adhering to the interventions . Results Between July 2007 and October 2009 , 171 people with impaired glycaemia , along with 124 family volunteers , were r and omised . In total , 95 % ( 171/196 ) of eligible participants agreed to proceed to the 3-year trial . Only 13 of the 156 families contained more than one recruit with impaired glycaemia . We have recruited sufficient participants to undertake an adequately powered trial to detect a mean difference in weight of 2.5 kg between the intensive and light intervention groups at the 5 % significance level . Over half the families include family volunteers . The main participants have a mean age of 52 years and 64 % are women . Conclusions Prevention of Diabetes & Obesity in South Asians ( PODOSA ) is one of the first community-based , r and omised lifestyle intervention trials in a UK South Asian population . The main trial results will be su bmi tted for publication during 2013 . Trial registration Current controlled trials IS RCT N25729565 ( http://www.controlled-trials.com/is rct n/ ) Background Effective diabetes prevention strategies that can be implemented in daily practice , without huge amounts of money and a lot of personnel are needed . The Dutch Diabetes Federation developed a protocol for coaching people with impaired fasting glucose ( IFG ; according to WHO criteria : 6.1 to 6.9 mmol/l ) to a sustainable healthy lifestyle change : ‘ the road map towards diabetes prevention ’ ( abbreviated : Road Map : RM ) . This protocol is applied within a primary health care setting by a general practitioner and a practice nurse . The feasibility and ( cost- ) effectiveness of care provided according to the RM protocol will be evaluated . Methods / Design A cluster r and omised clinical trial is performed , with r and omisation at the level of the general practice s. Both opportunistic screening and active case finding took place among clients with high risk factors for diabetes . After IFG is diagnosed , motivated people in the intervention practice s receive 3–4 consultations by the practice nurse within one year . During these consultations they are coached to increase the level of physical activity and healthy dietary habits . If necessary , participants are referred to a dietician , physiotherapist , lifestyle programs and /or local sports activities . The control group receives care as usual . The primary outcome measure in this study is change in Body Mass Index ( BMI ) . Secondary outcome measures are waist circumference , physical activity , total and saturated fat intake , systolic blood pressure , blood glucose , total cholesterol , HDL cholesterol , triglycerides and behaviour determinants like risk perception , perceived knowledge and motivation . Based on a sample size calculation 120 people in each group are needed . Measurements are performed at baseline , and after one ( post-intervention ) and two years follow up . Anthropometrics and biochemical parameters are assessed in the practice s and physical activity , food intake and their determinants by a vali date d question naire . The cost-effectiveness is estimated by using the Chronic Disease Model ( CDM ) . Feasibility will be tested by interviews among health care professionals . Discussion The results of the study will provide valuable information for both health care professionals and policy makers . If this study shows the RM to be both effective and cost-effective the protocol can be implemented on a large scale . Trial registration IS RCT N41209683 . Ethical approval number : NL31342.075.10 Background The worldwide epidemic of type 2 diabetes requires effective prevention . We determined the long-term extent of beneficial effects of lifestyle intervention and metformin on diabetes prevention , originally demonstrated during the 3-year Diabetes Prevention Program ( DPP ) , and whether diabetes-associated microvascular complications are reduced . Methods The DPP ( 1996–2001 ) was a r and omized trial comparing an intensive lifestyle intervention or masked metformin with placebo in a cohort selected to be at very high risk to develop diabetes . All participants were offered lifestyle training at DPP-end . 2776 ( 88 % ) of the surviving DPP cohort were followed in the DPP Outcome Study ( DPPOS 2002–2013 ) and analyzed by intention-to-treat based on original DPP assignment . During DPPOS , the lifestyle group was offered lifestyle reinforcement semi-annually and the metformin group received unmasked metformin . Findings During 15 years of average follow-up , lifestyle intervention and metformin reduced diabetes incidence rates by 27 % ( p<0.0001 ) and 18 % ( p=0.001 ) , respectively , compared with the placebo group , with declining between group differences over time . At year 15 , the cumulative incidences of diabetes were 55 , 56 and 62 % , respectively . The prevalences at study -end of the aggregate microvascular outcome , composed of nephropathy , neuropathy , and retinopathy , were not significantly different among the treatment groups ( 11–13 % ) in the total cohort . However , in women ( n=1887 ) lifestyle intervention was associated with a lower prevalence ( 8.7 % ) than in the placebo ( 11 % ) and metformin ( 11.2 % ) groups , with 21 % ( p=0.03 ) and 22 % ( p=0.02 ) reductions with lifestyle compared with placebo and metformin , respectively . Compared with participants who progressed to diabetes , those who did n’t progress had a 28 % lower prevalence of microvascular complications ( p<0.0001 ) . Interpretation Lifestyle intervention or metformin significantly reduce diabetes development over 15 years . There were no overall differences in the aggregate microvascular outcome among treatment groups ; however , those who did not progress to diabetes had a lower prevalence of microvascular complications than those who progressed . Funding National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK CONTEXT As of 2005 , the International Committee of Medical Journal Editors required investigators to register their trials prior to participant enrollment as a precondition for publishing the trial 's findings in member journals . OBJECTIVE To assess the proportion of registered trials with results recently published in journals with high impact factors ; to compare the primary outcomes specified in trial registries with those reported in the published articles ; and to determine whether primary outcome reporting bias favored significant outcomes . DATA SOURCES AND STUDY SELECTION MEDLINE via PubMed was search ed for reports of r and omized controlled trials ( RCTs ) in 3 medical areas ( cardiology , rheumatology , and gastroenterology ) indexed in 2008 in the 10 general medical journals and specialty journals with the highest impact factors . DATA EXTRACTION For each included article , we obtained the trial registration information using a st and ardized data extraction form . RESULTS Of the 323 included trials , 147 ( 45.5 % ) were adequately registered ( ie , registered before the end of the trial , with the primary outcome clearly specified ) . Trial registration was lacking for 89 published reports ( 27.6 % ) , 45 trials ( 13.9 % ) were registered after the completion of the study , 39 ( 12 % ) were registered with no or an unclear description of the primary outcome , and 3 ( 0.9 % ) were registered after the completion of the study and had an unclear description of the primary outcome . Among articles with trials adequately registered , 31 % ( 46 of 147 ) showed some evidence of discrepancies between the outcomes registered and the outcomes published . The influence of these discrepancies could be assessed in only half of them and in these statistically significant results were favored in 82.6 % ( 19 of 23 ) . CONCLUSION Comparison of the primary outcomes of RCTs registered with their subsequent publication indicated that selective outcome reporting is prevalent OBJECTIVE To describe the 1 ) lifestyle intervention used in the Finnish Diabetes Prevention Study , 2 ) short- and long-term changes in diet and exercise behavior , and 3 ) effect of the intervention on glucose and lipid metabolism . RESEARCH DESIGN AND METHODS There were 522 middle-aged , overweight subjects with impaired glucose tolerance who were r and omized to either a usual care control group or an intensive lifestyle intervention group . The control group received general dietary and exercise advice at baseline and had an annual physician 's examination . The subjects in the intervention group received additional individualized dietary counseling from a nutritionist . They were also offered circuit-type resistance training sessions and advised to increase overall physical activity . The intervention was the most intensive during the first year , followed by a maintenance period . The intervention goals were to reduce body weight , reduce dietary and saturated fat , and increase physical activity and dietary fiber . RESULTS The intervention group showed significantly greater improvement in each intervention goal . After 1 and 3 years , weight reductions were 4.5 and 3.5 kg in the intervention group and 1.0 and 0.9 kg in the control group , respectively . Measures of glycemia and lipemia improved more in the intervention group . CONCLUSIONS The intensive lifestyle intervention produced long-term beneficial changes in diet , physical activity , and clinical and biochemical parameters and reduced diabetes risk . This type of intervention is a feasible option to prevent type 2 diabetes and should be implemented in the primary health care system Context The Diabetes Prevention Program ( DPP ) showed that lifestyle changes or metformin effectively decreased the development of type 2 diabetes in adults with impaired glucose tolerance . The economics of these interventions is important to policymakers . Contribution This cost-effectiveness model estimates that the DPP life-style intervention would cost society about $ 8800 and metformin would cost about $ 29900 per quality -adjusted life-year saved . While lifestyle intervention had a favorable cost-effectiveness profile at any adult age , metformin was not cost-effective after age 65 years . Implication s The cost-effectiveness of lifestyle intervention to prevent type 2 diabetes in high-risk individuals is within the range that American society typically finds acceptable for health care interventions . The Editors During the past half century , the number of persons with diagnosed diabetes in the United States has increased 4- to 6-fold ( 1 ) . Recent large clinical trials from Asia , Europe , and North America have demonstrated that behavioral and medication interventions can delay or prevent the development of type 2 diabetes in persons with impaired glucose tolerance , which is defined by a plasma glucose level between 7.77 mmol/L ( 140 mg/dL ) and 11.04 mmol/L ( 199 mg/dL ) 2 hours after a 75-g oral glucose load ( 2 - 6 ) . The Diabetes Prevention Program ( DPP ) r and omly assigned 3234 nondiabetic persons 25 years of age or older with impaired glucose tolerance and fasting glucose levels between 5.27 mmol/L ( 95 mg/dL ) and 6.94 mmol/L ( 125 mg/dL ) to placebo ; a lifestyle-modification program with the goals of at least a 7 % weight loss and 150 minutes of physical activity per week ; or metformin , 850 mg twice daily ( 4 ) . The mean age of participants was 51 years , and the mean body mass index was 34.0 kg/m2 ; 68 % were women and 45 % were members of minority groups ( 4 ) . The average follow-up was 2.8 years . Compared with the placebo intervention , the lifestyle intervention reduced the incidence of type 2 diabetes by 58 % and the metformin intervention reduced the incidence of type 2 diabetes by 31 % ( 4 ) . We have previously described the costs of the DPP interventions and their cost-effectiveness within the 3-year trial period ( 7 , 8) . In this analysis , we project the costs , health outcomes , and cost-effectiveness of the DPP lifestyle and metformin interventions over a lifetime relative to the placebo intervention . Methods Clinical Trial The lifestyle intervention involved a healthy , low-calorie , low-fat diet and moderate physical activity , such as brisk walking . The lifestyle intervention was implemented with a 16-lesson core curriculum covering diet , exercise , and behavior modification that was taught by case managers on a one-on-one basis , followed by individual sessions ( usually monthly ) and group sessions with case managers ( 9 ) . At the end of the study , 38 % of participants in the lifestyle intervention group had lost at least 7 % of their initial body weight . The metformin and placebo interventions were initiated at a dosage of 850 mg once a day . At 1 month , the dosage of metformin or placebo was increased to 850 mg twice daily . Case managers reinforced adherence during individual quarterly sessions ( 10 ) . At the end of the study , 72 % of participants in the metformin intervention group and 77 % of participants in the placebo intervention group took at least 80 % of the prescribed dose . All participants received st and ard lifestyle recommendations through written information and an annual 20- to 30-minute individual session that emphasized the importance of a healthy lifestyle ( 10 ) . Simulation Model We assessed the progression from impaired glucose tolerance to onset of diabetes to clinical ly diagnosed diabetes to diabetes with complications and death by using a lifetime simulation model originally developed by the Centers for Disease Control and Prevention and Research Triangle Institute International . The model has a Markov structure and includes annual transition probabilities between disease states ( 11 ) . In addition to disease progression , the model tracks costs and quality -adjusted life-years ( QALYs ) . The model has been described elsewhere ( 11 ) . For our analyses , we modified the model to include data from the DPP on progression , costs , and quality of life associated with impaired glucose tolerance , data from the United Kingdom Prospect i ve Diabetes Study ( UKPDS ) on diabetes progression and complications , and new data on cost and quality of life associated with diabetes . A technical report describing the model is available . Supplement . Technical Report Disease Progression , Complications , and Comorbid Conditions Impaired Glucose Tolerance to Onset of Type 2 Diabetes We analyzed data from the DPP to assess the annual hazard of diabetes onset in the lifestyle , metformin , and placebo intervention groups . For patients receiving the placebo intervention , the annual hazard of diabetes onset was 10.8 per 100 person-years . At 3 years of follow-up , the risk reductions for the lifestyle and metformin interventions were 55.8 % and 29.9 % , respectively . In the base-case analysis , we assumed that the lifestyle and metformin interventions would be applied until diabetes onset and that the health and quality -of-life benefits associated with the interventions persisted until diabetes onset . Complications and Comorbid Conditions Associated with Impaired Glucose Tolerance We analyzed data from the DPP and other published sources to assess the prevalence of complications and comorbid conditions in participants with impaired glucose tolerance . At baseline , 6.0 % of DPP participants had microalbuminuria and 0.4 % had nephropathy . The DPP did not measure peripheral neuropathy , but previous studies found that the prevalence of neuropathy in persons with impaired glucose tolerance was 74 % of that in persons with newly diagnosed type 2 diabetes ( 12 ) and 12.3 % of persons with newly diagnosed type 2 diabetes have neuropathy ( 13 ) . Therefore , we assumed that at baseline , 8.5 % of DPP participants had clinical neuropathy . At baseline , 28 % of DPP participants had hypertension , 45 % had dyslipidemia , 7 % were smokers , 1.1 % had a history of cerebrovascular disease , and 2.0 % had a history of myocardial infa rct ion . No other complications were present . We assumed that during impaired glucose tolerance , microvascular or neuropathic complications would not progress . We assumed that hypertension and dyslipidemia developed at the rates observed in the DPP . On the basis of 2 large studies ( 14 , 15 ) , we assumed that the incidences of coronary heart disease and cerebrovascular disease in patients with impaired glucose tolerance were 58 % and 56 % , respectively , of those observed in patients with type 2 diabetes . We further assumed that nondiabetes-related mortality for persons with impaired glucose tolerance was the same as for persons with diabetes ( 16 ) . Onset of Type 2 Diabetes to Clinical Diagnosis of Type 2 Diabetes In the DPP , participants were tested for diabetes every 6 months ; diabetes was diagnosed at onset . In routine clinical practice , type 2 diabetes is estimated to develop 8 to 12 years before its clinical diagnosis ( 17 , 18 ) . In our base-case analysis , we therefore assumed that a 10-year delay occurred between the onset and clinical diagnosis of diabetes . Participants in the DPP had a mean hemoglobin A1c level of 6.4 % at the onset of diabetes . Participants in the UKPDS had a mean hemoglobin A1c of 7.1 % after a dietary run-in period but before r and omization ( 13 ) . Both DPP placebo participants and UKPDS participants received st and ard lifestyle recommendations . Accordingly , we assumed that during the 10-year interval between onset and clinical diagnosis of diabetes , patients were treated for type 2 diabetes and that hemoglobin A1c level increased at 0.07 % per year from 6.4 % to 7.1 % . Complications and Comorbid Conditions Associated with Undiagnosed Diabetes We further assumed that between onset and clinical diagnosis of diabetes , microvascular and neuropathic complications progressed slowly , such that by clinical diagnosis of type 2 diabetes , their prevalence reached the level observed in the UKPDS cohort at r and omization ( 13 , 19 , 20 ) . We assumed that blood pressure and lipid levels progressed as they did in DPP participants and that cardiovascular complications occurred as they would in type 2 diabetes according to risk factors and hemglobin A1c level ( 21 , 22 ) . Clinical Diagnosis of Type 2 Diabetes to Diabetes with Complications and Death We assumed that after clinical diagnosis , all persons with type 2 diabetes received intensive glycemic management as described in the UKPDS ( 13 ) . We modeled changes in hemoglobin A1c and diabetes treatments to reflect those observed in the UKPDS intensive therapy group . We based risk for retinopathy progression on UKPDS 38 ( 23 ) , risk for nephropathy progression on UKPDS 64 ( 20 ) , and risk for neuropathy progression on UKPDS 33 ( 13 ) . We based risk for cerebrovascular disease on UKPDS 60 ( 22 ) and risk for coronary heart disease on UKPDS 56 ( 21 ) . Costs Costs of Impaired Glucose Tolerance To estimate the total direct medical costs of impaired glucose tolerance , we considered the costs of the DPP interventions ( the cost of identifying participants , implementing and maintaining the interventions , and monitoring and treating the side effects of the interventions ) and the costs of the medical care outside the DPP ( 7 ) . In analyses from the perspective of society , we included both direct medical costs and direct nonmedical costs . We did not include indirect costs because they are captured in the assessment of QALYs ( 24 ) . Table 1 shows the total direct medical costs by treatment group , sex , and year in the DPP ( 7 ) . Costs were higher in the lifestyle and metformin interventions than in the placebo intervention and higher in women than in men . Costs decreased over time in all 3 intervention groups but after year 1 tended to decrease more in the lifestyle than OBJECTIVE We evaluate whether lifestyle and metformin interventions used to prevent diabetes have durable effects on markers of inflammation and coagulation and whether the effects are influenced by the development of diabetes . RESEARCH DESIGN AND METHODS The Diabetes Prevention Program was a controlled clinical trial of 3,234 subjects at high risk for diabetes who were r and omized to lifestyle , metformin , or placebo interventions for 3.4 years . Diabetes was diagnosed semiannually by fasting glucose and annually by oral glucose tolerance testing . In addition to baseline testing , anthropometry was performed every 6 months ; fasting insulin yearly ; and hs-CRP , tissue plasminogen activator ( tPA ) , and fibrinogen at 1 year and end of study ( EOS ) . RESULTS CRP and tPA levels were unchanged in the placebo group but fell in the lifestyle and metformin groups at 1 year and remained lower at EOS . These reductions were not seen in those who developed diabetes over the course of the study despite intervention . Fibrinogen was lower at 1 year in the lifestyle group . Differences in weight and weight change explained most of the influence of diabetes on the CRP response in the lifestyle group , but only partly in the placebo and metformin groups . Weight , insulin sensitivity , and hyperglycemia differences each accounted for the influence of diabetes on the tPA response . CONCLUSIONS Lifestyle and metformin interventions have durable effects to lower hs-CRP and tPA . Incident diabetes prevented these improvements , and this was accounted for by differences in weight , insulin resistance , and glucose levels Clinical trials have demonstrated that lifestyle changes can prevent type 2 diabetes , but the importance of leisure-time physical activity ( LTPA ) is still unclear . We carried out post hoc analyses on the role of LTPA in preventing type 2 diabetes in 487 men and women with impaired glucose tolerance who had completed 12-month LTPA question naires . The subjects were participants in the Finnish Diabetes Prevention Study , a r and omized controlled trial of lifestyle changes including diet , weight loss , and LTPA . There were 107 new cases of diabetes during the 4.1-year follow-up period . Individuals who increased moderate-to-vigorous LTPA or strenuous , structured LTPA the most were 63 - 65 % less likely to develop diabetes . Adjustment for changes in diet and body weight during the study attenuated the association somewhat ( upper versus lower third : moderate-to-vigorous LTPA , relative risk 0.51 , 95 % CI 0.26 - 0.97 ; strenuous , structured LTPA , 0.63 , 0.35 - 1.13 ) . Low-intensity and lifestyle LTPA and walking also conferred benefits , consistent with the finding that the change in total LTPA ( upper versus lower third : 0.34 , 0.19 - 0.62 ) was the most strongly associated with incident diabetes . Thus increasing physical activity may substantially reduce the incidence of type 2 diabetes in high-risk individuals Background A r and omized control trial was performed to test whether a lifestyle intervention program , carried out in a primary healthcare setting using existing re sources , can reduce the incidence of type 2 diabetes in Japanese with impaired glucose tolerance ( IGT ) . The results of 3 years ' intervention are summarized . Methods Through health checkups in communities and workplaces , 304 middle-aged IGT subjects with a mean body mass index ( BMI ) of 24.5 kg/m2 were recruited and r and omized to the intervention group or control group . The lifestyle intervention was carried out for 3 years by public health nurses using the curriculum and educational material s provided by the study group . Results After 1 year , the intervention had significantly improved body weight ( -1.5 ± 0.7 vs. -0.7 ± 2.5 kg in the control ; p = 0.023 ) and daily non-exercise leisure time energy expenditure ( 25 ± 113 vs. -3 ± 98 kcal ; p = 0.045 ) . Insulin sensitivity assessed by the Matsuda index was improved by the intervention during the 3 years . The 3-year cumulative incidence tended to be lower in the intervention group ( 14.8 % vs.8.2 % , log-rank test : p = 0.097 ) . In a sub- analysis for the subjects with a BMI > 22.5 kg/m2 , a significant reduction in the cumulative incidence was found ( p = 0.027 ) . Conclusions The present lifestyle intervention program using existing healthcare re sources is beneficial in preventing diabetes in Japanese with IGT . This has important implication s for primary healthcare-based diabetes prevention . Trial registration OBJECTIVE Metformin produced weight loss and delayed or prevented diabetes in the Diabetes Prevention Program ( DPP ) . We examined its long-term safety and tolerability along with weight loss , and change in waist circumference during the DPP and its long-term follow-up . RESEARCH DESIGN AND METHODS The r and omized double-blind clinical trial of metformin or placebo followed by a 7–8-year open-label extension and analysis of adverse events , tolerability , and the effect of adherence on change in weight and waist circumference . RESULTS No significant safety issues were identified . Gastrointestinal symptoms were more common in metformin than placebo participants and declined over time . During the DPP , average hemoglobin and hematocrit levels were slightly lower in the metformin group than in the placebo group . Decreases in hemoglobin and hematocrit in the metformin group occurred during the first year following r and omization , with no further changes observed over time . During the DPP , metformin participants had reduced body weight and waist circumference compared with placebo ( weight by 2.06 ± 5.65 % vs. 0.02 ± 5.52 % , P < 0.001 , and waist circumference by 2.13 ± 7.06 cm vs. 0.79 ± 6.54 cm , P < 0.001 in metformin vs. placebo , respectively ) . The magnitude of weight loss during the 2-year double-blind period was directly related to adherence ( P < 0.001 ) . Throughout the unblinded follow-up , weight loss remained significantly greater in the metformin group than in the placebo group ( 2.0 vs. 0.2 % , P < 0.001 ) , and this was related to the degree of continuing metformin adherence ( P < 0.001 ) . CONCLUSIONS Metformin used for diabetes prevention is safe and well tolerated . Weight loss is related to adherence to metformin and is durable for at least 10 years of treatment Background The Finnish Diabetes Prevention Study ( DPS ) was a r and omized controlled trial , which showed that it is possible to prevent type 2 diabetes by lifestyle changes . The aim of the present study was to examine whether the lifestyle intervention had an effect on the ten-year mortality and cardiovascular morbidity in the DPS participants originally r and omized either into an intervention or control group . Furthermore , we compared these results with a population -based cohort comprising individuals of varying glucose tolerance states . Methods and Findings Middle-aged , overweight people with IGT ( n = 522 ) were r and omized into intensive intervention ( including physical activity , weight reduction and dietary counseling ) , or control “ mini-intervention ” group . Median length of the intervention period was 4 years and the mean follow-up was 10.6 years . The population -based reference study cohort included 1881 individuals ( 1570 with normal glucose tolerance , 183 with IGT , 59 with screen-detected type 2 diabetes , 69 with previously known type 2 diabetes ) with the mean follow-up of 13.8 years . Mortality and cardiovascular morbidity data were collected from the national Hospital Discharge Register and Causes of Death Register . Among the DPS participants who consented for register linkage ( n = 505 ) , total mortality ( 2.2 vs. 3.8 per 1000 person years , hazard ratio HR = 0.57 , 95 % CI 0.21–1.58 ) and cardiovascular morbidity ( 22.9 vs. 22.0 per 1000 person years , HR = 1.04 , 95 % CI 0.72–1.51 ) did not differ significantly between the intervention and control groups . Compared with the population -based cohort with impaired glucose tolerance , adjusted HRs were 0.21 ( 95 % CI 0.09–0.52 ) and 0.39 ( 95 % CI 0.20–0.79 ) for total mortality , and 0.89 ( 95 % CI 0.62–1.27 ) and 0.87 ( 0.60–1.27 ) for cardiovascular morbidity in the intervention and control groups of the DPS , respectively . The risk of death in DPS combined cohort was markedly lower than in FINRISK IGT cohort ( adjusted HR 0.30 , 95 % CI 0.17–0.54 ) , but there was no significant difference in the risk of CVD ( adjusted HR 0.88 , 95 % CI 0.64–1.21 ) . Conclusions Lifestyle intervention among persons with IGT did not decrease cardiovascular morbidity during the first 10 years of follow-up . However , the statistical power may not be sufficient to detect small differences between the intervention and control groups . Low total mortality among participants of the DPS compared with individuals with IGT in the general population could be ascribed to a lower cardiovascular risk profile at baseline and regular follow-up . Trial Registration Clinical Trials.gov Background The prevention of type 2 diabetes is a globally recognised health care priority , but there is a lack of rigorous research investigating optimal methods of translating diabetes prevention programmes , based on the promotion of a healthy lifestyle , into routine primary care . The aim of the study is to establish whether a pragmatic structured education programme targeting lifestyle and behaviour change in conjunction with motivational maintenance via the telephone can reduce the incidence of type 2 diabetes in people with impaired glucose regulation ( a composite of impaired glucose tolerance and /or impaired fasting glucose ) identified through a vali date d risk score screening programme in primary care . Design Cluster r and omised controlled trial undertaken at the level of primary care practice s. Follow-up will be conducted at 12 , 24 and 36 months . The primary outcome is the incidence of type 2 diabetes . Secondary outcomes include changes in HbA1c , blood glucose levels , cardiovascular risk , the presence of the Metabolic Syndrome and the cost-effectiveness of the intervention . Methods The study consists of screening and intervention phases within 44 general practice s coordinated from a single academic research centre . Those at high risk of impaired glucose regulation or type 2 diabetes are identified using a risk score and invited for screening using a 75 g-oral glucose tolerance test . Those with screen detected impaired glucose regulation will be invited to take part in the trial . Practice s will be r and omised to st and ard care or the intensive arm . Participants from intensive arm practice s will receive a structured education programme with motivational maintenance via the telephone and annual refresher sessions . The study will run from 2009–2014 . Discussion This study will provide new evidence surrounding the long-term effectiveness of a diabetes prevention programme conducted within routine primary care in the United Kingdom . Trial registration 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 Objectives Prevention of type 2 diabetes mellitus ( TD2 M ) is a priority for healthcare systems . We estimated the cost-effectiveness compared with st and ard care of a structured education programme ( Let 's Prevent ) targeting lifestyle and behaviour change to prevent progression to T2DM in people with prediabetes . Design Cost-effectiveness analysis alongside r and omised controlled trial . Setting 44 general practice s in Leicestershire , Engl and . Participants 880 participants with prediabetes r and omised to receive either st and ard care or a 6-hour group structured education programme with follow-up sessions in a primary care setting . Main outcome measure Incremental cost utility from the UK National Health Service ( NHS ) perspective . Quality of life and re source use measured from baseline and during the 36 months follow-up using the EuroQoL EQ-5D and 15D instruments and an economic question naire . Outcomes measured using quality -adjusted life years ( QALYs ) and healthcare costs calculated in 2012–2013 prices . Results After accounting for clustering and missing data , the intervention group was found to have a net gain of 0.046 ( 95 % CI −0.0171 to 0.109 ) QALYs over 3 years , adjusted for baseline utility , at an additional cost of £ 168 ( 95 % CI −395 to 732 ) per patient compared with the st and ard care group . The incremental cost-effectiveness ratio is £ 3643/QALY with an 86 % probability of being cost-effective at a willingness to pay threshold of £ 20 000/QALY . Conclusions The education programme had higher costs and higher quality of life compared with the st and ard care group . The Let 's Prevent programme is very likely to be cost-effective at a willingness to pay threshold of £ 20 000/QALY gained . Trial registration number IS RCT N80605705 BACKGROUND Type 2 diabetes can often be prevented by lifestyle modification ; however , successful lifestyle intervention programmes are labour intensive . Mobile phone messaging is an inexpensive alternative way to deliver educational and motivational advice about lifestyle modification . We aim ed to assess whether mobile phone messaging that encouraged lifestyle change could reduce incident type 2 diabetes in Indian Asian men with impaired glucose tolerance . METHODS We did a prospect i ve , parallel-group , r and omised controlled trial between Aug 10 , 2009 , and Nov 30 , 2012 , at ten sites in southeast India . Working Indian men ( aged 35 - 55 years ) with impaired glucose tolerance were r and omly assigned ( 1:1 ) with a computer-generated r and omisation sequence to a mobile phone messaging intervention or st and ard care ( control group ) . Participants in the intervention group received frequent mobile phone messages compared with controls who received st and ard lifestyle modification advice at baseline only . Field staff and participants were , by necessity , not masked to study group assignment , but allocation was concealed from laboratory personnel as well as principal and co-investigators . The primary outcome was incidence of type 2 diabetes , analysed by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00819455 . RESULTS We assessed 8741 participants for eligibility . 537 patients were r and omly assigned to either the mobile phone messaging intervention ( n=271 ) or st and ard care ( n=266 ) . The cumulative incidence of type 2 diabetes was lower in those who received mobile phone messages than in controls : 50 ( 18 % ) participants in the intervention group developed type 2 diabetes compared with 73 ( 27 % ) in the control group ( hazard ratio 0·64 , 95 % CI 0·45 - 0·92 ; p=0·015 ) . The number needed to treat to prevent one case of type 2 diabetes was 11 ( 95 % CI 6 - 55 ) . One patient in the control group died suddenly at the end of the first year . We recorded no other serious adverse events . INTERPRETATION Mobile phone messaging is an effective and acceptable method to deliver advice and support towards lifestyle modification to prevent type 2 diabetes in men at high risk . FUNDING The UK India Education and Research Initiative , the World Diabetes Foundation Background : Positive predictive value ( PPV ) of hemoglobin A1c ( HbA1c ) for diagnosis of prediabetes in clinical practice has not been well studied . Methods : In a prospect i ve study , patients diagnosed with prediabetes based on HbA1c ( 5.7%–6.4 % ) underwent a 75-g oral glucose tolerance test ( OGTT ) as the gold st and ard test to diagnose dysglycemia . Demographics , anthropometrics , comorbidity , concomitant prescription medications and biochemical data were collected . Results : We identified 66 patients with HbA1c-based prediabetes with a mean HbA1c of 6.00 ± 0.20 % . However , based on the OGTT , 32 had normal glucose tolerance ( NGT ) , 26 had prediabetes and 8 had diabetes yielding a PPV of HbA1c of 39.4 % . In univariate analysis , the patients with the OGTT-based prediabetes administered more medications for associated medical problems compared with the NGT group ( 5.9 ± 2.2 versus 2.6 ± 1.8 , P < 0.0001 ) . After adjustment for baseline variables , the medication use remained significantly different between OGTT-based prediabetes and NGT groups ( P = 0.041 ) . Conclusions : PPV of HbA1c for diagnosis of prediabetes in clinical setting is low . Patients with HbA1c of 5.7 % to 6.4 % should undergo OGTT to confirm diagnosis of dysglycemia OBJECTIVE The Diabetes Prevention Program ( DPP ) showed that intensive lifestyle intervention reduced the risk of diabetes by 58 % . This paper examines demographic , psychosocial , and behavioral factors related to achieving weight loss and physical activity goals in the DPP lifestyle participants . RESEARCH METHODS AND PROCEDURES Lifestyle participants ( n = 1079 ; mean age = 50.6 , BMI = 33.9 , 68 % female , and 46 % from minority groups ) had goals of 7 % weight loss and 150 min/wk of physical activity . Goal achievement was assessed at the end of the 16-session core curriculum ( approximately week 24 ) and the final intervention visit ( mean = 3.2 years ) as a function of demographic , psychosocial , and behavioral variables . RESULTS Forty-nine percent met the weight loss goal and 74 % met the activity goal initially , while 37 % and 67 % , respectively , met these goals long-term . Men and those with lower initial BMI were more likely to meet activity but not weight loss goals . Hispanic , Asian , and Native Americans were more likely to meet the long-term activity goals , and whites were more likely to meet the initial weight loss goal . In multivariate analyses , meeting the long-term weight loss goal and both activity goals increased with age , while psychosocial and depression measures were unrelated to goal achievement . Dietary self-monitoring was positively related to meeting both weight loss and activity goals , and meeting the activity goal was positively related to meeting the weight loss goal . Participants who met initial goals were 1.5 to 3.0 times more likely to meet these goals long-term . DISCUSSION Success at meeting the weight loss and activity goals increased with age . Initial success predicted long-term success . Self-monitoring and meeting activity goals were related to achieving and sustaining weight loss Type 2 diabetes mellitus is increasing worldwide largely as a result from increasing obesity and sedentary lifestyle . The Finnish Diabetes Prevention Study ( DPS ) is the first individually r and omized controlled clinical trial to test the feasibility and efficacy of lifestyle modification in high-risk subjects . We r and omly assigned 522 ( 172 men , 350 women ) middle-aged ( mean age 55 yr ) , overweight ( mean body mass index 31 kg/m(2 ) ) subjects with impaired glucose tolerance either to the lifestyle intervention or control group . Each subject in the intervention group received individualized counseling aim ed at reducing weight and intake of total and saturated fat , and increasing intake of fiber and physical activity . An oral glucose tolerance test was performed annually to detect incident cases of diabetes and to measure changes in metabolic parameters . The mean ( + /- SD ) weight reduction from baseline to year 1 and to year 2 , respectively , was 4.2 + /- 5.1 kg and 3.5 + /- 5.5 in the intervention group and 0.8 + /- 3.7 kg and 0.8 + /- 4.4 in the control group ( P < 0.001 between the groups ) . At the time of first analysis of the outcome data the mean duration of follow-up was 3.2 yr . The risk of diabetes was reduced by 58 % ( P < 0.001 ) in the intervention group compared with the control group . The reduction in the incidence of diabetes was directly associated with number and magnitude of lifestyle changes made . In conclusion , the DPS is the first controlled trial demonstrating that type 2 diabetes can be prevented by changes in lifestyle in high-risk subjects BACKGROUND Type 2 diabetes mellitus is increasingly common , primarily because of increases in the prevalence of a sedentary lifestyle and obesity . Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known . METHODS We r and omly assigned 522 middle-aged , overweight subjects ( 172 men and 350 women ; mean age , 55 years ; mean body-mass index [ weight in kilograms divided by the square of the height in meters ] , 31 ) with impaired glucose tolerance to either the intervention group or the control group . Each subject in the intervention group received individualized counseling aim ed at reducing weight , total intake of fat , and intake of saturated fat and increasing intake of fiber and physical activity . An oral glucose-tolerance test was performed annually ; the diagnosis of diabetes was confirmed by a second test . The mean duration of follow-up was 3.2 years . RESULTS The mean ( + /-SD ) amount of weight lost between base line and the end of year 1 was 4.2+/-5.1 kg in the intervention group and 0.8+/-3.7 kg in the control group ; the net loss by the end of year 2 was 3.5+/-5.5 kg in the intervention group and 0.8+/-4.4 kg in the control group ( P<0.001 for both comparisons between the groups ) . The cumulative incidence of diabetes after four years was 11 percent ( 95 percent confidence interval , 6 to 15 percent ) in the intervention group and 23 percent ( 95 percent confidence interval , 17 to 29 percent ) in the control group . During the trial , the risk of diabetes was reduced by 58 percent ( P<0.001 ) in the intervention group . The reduction in the incidence of diabetes was directly associated with changes in lifestyle . CONCLUSIONS Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects Healthy Living Partnerships to Prevent Diabetes ( HELP PD ) is a r and omized controlled trial design ed to translate the Diabetes Prevention Program ( DPP ) lifestyle intervention into a community setting using community health workers engaged through an existing Diabetes Care Center ( DCC ) . Overweight and obese ( BMI 25 - 40 kg/m² ) individuals with pre-diabetes ( fasting blood glucose 95 - 125 mg/dl ) with no medical contraindications to participate in a lifestyle intervention were recruited for participation in this study . St and ard recruitment strategies were employed , including mass mailing , direct provider referral , and community events . Participant recruitment and r and omization for this trial began in 2007 and was concluded in 2009 . 1818 screenings were conducted ; of these , 326 ( 17.9 % ) qualified and 301 ( 16.6 % ) participants were r and omized over a 21 month period . 23.8 % of potential participants were excluded during the initial telephone screening , primarily for BMI and recent history of CVD . The majority of participants ( 220 , 73.1 % ) reported mass mailing as their primary source of information about the study . Mass mailing was more effective with participants who identified themselves as white when compared to African-Americans . The cost of recruitment per r and omized participant was $ 816 , which includes direct costs and staff effort . 41 % of the r and omized participants were male and approximately 27 % reported a race or ethnicity other than white . In comparison to the DPP study cohort , the HELP PD population is older , more educated and predominately white . These differences , reflecting in part the community in which HELP PD was conducted , may have implication s for retention and adherence in the lifestyle intervention group Aims /hypothesisLifestyle modification helps in the primary prevention of diabetes in multiethnic American , Finnish and Chinese population s. In a prospect i ve community-based study , we tested whether the progression to diabetes could be influenced by interventions in native Asian Indians with IGT who were younger , leaner and more insulin resistant than the above population s. Methods We r and omised 531 ( 421 men 110 women ) subjects with IGT ( mean age 45.9±5.7 years , BMI 25.8±3.5 kg/m2 ) into four groups . Group 1 was the control , Group 2 was given advice on lifestyle modification ( LSM ) , Group 3 was treated with metformin ( MET ) and Group 4 was given LSM plus MET . The primary outcome measure was type 2 diabetes as diagnosed using World Health Organization criteria . Results The median follow-up period was 30 months , and the 3-year cumulative incidences of diabetes were 55.0 % , 39.3 % , 40.5 % and 39.5 % in Groups 1–4 , respectively . The relative risk reduction was 28.5 % with LSM ( 95 % CI 20.5–37.3 , p=0.018 ) , 26.4 % with MET ( 95 % CI 19.1–35.1 , p=0.029 ) and 28.2 % with LSM + MET ( 95 % CI 20.3–37.0 , p=0.022 ) , as compared with the control group . The number needed to treat to prevent one incident case of diabetes was 6.4 for LSM , 6.9 for MET and 6.5 for LSM + MET . Conclusions /interpretationProgression of IGT to diabetes is high in native Asian Indians . Both LSM and MET significantly reduced the incidence of diabetes in Asian Indians with IGT ; there was no added benefit from combining them This study was undertaken to determine whether impaired glucose tolerance and associated risk factors for cardiovascular disease can be improved with ' healthy living ' by diet and exercise or with sulphonylurea therapy . Patients were recruited by screening subjects with either a family history of type II diabetes , previous gestational diabetes , or a previously raised plasma glucose ( 5.6 - 6.6 mmol/l ) . Impaired glucose tolerance was defined as hyperglycaemia on two separate tests , an achieved glucose level after a glucose infusion test above the 90th percentile of an age-matched normal population ( > 9.3 mmol/l ) or a fasting plasma glucose above the 95th percentile ( > 5.6 mmol/l ) . Thirty-seven subjects with impaired glucose tolerance were entered into a r and omized , prospect i ve study for 6 months with allocations to healthy living or double blind to sulphonylurea ( gliclazide 40 mg twice daily ) or placebo tablets . The study took place in an out-patient setting , with three times weekly exercise sessions at a Sports Centre . After 6 months the placebo group showed no change in plasma glucose , cholesterol and blood pressure . The subjects receiving gliclazide showed improved glucose levels ( mean fasting plasma glucose levels fell from 5.8 to 5.1 mmol/l , p < 0.05 ) but no significant change in plasma cholesterol or blood pressure . The healthy living group , after exclusion of four non-compliant subjects , showed no change in glucose levels , but a decreased systolic blood pressure ( fall in mean from 124 to 116 mmHg , p < 0.05 ) and plasma cholesterol levels ( fall in mean from 5.2 to 4.5 mmol/l , p < 0.01 ) . with an increase in HDL : LDL ratio ( rise in mean from 0.39 to 0.46 , p < 0.05 ) . Subjects with impaired glucose tolerance may benefit in different ways from gliclazide and healthy living . The metabolic responses to each therapy may help to decrease the risk of developing diabetes and cardiovascular disease The Diabetes Prevention Program is a r and omized clinical trial testing strategies to prevent or delay the development of type 2 diabetes in high-risk individuals with elevated fasting plasma glucose concentrations and impaired glucose tolerance . The 27 clinical centers in the U.S. are recruiting at least 3,000 participants of both sexes , approximately 50 % of whom are minority patients and 20 % of whom are > or = 65 years old , to be assigned at r and om to one of three intervention groups : an intensive lifestyle intervention focusing on a healthy diet and exercise and two masked medication treatment groups -- metformin or placebo -- combined with st and ard diet and exercise recommendations . Participants are being recruited during a 2 2/3-year period , and all will be followed for an additional 3 1/3 to 5 years after the close of recruitment to a common closing date in 2002 . The primary outcome is the development of diabetes , diagnosed by fasting or post-challenge plasma glucose concentrations meeting the 1997 American Diabetes Association criteria . The 3,000 participants will provide 90 % power to detect a 33 % reduction in an expected diabetes incidence rate of at least 6.5 % per year in the placebo group . Secondary outcomes include cardiovascular disease and its risk factors ; changes in glycemia , beta-cell function , insulin sensitivity , obesity , diet , physical activity , and health-related quality of life ; and occurrence of adverse events . A fourth treatment group -- troglitazone combined with st and ard diet and exercise recommendations --was included initially but discontinued because of the liver toxicity of the drug . This r and omized clinical trial will test the possibility of preventing or delaying the onset of type 2 diabetes in individuals at high risk Aims : To compare data on cardiovascular risk factor changes in lipids , insulin , proinsulin , fibrinolysis , leptin and C-reactive protein , and on diabetes incidence , in relation to changes in lifestyle . Methods : The study was a r and omized lifestyle intervention trial conducted in northern Sweden between 1995 and 2000 , in 168 individuals with impaired glucose tolerance ( IGT ) and body mass index above 27 at start . The intensive intervention group ( n = 83 ) was subjected to a 1-month residential lifestyle programme . The usual care group ( n = 85 ) participated in a health examination ending with a single counselling session . Follow-up was conducted at 1 , 3 and 5 years . Results : At 1-year follow-up , an extensive cardio-metabolic risk factor reduction was demonstrated in the intensive intervention group , along with a 70 % decrease of progress to type 2 diabetes . At 5-year follow-up , most of these beneficial effects had disappeared . Reported physical activity and fibre intake as well as high-density lipoprotein cholesterol were still increased , and fasting insulin and proinsulin were lower . Conclusions : The intervention affected several important cardio-metabolic risk variables beneficially , and reduced the risk for type 2 diabetes , but the effects persisted only as long as the new lifestyle was maintained . Increased physical activity seemed to be the behaviour that was most easy to preserve OBJECTIVE To assess the effects of lifestyle intervention on cardiovascular risk factors in general and especially on fibrinolysis . DESIGN R and omized clinical study . SUBJECTS A total of 186 subjects with impaired glucose tolerance and obesity . INTERVENTIONS The intervention programme included a low-fat , high-fibre diet and regular physical exercise . Half of the participants ( n = 93 ) took part in a one-month learning and training session using different behavioural modification techniques and conducted in a full-board wellness centre ( intense intervention group ) . The other half ( n = 93 ) was r and omized a one-hour counselling session with a specially trained nurse ( usual care group ) . Follow-up was carried out after 12 months . MAIN OUTCOME MEASURES Body weight , oxygen consumption , plasminogen activator inhibitor type 1 ( PAI-1 ) activity , tissue plasminogen activator ( tPA ) antigen , fibrinogen and fasting plasma insulin measured at the start of the programme and at follow-up after 1 year . RESULTS The intense intervention group had a mean weight decline by 1 year of 5.4 kg compared to 0.5 kg in the usual care group . Oxygen consumption in the intense group increased 10 % vs. a 1 % decline in the usual care group . In the intense group , PAI-1 activity decreased 31 % ( -10.1 U mL(-1 ) ) , which was significantly more than in the usual care group ( 12 % ; -3.0 U mL(-1 ) ) . The corresponding reductions in tPA antigen were 14 % ( -1.65 microg L(-1 ) ) and 6 % ( -0.69 microg L(-1 ) ) . CONCLUSIONS The present r and omized study shows that an intense lifestyle programme has sustained beneficial effects on fibrinolysis OBJECTIVE To investigate if a six-year intensive lifestyle intervention in people with pre-diabetes lead to reduction of cardiovascular events and cardiovascular disease ( CVD ) mortality in subsequent 23 years . METHODS Five hundreds and nineteen subjects with normal glucose tolerance ( NGT ) and 577 subjects with impaired glucose tolerance ( IGT ) in Da Qing city were recruited in the study in 1986 . The IGT subjects r and omly assigned to either the no-intervention group or one of three lifestyle intervention groups ( diet , exercise , or diet plus exercise ) to receive a 6-year lifestyle intervention . In 2009 , the participants were followed up to assess the primary outcomes of cardiovascular events and CVD mortality by a question naire and medical records . RESULTS Subjects in IGT no-intervention group had the highest incidences of cardiovascular events ( 44.44 % ) and CVD mortality ( 20.00 % ) , while those in NGT group had the lowest incidences of cardiovascular events ( 29.59 % ) and CVD mortality ( 7.52 % ) after 23-year follow-up . The incidences of cardiovascular events and CVD mortality in IGT intervention subjects were 37.84 % and 12.53 % , respectively . The multivariable analyses showed that , after controlling of age , gender , BMI smoking , blood pressure and cardiovascular event at baseline , the CVD mortality and incidence of cardiovascular events in IGT no-intervention group was 1.89 ( HR = 1.89 , 95%CI 1.11 - 3.22 , P = 0.02 ) and 1.38 ( HR = 1.38 , 95%CI 1.01 - 1.90 , P = 0.04 ) times of those in NGT group . However , the CVD mortality and incidence of cardiovascular events were not different in the IGT intervention group compared with those in the NGT group ( HR = 1.39 , 95%CI 0.89 - 2.18 , P = 0.15 and HR = 1.25 , 95%CI 0.98 - 1.59 , P = 0.07 , respectively ) . CONCLUSIONS Subjects with IGT were at high risk for cardiovascular events and mortality . A six-year lifestyle intervention in this population can reduce both the incidence of cardiovascular event and CVD mortality Type 2 diabetes is increasing among youth , with minority youth at highest risk . This preliminary study tested the feasibility of a school-based program to prevent type 2 diabetes in youth at risk . Forty-one participants ( age 12.6 + /- 1.1 years ; 63 % female , 51 % African American , 44 % Hispanic , and 5 % Caucasian ) were r and omly assigned to one of two groups . Both the experimental and control groups received nutrition education and exercise training . The experimental group also received coping skills training . Data collected included body mass index ( BMI ) , insulin resistance , dietary intake ( 24-Hour Food Recall ) , self-efficacy ( Health Behavior Question naire ) , activity ( Revised Godin-Shepard Activity Survey ) , and parents ' health promoting behaviors ( Health Promoting Lifestyle Profile III ) . At baseline BMI ranged from 27 to 53 ( M = 36.2 + /- 6.0 ) , and 95 % ( n = 39 ) demonstrated insulin resistance or pre-diabetes on an oral glucose tolerance test . After 12 months , the experimental group showed trends in improved usual food choices ( p = .1 ) and increased dietary knowledge ( p = .3 ) . They also demonstrated lower glucose ( p = .07 ) and insulin levels ( p = .2 ) . Experimental group parents demonstrated improved health responsibility ( p = .03 ) , healthier nutrition choices ( p = .05 ) , improved stress management skills ( p = .05 ) , increased activity ( p = .2 ) , and increased spirituality ( p = .2 ) . Data suggest a school-based program tailored to multiethnic youth may prove successful in helping these youth increase activity , improve nutrition status , and stabilize glucose and insulin metabolism , and also may be effective in changing parent health behavior The study on lifestyle-intervention and impaired glucose tolerance Maastricht ( SLIM ) is a 3 years r and omised clinical trial design ed to evaluate the effect of a combined diet and physical activity intervention program on glucose tolerance in a Dutch population at increased risk for developing type 2 diabetes . Here the design of the lifestyle-intervention study is described and results are presented from the preliminary population screening , conducted between March 1999 and June 2000 . In total , 2,820 subjects with an increased risk of having disturbances in glucose homeostasis ( i.e. age > 40 years and BMI > 25 kg/m(2 ) or a family history of diabetes ) underwent a first oral glucose tolerance test ( OGTT ) . Abnormal glucose homeostasis was detected in 826 subjects ( 30.4 % ) : 226 type 2 diabetes ( type 2DM , 8.3 % ) , 215 impaired fasting glucose ( IFG , 7.9 % ) and 385 impaired glucose tolerance ( IGT , 14.2 % ) . Both increasing age and BMI were strongly related to the prevalence of IGT and diabetes . After a second OGTT , 114 subjects with glucose intolerance and in otherwise good health were eligible for participation in the intervention study ( SLIM ) . The high prevalence of disturbances in glucose homeostasis observed in the preliminary screening underscore the importance of early ( lifestyle ) interventions in those at risk for developing diabetes . SLIM will address this topic in the Dutch population BACKGROUND Although numerous studies have translated the Diabetes Prevention Program lifestyle intervention into various setting s , no study to date has reported a formal cost analysis . PURPOSE To describe costs associated with the Healthy Living Partnerships to Prevent Diabetes ( HELP PD ) trial . DESIGN HELP PD was a 24-month RCT testing the impact of a lifestyle weight-loss intervention administered through a diabetes education program and delivered by community health workers ( CHWs ) on blood glucose and body weight among prediabetics . SETTING / PARTICIPANTS In all , 301 participants with prediabetes were r and omized in Forsyth County NC . Data reported in these analyses were collected in 2007 - 2011 and analyzed in 2011 - 2012 . INTERVENTION The lifestyle weight-loss group had a 7 % weight loss goal achieved and maintained by caloric restriction and increased physical activity . The usual care group received two visits with a registered dietitian and monthly newsletters . MAIN OUTCOME MEASURES Measures are direct medical costs , direct nonmedical costs , and indirect costs over the 2-year study period . Research costs are excluded . RESULTS The direct medical cost ( in 2010 dollars ) to identify one participant was $ 16.85 . Direct medical costs per capita for participants in the usual care group were $ 142 and $ 850 for lifestyle weight-loss participants . Per capita direct costs of care outside the study were $ 7454 for the usual care group and $ 5177 for the lifestyle weight-loss group . Per capita direct nonmedical costs were $ 12,881 for the usual care group and $ 13,836 for the lifestyle weight-loss group . The lifestyle weight-loss group in HELP PD cost $ 850 in direct medical costs for 2 years , compared to $ 2631 in direct medical costs for the first 2 years of DPP . CONCLUSIONS A community-based translation of the DPP can be delivered effectively and with reduced costs BACKGROUND Lifestyle interventions can prevent the deterioration of impaired glucose tolerance to manifest type 2 diabetes , at least as long as the intervention continues . In the extended follow-up of the Finnish Diabetes Prevention Study , we assessed the extent to which the originally-achieved lifestyle changes and risk reduction remain after discontinuation of active counselling . METHODS Overweight , middle-aged men ( n=172 ) and women ( n=350 ) with impaired glucose tolerance were r and omly assigned to intensive lifestyle intervention or control group . After a median of 4 years of active intervention period , participants who were still free of diabetes were further followed up for a median of 3 years , with median total follow-up of 7 years . Diabetes incidence , bodyweight , physical activity , and dietary intakes of fat , saturated fat , and fibre were measured . FINDINGS During the total follow-up , the incidence of type 2 diabetes was 4.3 and 7.4 per 100 person-years in the intervention and control group , respectively ( log-rank test p=0.0001 ) , indicating 43 % reduction in relative risk . The risk reduction was related to the success in achieving the intervention goals of weight loss , reduced intake of total and saturated fat and increased intake of dietary fibre , and increased physical activity . Beneficial lifestyle changes achieved by participants in the intervention group were maintained after the discontinuation of the intervention , and the corresponding incidence rates during the post-intervention follow-up were 4.6 and 7.2 ( p=0.0401 ) , indicating 36 % reduction in relative risk . INTERPRETATION Lifestyle intervention in people at high risk for type 2 diabetes result ed in sustained lifestyle changes and a reduction in diabetes incidence , which remained after the individual lifestyle counselling was stopped Summary From a previously reported 5-year screening programme of 6,956 47–49-year-old Malmö males , a series of 41 subjects with early-stage Type 2 ( non-insulin-dependent ) diabetes mellitus and 181 subjects with impaired glucose tolerance were selected for prospect i ve study and to test the feasibility aspect of long-term intervention with an emphasis on life-style changes . A 5-year protocol , including an initial 6-months ( r and omised ) pilot study , consisting of dietary treatment and /or increase of physical activity or training with annual check-ups , was completed by 90 % of subjects . Body weight was reduced by 2.3–3.7 % among participants , whereas values increased by 0.5–1.7 % in non-intervened subjects with impaired glucose tolerance and in normal control subjects ( p<0.0001 ) ; maximal oxygen uptake ( ml · min−1 · kg−1 ) was increased by 10–14 % vs decreased by 5–9 % , respectively ( p<0.0001 ) . Glucose tolerance was normalized in > 50 % of subjects with impaired glucose tolerance , the accumulated incidence of diabetes was 10.6 % , and more than 50 % of the diabetic patients were in remission after a mean follow-up of 6 years . Blood pressure , lipids , and hyperinsulinaemia were reduced and early insulin responsiveness to glucose loading preserved . Improvement in glucose tolerance was correlated to weight reduction ( r=0.19 , p<0.02 ) and increased fitness ( r=0.22 , p<0.02 ) . Treatment was safe , and mortality was low ( in fact 33 % lower than in the remainder of the cohort ) . We conclude that long-term intervention in the form of diet and physical exercise is feasible even on a large scale , and that substantial metabolic improvement can be achieved which may contribute to prevent or postpone manifest diabetes OBJECTIVE To assess the effect of lifestyle intervention over 2 years on changes in weight , coronary heart disease ( CHD ) risk factors , and incidence of diabetes in overweight individuals with a parental history of diabetes . RESEARCH DESIGN AND METHODS Participants ( n = 154 ) , who were 30–100 % over ideal body weight , had one or both parents with diabetes , and were currently nondiabetic , were r and omly assigned to 2-year treatments focused on diet ( decreasing calories and fat intake ) , exercise ( goal of 1,500 kcal/week of moderate activity ) , or the combination of diet plus exercise or to a no-treatment control group . Subjects were reassessed at 6 months , 1 year , and 2 years . RESULTS At 6 months , the groups differed significantly on measures of eating , exercise , and fitness ; weight losses in the diet and diet-plus-exercise groups were significantly > in the exercise and control conditions . Weight losses were associated with positive changes in CHD risk factors . After 6 months , there was gradual deterioration of behavioral and physiological changes , so that at 2 years , almost no between-group differences were maintained . Differences between groups in risk of developing diabetes were of borderline significance ( P = 0.08 ) . Strongest predictors were impaired glucose tolerance at baseline , which was positively related to risk of developing diabetes , and weight loss from baseline to 2 years , which was negatively related ; in all treatment groups , a modest weight loss of 4.5 kg reduced the risk of type 2 diabetes by ∼ 30 % compared with no weight loss . CONCLUSIONS Although initially successful , the interventions studied here were not effective in producing long-term changes in behavior , weight , or physiological parameters . However , weight loss from 0 to 2 years reduced the risk of developing type 2 diabetes . Since modest weight loss significantly reduced risk of type 2 diabetes , further research is needed to determine how best to increase the percentage of subjects achieving at least a modest weight loss Subjects at increased risk for developing non-insulin-dependent diabetes mellitus ( NIDDM ) were encouraged via a public awareness campaign , general practitioners , or a direct approach ( in the case of women with previous gestational diabetes ) to attend one of three English and two French centers for fasting plasma glucose ( FPG ) measurement . Of 1,580 subjects ( mean + /- SD age , 47 + /- 10 years ) , 29 % were male , 56 % had a diabetic relative , 20 % had a history of elevated blood glucose or glycosuria , and 9 % previously had gestational diabetes . Thirty-one percent ( 493 ) had an initial increased fasting glucose ( [ IFG ] 5.5 to 7.7 mmol . L-1 ) , 3 % ( 41 ) a diabetic fasting glucose ( [ DFG ] > or = 7.8 mmol . L-1 ) , and 66 % ( 1,046 ) a normal fasting glucose ( [ NFG ] < 5.5 mmol . L-1 ) . Four hundred forty-one of the 493 returned for a second FPG measurement , and 67 % ( 293 ) of these had a similar value on repeat testing 2 weeks later . A 75-g , 2-hour oral glucose tolerance test ( OGTT ) in 223 of these subjects showed that 37 % ( 83 ) had impaired glucose tolerance ( IGT ) , 26 % ( 58 ) diabetes mellitus ( DM ) , and 37 % ( 82 ) normal glucose tolerance ( NGT ) . Seven percent of self-referred patients had NIDDM by World Health Organization ( WHO ) criteria . Eighty-eight percent of those with an initial DFG had an increased glycated hemoglobin ( > 6.2 % ) , and 75 % an increased fructosamine ( > 282 mumol . L-1 ) . While these two glycemic measures provided good discrimination for diabetes , neither were reliable in detecting those with increased but not diabetic FPG values . In conclusion , 293 ( 19 % ) of 1,580 self-referred subjects were identified as having persistently increased FPG , and 227 have been entered into a r and omized NIDDM prevention trial evaluating healthy-living advice and sulfonylurea therapy BACKGROUND Declining physical activity is associated with a rising burden of global disease . Efforts to reverse this trend have not been successful . We aim ed to assess the efficacy of a facilitated behavioural intervention to increase the physical activity of sedentary individuals at familial risk of diabetes . METHODS We enrolled 365 sedentary adults who had a parental history of type 2 diabetes . They were recruited from either diabetes or family history registers at 20 general practice clinics in the UK . Eligible participants were r and omly assigned to one of two intervention groups , or to a comparison group . All participants were posted a brief advice leaflet . One intervention group was offered a 1-year behaviour-change programme , to be delivered by trained facilitators in participants ' homes , and the other the same programme by telephone . The programme was design ed to alter behavioural determinants , as defined by the theory of planned behaviour , and to teach behaviour-change strategies . The principal outcome at 1 year was daytime physical activity , which was objective ly measured as a ratio to resting energy expenditure . Analysis was by intention to treat . This study is registered as IS RCT N61323766 . FINDINGS Of 365 patients , we analysed primary endpoints for 321 ( 88 % ) for whom we had data after 1 year of follow-up . At 1 year , the physical-activity ratio of participants who received the intervention , by either delivery route , did not differ from the ratio in those who were given a brief advice leaflet . The mean difference in daytime physical-activity ratio , adjusted for baseline , was -0.04 ( 95 % CI -0.16 to 0.08 ) . The physical-activity ratio did not differ between participants who were delivered the intervention face-to-face or by telephone ( mean difference -0.05 ; 95 % CI -0.19 to 0.10 ) . INTERPRETATION A facilitated theory-based behavioural intervention was no more effective than an advice leaflet for promotion of physical activity in an at-risk group ; therefore health-care providers should remain cautious about commissioning behavioural programmes into individual preventive health-care services OBJECTIVE The Diabetes Prevention Program ( DPP ) is a 27-center r and omized clinical trial design ed to evaluate the safety and efficacy of interventions that may delay or prevent development of diabetes in people at increased risk for type 2 diabetes . RESEARCH DESIGN AND METHODS Eligibility requirements were age > or = 25 years , BMI > or = 24 kg/m2 ( > or = 22 kg/m2 for Asian-Americans ) , and impaired glucose tolerance plus a fasting plasma glucose of 5.3 - 6.9 mmol/l ( or < or = 6.9 mmol for American Indians ) . R and omization of participants into the DPP over 2.7 years ended in June 1999 . Baseline data for the three treatment groups -- intensive lifestyle modification , st and ard care plus metformin , and st and ard care plus placebo -- are presented for the 3,234 participants who have been r and omized . RESULTS Of all participants , 55 % were Caucasian , 20 % were African-American , 16 % were Hispanic , 5 % were American Indian , and 4 % were Asian-American . Their average age at entry was 51 + /- 10.7 years ( mean + /- SD ) , and 67.7 % were women . Moreover , 16 % were < 40 years of age , and 20 % were > or = 60 years of age . Of the women , 48 % were postmenopausal . Men and women had similar frequencies of history of hypercholesterolemia ( 37 and 33 % , respectively ) or hypertension ( 29 and 26 % , respectively ) . On the basis of fasting lipid determinations , 54 % of men and 40 % of women fit National Cholesterol Education Program criteria for abnormal lipid profiles . More men than women were current or former cigarette smokers or had a history of coronary heart disease . Furthermore , 66 % of men and 71 % of women had a first-degree relative with diabetes . Overall , BMI averaged 34.0 + /- 6.7 kg/m2 at baseline with 57 % of the men and 73 % of women having a BMI > or = 30 kg/m2 . Average fasting plasma glucose ( 6.0 + /- 0.5 mmol/l ) and HbA1c ( 5.9 + /- 0.5 % ) in men were comparable with values in women ( 5.9 + /- 0.4 mmol/l and 5.9 + /- 0.5 % , respectively ) . CONCLUSIONS The DPP has successfully r and omized a large cohort of participants with a wide distribution of age , obesity , and ethnic and racial background s who are at high risk for developing type 2 diabetes . The study will examine the effects of interventions on the development of diabetes OBJECTIVE To examine prospect ively the association between regular exercise and the subsequent development of non-insulin-dependent diabetes mellitus ( NIDDM ) . DESIGN Prospect i ve cohort study including 5 years of follow-up . PARTICIPANTS 21,271 US male physicians participating in the Physicians ' Health Study , aged 40 to 84 years and free of diagnosed diabetes mellitus , myocardial infa rct ion , cerebrovascular disease , and cancer at baseline . Morbidity follow-up was 99.7 % complete . MAIN OUTCOME MEASURE Incidence of NIDDM . RESULTS At baseline , information was obtained about frequency of vigorous exercise and other risk indicators . During 105,141 person-years of follow-up , 285 new cases of NIDDM were reported . The age-adjusted incidence of NIDDM ranged from 369 cases per 100,000 person-years in men who engaged in vigorous exercise less than once weekly to 214 cases per 100,000 person-years in those exercising at least five times per week ( P , trend , less than .001 ) . Men who exercised at least once per week had an age-adjusted relative risk ( RR ) of NIDDM of 0.64 ( 95 % Cl , 0.51 to 0.82 ; P = .0003 ) compared with those who exercised less frequently . The age-adjusted RR of NIDDM decreased with increasing frequency of exercise : 0.77 for once weekly , 0.62 for two to four times per week , and 0.58 for five or more times per week ( P , trend , .0002 ) . A significant reduction in risk of NIDDM persisted after adjustment for both age and body-mass index : RR , 0.71 ( 95 % Cl , 0.56 to 0.91 ; P = .006 ) for at least once per week compared with less than once weekly , and P , trend , .009 , for increasing frequency of exercise . Further control for smoking , hypertension , and other coronary risk factors did not material ly alter these associations . The inverse relation of exercise to risk of NIDDM was particularly pronounced among overweight men . CONCLUSIONS Exercise appears to reduce the development of NIDDM even after adjusting for body-mass index . Increased physical activity may be a promising approach to the primary prevention of NIDDM OBJECTIVE To determine whether diet and endurance exercise improved adiposity-related measurements in Japanese Americans with impaired glucose tolerance ( IGT ) . RESEARCH DESIGN AND METHODS This study compared the effects of an American Heart Association ( AHA ) step 2 diet ( < 30 % of total calories as fat , < 7 % saturated fat , 55 % carbohydrate , and < 200 mg cholesterol daily ) plus endurance exercise for 1 h three times a week ( treatment group ) with an AHA step 1 diet ( 30 % of total calories as fat , 10 % saturated fat , 50 % carbohydrate , and < 300 mg cholesterol ) plus stretching exercise three times a week ( control group ) on BMI , body composition ( % fat ) , and body fat distribution at 6 and 24 months of follow-up in 64 Japanese American men and women with IGT , 58 of whom completed the study . RESULTS At 6 months , the treatment group showed significantly greater reduction in percent , body fat ( -1.4 + /- 0.4 vs. -0.3 + /- 0.3 % ) ; BMI ( -1.1 + /- 0.2 vs. -0.4 + /- 0.1 kg/m(2 ) ) ; subcutaneous fat by computed tomography at the abdomen ( -29.3 + /- 4.2 vs. -5.7 + /- 5.9 cm(2 ) ) , thigh ( -13.2 + /- 3.6 vs. -3.6 + /- 3.0 cm(2 ) ) , and thorax ( -19.6 + /- 3.6 vs. -8.9 + /- 2.6 cm(2 ) ) ; and skinfold thickness at the bicep ( -2.0 + /- 0.6 vs. 1.1 + /- 0.6 mm ) and tricep ( -3.7 + /- 0.8 vs. -0.9 + /- 0.6 mm ) , which continued despite moving to home-based exercise for the last 18 months . CONCLUSIONS Diet and endurance exercise improved BMI , body composition , and body fat distribution and , thus , may delay or prevent type 2 diabetes in Japanese Americans with IGT Thirty-one subjects with impaired glucose tolerance were r and omly allocated to a group receiving advice to improve their diet and physical activity levels over 6 months ( n = 23 ) or to a control group ( n = 8) . At 6 months , 18 of the 23 subjects receiving ' healthy living ' advice were re-examined ( five subjects had withdrawn ) . Fourteen of the 18 subjects showed an alteration in diet or an increase in exercise . The 18 subjects re-evaluated showed a reduction in systolic blood pressure ( 118 + /- 15 vs 124 + /- 15 mmHg , p less than 0.05 ) and decrease in total plasma cholesterol ( 4.5 + /- 1 vs 5.2 + /- 1 mmol l-1 , p less than 0.01 ) and LDL-cholesterol levels ( 2.8 + /- 0.9 vs 3.2 + /- 0.9 mmol l-1 , p less than 0.05 ) . Plasma glucose levels were unchanged . One subject withdrew from the control group . At 6 months , the seven control subjects examined showed no significant change in metabolic parameters , with little measurable change in diet or exercise . At 2 years , 17 of the 23 ' healthy living ' subjects were reassessed . Nine of the subjects had continued to exercise or maintained a decreased weight compared to baseline . Fasting plasma glucose levels had increased ( 6.0 + /- 1.2 vs 5.5 + /- 0.6 mmol l-1 , p less than 0.05 ) , with the only continued improvement being a reduced LDL level ( 2.8 + /- 0.7 vs 3.1 + /- 0.9 mmol l-1 , p less than 0.05 ) . At 2 years , a similar proportion of the control group were taking regular exercise compared with the ' healthy living ' group . ( ABSTRACT TRUNCATED AT 250 WORDS AIMS : Important risk factors for the progression from impaired glucose tolerance to type II diabetes mellitus are obesity , diet and physical inactivity . The aim of this study is to evaluate the effect of a lifestyle-intervention programme on glucose tolerance in Dutch subjects with impaired glucose tolerance ( IGT ) . METHODS : A total of 102 subjects were studied , r and omised into two groups . Subjects in the intervention group received regular dietary advice , and were stimulated to lose weight and to increase their physical activity . The control group received only brief information about the beneficial effects of a healthy diet and increased physical activity . Before and after the first year , glucose tolerance was measured and several other measurements were done . RESULTS : Body weight loss after 1 y was higher in the intervention group . The 2-h blood glucose concentration decreased 0.8±0.3 mmol/l in the intervention group and increased 0.2±0.3 mmol/l in the control group ( P<0.05 ) . Body weight loss and increased physical fitness were the most important determinants of improved glucose tolerance and insulin sensitivity . CONCLUSION : A lifestyle-intervention programme according to general recommendations is effective and induces beneficial changes in lifestyle , which improve glucose tolerance in subjects with IGT . Body weight loss and increased physical fitness were the most important determinants of improved glucose tolerance and insulin sensitivity OBJECTIVE Individuals with impaired glucose tolerance ( IGT ) have a high risk of developing NIDDM . The purpose of this study was to determine whether diet and exercise interventions in those with IGT may delay the development of NIDDM , i.e. , reduce the incidence of NIDDM , and thereby reduce the overall incidence of diabetic complications , such as cardiovascular , renal , and retinal disease , and the excess mortality attributable to these complications . RESEARCH DESIGN AND METHODS In 1986 , 110,660 men and women from 33 health care clinics in the city of Da Qing , China , were screened for IGT and NIDDM . Of these individuals , 577 were classified ( using World Health Organization criteria ) as having IGT . Subjects were r and omized by clinic into a clinical trial , either to a control group or to one of three active treatment groups : diet only , exercise only , or diet plus exercise . Follow-up evaluation examinations were conducted at 2-year intervals over a 6-year period to identify subjects who developed NIDDM . Cox 's proportional hazard analysis was used to determine if the incidence of NIDDM varied by treatment assignment . RESULTS The cumulative incidence of diabetes at 6 years was 67.7 % ( 95 % CI , 59.8–75.2 ) in the control group compared with 43.8 % ( 95 % CI , 35.5–52.3 ) in the diet group , 41.1 % ( 95 % CI , 33.4–49.4 ) in the exercise group , and 46.0 % ( 95 % CI , 37.3–54.7 ) in the diet-plus-exercise group ( P < 0.05 ) . When analyzed by clinic , each of the active intervention groups differed significantly from the control clinics ( P < 0.05 ) . The relative decrease in rate of development of diabetes in the active treatment groups was similar when subjects were stratified as lean or overweight ( BMI < or ≥ 25 kg/m2 ) . In a proportional hazards analysis adjusted for differences in baseline BMI and fasting glucose , the diet , exercise , and diet-plus-exercise interventions were associated with 31 % ( P < 0.03 ) , 46 % ( P < 0.0005 ) , and 42 % ( P < 0.005 ) reductions in risk of developing diabetes , respectively . CONCLUSIONS Diet and /or exercise interventions led to a significant decrease in the incidence of diabetes over a 6-year period among those with IGT OBJECTIVES Prevention of type 2 diabetes ( T2DM ) is a priority in healthcare , but there is a lack of evidence investigating how to effectively translate prevention research into a UK primary care setting . We assessed whether a structured education programme targeting lifestyle and behaviour change was effective at preventing progression to T2DM in people with pre-diabetes . MATERIAL S AND METHODS Forty-four general practice s were r and omised to receive either st and ard care or a 6hour group structured education programme with an annual refresher course , and regular phone contact . Participants were followed up for 3years . The primary outcome was progression to T2DM . RESULTS Eight hundred and eighty participants were included ( 36 % female , mean age 64years , 16 % ethnic minority group ) ; 131 participants developed T2DM . There was a non-significant 26 % reduced risk of developing T2DM in the intervention arm compared to st and ard care ( HR 0.74 , 95 % CI 0.48 , 1.14 , p=0.18 ) . The reduction in T2DM risk when excluding those who did not attend the initial education session was also non-significant ( HR 0.65 , 0.41 , 1.03 , p=0.07 ) . There were statistically significant improvements in HbA1c ( -0.06 , -0.11 , -0.01 ) , LDL cholesterol ( -0.08 , -0.15 , -0.01 ) , sedentary time ( -26.29 , -45.26 , -7.32 ) and step count ( 498.15 , 162.10 , 834.20 ) when data were analysed across all time points . CONCLUSIONS This study suggests that a relatively low re source , pragmatic diabetes prevention programme result ed in modest benefits to biomedical , lifestyle and psychosocial outcomes , however the reduction to the risk of T2DM did not reach significance . The findings have important implication s for future research and primary care BACKGROUND Intensive lifestyle interventions can reduce the incidence of type 2 diabetes in people with impaired glucose tolerance , but how long these benefits extend beyond the period of active intervention , and whether such interventions reduce the risk of cardiovascular disease ( CVD ) and mortality , is unclear . We aim ed to assess whether intensive lifestyle interventions have a long-term effect on the risk of diabetes , diabetes-related macrovascular and microvascular complications , and mortality . METHODS In 1986 , 577 adults with impaired glucose tolerance from 33 clinics in China were r and omly assigned to either the control group or to one of three lifestyle intervention groups ( diet , exercise , or diet plus exercise ) . Active intervention took place over 6 years until 1992 . In 2006 , study participants were followed-up to assess the long-term effect of the interventions . The primary outcomes were diabetes incidence , CVD incidence and mortality , and all-cause mortality . FINDINGS Compared with control participants , those in the combined lifestyle intervention groups had a 51 % lower incidence of diabetes ( hazard rate ratio [ HRR ] 0.49 ; 95 % CI 0.33 - 0.73 ) during the active intervention period and a 43 % lower incidence ( 0.57 ; 0.41 - 0.81 ) over the 20 year period , controlled for age and clustering by clinic . The average annual incidence of diabetes was 7 % for intervention participants versus 11 % in control participants , with 20-year cumulative incidence of 80 % in the intervention groups and 93 % in the control group . Participants in the intervention group spent an average of 3.6 fewer years with diabetes than those in the control group . There was no significant difference between the intervention and control groups in the rate of first CVD events ( HRR 0.98 ; 95 % CI 0.71 - 1.37 ) , CVD mortality ( 0.83 ; 0.48 - 1.40 ) , and all-cause mortality ( 0.96 ; 0.65 - 1.41 ) , but our study had limited statistical power to detect differences for these outcomes . INTERPRETATION Group-based lifestyle interventions over 6 years can prevent or delay diabetes for up to 14 years after the active intervention . However , whether lifestyle intervention also leads to reduced CVD and mortality remains unclear Background Prevention of type 2 diabetes mellitus ( T2DM ) is a global priority . Let ’s Prevent Diabetes is a group-based diabetes prevention programme ; it was evaluated in a cluster-r and omised trial , in which the primary analysis showed a reduction in T2DM ( hazard ratio [ HR ] 0.74 , 95 % CI 0.48–1.14 , p = 0.18 ) . We examined the association of engagement and retention with the Let ’s Prevent Diabetes prevention programme and T2DM incidence . Methods and Findings We used data from a completed cluster-r and omised controlled trial including 43 general practice s r and omised to receive either st and ard care or a 6-h group structured education programme with an annual refresher course for 2 y. The primary outcome was progression to T2DM at 3 y. The characteristics of those who attended the initial education session ( engagers ) versus nonengagers and those who attended all sessions ( retainers ) versus nonretainers were compared . Risk reduction of progression to T2DM by level of attendance was compared to st and ard care . Eight hundred and eighty participants were recruited , with 447 to the intervention arm , of which 346 ( 77.4 % ) were engagers and 130 ( 29.1 % ) were retainers . Retainers and engagers were more likely to be older , leaner , and nonsmokers than nonretainers/nonengagers . Engagers were also more likely to be male and be from less socioeconomically deprived areas than nonengagers . Participants who attended the initial session and at least one refresher session were less likely to develop T2DM compared to those in the control arm ( 30 people of 248 versus 67 people of 433 , HR 0.38 [ 95 % CI 0.24–0.62 ] ) . Participants who were retained in the programme were also less likely to develop T2DM compared to those in the control arm ( 7 people of 130 versus 67 people of 433 , HR 0.12 [ 95 % CI 0.05–0.28 ] ) . Being retained in the programme was also associated with improvements in glucose , glycated haemoglobin ( HbA1c ) , weight , waist circumference , anxiety , quality of life , and daily step count . Given that the data used are from a clinical trial , those taking part might reflect a more motivated sample than the population , which should be taken into account when interpreting the results . Conclusions This study suggests that being retained/engaged in a relatively low-re source , pragmatic diabetes prevention programme for those at high risk is associated with reductions in the progression to T2DM in comparison to those who receive st and ard care . Nonengagers and nonretainers share similar high-risk traits . Service providers of programmes should focus on reaching these hard-to-reach groups . Trial Registration Clinical Trials.gov IS RCT AIMS The Diabetes Community Lifestyle Improvement Program ( D-CLIP ) aims to implement and evaluate in a controlled , r and omized trial the effectiveness , cost-effectiveness , and sustainability of a culturally appropriate , low-cost , and sustainable lifestyle intervention for the prevention of type 2 diabetes mellitus in India . METHODS D-CLIP , a translational research project adapted from the methods and curriculum developed and tested for efficacy in the Diabetes Prevention Program , utilizes innovated methods ( a step-wise model of diabetes prevention with lifestyle and metformin added when needed ; inclusion of individuals with isolated glucose tolerance , impaired fasting glucose , and both ; classes team-taught by professionals and trained community educators ) with the goals of increasing diabetes prevention , community acceptability , and long-term dissemination and sustainability of the program . The study outcomes are : diabetes incidence ( primary measure of effectiveness ) , cost-effectiveness , changes in anthropometric measures , plasma lipids , blood pressure , blood glucose , and HbA(1c , ) Program acceptability and sustainability will be assessed using a mixed methods approach . CONCLUSION D-CLIP , a low-cost , community-based , research program , addresses the key components of translational research and can be used as a model for prevention of chronic diseases in other low and middle-income country setting Self-referred subjects ( N = 227 ) thought to be at risk of developing non-insulin-dependent diabetes mellitus ( NIDDM ) and with fasting plasma glucose ( FPG ) in the range of 5.5 to 7.7 mmol . L-1 on two consecutive tests 2 weeks apart were r and omized to reinforced or basic healthy-living advice . They were simultaneously allocated either to a sulfonylurea group or a control group in a two-by-two factorial design . A total of 201 subjects in three English and two French centers completed 1 year 's follow-up study . Reinforced advice recommending dietary modification and increased exercise was given every 3 months , and basic advice was given once at the initial visit . Glycemia was monitored by FPG , dietary compliance by body weight and food diaries , and fitness compliance by bicycle ergometer assessment and exercise diaries . Both reinforced and basic advice groups had a significant mean reduction in body weight ( 1.5 kg ) at 3 months , although the weight subsequently returned to baseline . After 1 year , subjects allocated to reinforced advice versus basic advice ( 1 ) reported a lower fat intake ( 34.1 % v 35.8 % , P = .04 ) with no difference in lipid profiles , ( 2 ) had improved fitness as shown by increased calculated maximal oxygen uptake ( [ Vo2max ] 2.39 v 2.18 L.min-1 , P = .007 ) with no change in insulin sensitivity , ( 3 ) showed no change in FPG , glucose tolerance , or hemoglobin A1c ( HbA1c ) , and ( 4 ) showed a greater tendency to withdraw from the study ( 16 % v 7 % , P = .03 ) . In conclusion , reinforced healthy-living advice given to self-referred subjects with increased FPG did not encourage sufficiently pronounced life-style changes for significantly greater effects on body weight and glycemia in a 1-year study than basic healthy-living advice OBJECTIVE To describe the costs of the Diabetes Prevention Program ( DPP ) interventions to prevent or delay type 2 diabetes . RESEARCH DESIGN AND METHODS We describe the direct medical costs , direct nonmedical costs , and indirect costs of the placebo , metformin , and intensive lifestyle interventions over the 3-year study period of the DPP . Re source use and cost are summarized from the perspective of a large health system and society . Research costs are excluded . RESULTS The direct medical cost of laboratory tests to identify one subject with impaired glucose tolerance ( IGT ) was $ 139 . Over 3 years , the direct medical costs of the interventions were $ 79 per participant in the placebo group , $ 2,542 in the metformin group , and $ 2,780 in the lifestyle group . The direct medical costs of care outside the DPP were $ 272 less per participant in the metformin group and $ 432 less in the lifestyle group compared with the placebo group . Direct nonmedical costs were $ 9 less per participant in the metformin group and $ 1,445 greater in the lifestyle group compared with the placebo group . Indirect costs were $ 230 greater per participant in the metformin group and $ 174 less in the lifestyle group compared with the placebo group . From the perspective of a health system , the cost of the metformin intervention relative to the placebo intervention was $ 2,191 per participant and the cost of the lifestyle intervention was $ 2,269 per participant over 3 years . From the perspective of society , the cost of the metformin intervention relative to the placebo intervention was $ 2,412 per participant and the cost of the lifestyle intervention was $ 3,540 per participant over 3 years . CONCLUSIONS The metformin and lifestyle interventions are associated with modest incremental costs compared with the placebo intervention . The evaluation of costs relative to health benefits will determine the value of these interventions to health systems and society 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 OBJECTIVES We report the 10-year effectiveness and within-trial cost-effectiveness of the Diabetes Prevention Program ( DPP ) and its Outcomes Study ( DPPOS ) interventions among participants who were adherent to the interventions . STUDY DESIGN DPP was a 3-year r and omized clinical trial followed by 7 years of open-label modified intervention follow-up . METHODS Data on re source utilization , cost , and quality of life were collected prospect ively . Economic analyses were performed from health system and societal perspectives . Lifestyle adherence was defined as achieving and maintaining a 5 % reduction in initial body weight , and metformin adherence as taking metformin at 80 % of study visits . RESULTS The relative risk reduction was 49.4 % among adherent lifestyle participants and 20.8 % among adherent metformin participants compared with placebo . Over 10 years , the cumulative , undiscounted , per capita direct medical costs of the interventions , as implemented during the DPP , were greater for adherent lifestyle participants ( $ 4810 ) than adherent metformin participants ( $ 2934 ) or placebo ( $ 768 ) . Over 10 years , the cumulative , per capita non-interventionrelated direct medical costs were $ 4250 greater for placebo participants compared with adherent lifestyle participants and $ 3251 greater compared with adherent metformin participants . The cumulative quality -adjusted life-years ( QALYs ) accrued over 10 years were greater for lifestyle ( 6.80 ) than metformin ( 6.74 ) or placebo ( 6.67 ) . Without discounting , from a modified societal perspective ( excluding participant time ) and a full societal perspective ( including participant time ) , lifestyle cost < $ 5000 per QALY-gained and metformin was cost saving compared with placebo . CONCLUSIONS Over 10 years , lifestyle intervention and metformin were cost-effective or cost saving compared with placebo . These analyses confirm that lifestyle and metformin represent a good value for money The Finnish DPS ( Diabetes Prevention Study ) demonstrated that lifestyle intervention , aim ed at increasing physical activity , improving diet , and decreasing body weight , reduced the incidence of type 2 diabetes in individuals with overweight and impaired glucose tolerance by 58 % . Here , we studied which immunological markers at baseline predicted subsequent type 2 diabetes and whether there are immunologically defined subsets of subjects who are more or less responsive to the protective effects of lifestyle intervention . We r and omly assigned 522 participants to a control group ( n = 257 ) or a lifestyle intervention group ( n = 265 ) . Immunological parameters at baseline included high-sensitivity C-reactive protein ( CRP ) , serum amyloid A , interleukin-6 , regulated on activation normal T-cell expressed and secreted ( RANTES ) , macrophage migration inhibitory factor ( MIF ) , and soluble intercellular adhesion molecule . In the control group , CRP was the best immunological predictor for progression to overt type 2 diabetes . In the intervention group , progression to type 2 diabetes was significantly higher in subjects with the highest RANTES concentrations and was lower in subjects with the highest MIF levels . Ratios of RANTES to MIF in the upper tertile were highly predictive of incident type 2 diabetes in the intervention group ( P = 0.006 ) , whereas the association was less pronounced in the control group ( P = 0.088 ) . Thus , systemic concentrations of immune mediators appear to be associated with the progression to type 2 diabetes and the prevention of type 2 diabetes by lifestyle changes 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 Self-referred subjects ( N = 227 ) thought to be at increased risk of developing diabetes who had fasting plasma glucose ( FPG ) values in the range of 5.5 to 7.7 mmol . L-1 on two consecutive occasions 2 weeks apart were r and omized to sulfonylurea therapy ( gliclazide , < or = 160 mg.d-1 ) or to a control group allocated either to double-blind placebo or to no tablets . Subjects were r and omly allocated also to reinforced or basic healthy-living advice in a factorial design . A total of 201 subjects have been evaluated for 1 year in three English and two French hospital outpatient centers . Those allocated to sulfonylurea had a significant ( P < .001 ) reduction in median FPG compared with the control group ( 6.0 mmol . L-1 to 5.6 mmol . L-1 , P < .001 , v 6.0 mmol . L-1 to 6.0 mmol . L-1 , NS ) . Median hemoglobin A1c ( HbA1c ) also improved ( P < .0002 ; 5.8 % to 5.6 % , P < .001 , v 5.7 % to 5.6 % , NS ) , as did mean beta-cell function ( 62 % to 70 % , P < .01 , v 62 % to 61 % , NS ) . Mean body weight was unchanged in subjects allocated to sulfonylurea ( 81.7 kg to 82.4 kg , NS ) , but decreased in the control group ( 81.6 kg to 80.4 kg , P < .01 ) . More subjects in the sulfonylurea group versus the control group reported one or more minor symptoms of hypoglycemia over 1 year ( 50 % v 24 % , P < .0001 ) . Only two subjects reported major hypoglycemic episodes requiring assistance , both of whom were taking sulfonylurea . Insulin sensitivity did not change between groups . Sulfonylurea therapy with gliclazide improved glycemic control and beta-cell function significantly in subjects with increased but not diabetic FPG levels . The study is being extended to determine whether sulfonylurea therapy prevents progression to non-insulin-dependent diabetes mellitus ( NIDDM ) Background The Diabetes Prevention Program ( DPP ) was a r and omized , controlled clinical trial . It demonstrated that among high-risk individuals with impaired glucose tolerance , diabetes incidence was reduced by 58 % with lifestyle intervention and 31 % with metformin compared to placebo . During the Diabetes Prevention Program Outcomes Study ( DPPOS ) , all DPP participants were unmasked to their treatment assignments , the original lifestyle intervention group was offered additional lifestyle support , the metformin group continued metformin , and all three groups were offered a group-implemented lifestyle intervention . Over the 10 years of combined DPP/DPPOS follow-up , diabetes incidence was reduced by 34 % in the lifestyle group and 18 % in the metformin group compared to placebo . The purpose of this article is to review and synthesize analyses published by the DPP/DPPOS Research Group that have described the cost-effectiveness of diabetes prevention . Methods We describe the re source utilization and costs of the DPP and DPPOS interventions , the costs of non-intervention-related medical care , the impact of the interventions on diabetes progression and quality -of-life , and the cost-effectiveness of the interventions from health system and societal perspectives . Cost-effectiveness analyses were performed with a 3-year time horizon using DPP data , a lifetime time horizon that simulated 3-year DPP data , and a 10-year time horizon using combined DPP/DPPOS data . Results Although more expensive than the placebo intervention , the greater costs of the lifestyle and metformin interventions were offset by reductions in the costs of nonintervention-related medical care . Every year after r and omization , quality -of-life was better for participants in the lifestyle intervention compared to those in the metformin or placebo intervention . In both the simulated lifetime analysis and the 10-year within trial economic analysis , lifestyle and metformin were extremely cost-effective ( that is , improved outcomes at a low incremental cost ) or even cost-saving ( that is , improved outcomes and reduced total costs ) compared to the placebo intervention . Conclusions The implementation of diabetes prevention programs in high-risk individuals will result in important health benefits and represents a good value for money . Trial registration NCT00004992 ( DPP ) and NCT00038727 ( DPPOS ) BACKGROUND The susceptibility to type 2 diabetes of people of south Asian descent is established , but there is little trial-based evidence for interventions to tackle this problem . We assessed a weight control and physical activity intervention in south Asian individuals in the UK . METHODS We did this non-blinded trial in two National Health Service ( NHS ) regions in Scotl and ( UK ) . Between July 1 , 2007 , and Oct 31 , 2009 , we recruited men and women of Indian and Pakistani origin , aged 35 years or older , with waist circumference 90 cm or greater in men or 80 cm or greater in women , and with impaired glucose tolerance or impaired fasting glucose determined by oral glucose tolerance test . Families were r and omised ( using a r and om number generator program , with permuted blocks of r and om size , stratified by location [ Edinburgh or Glasgow ] , ethnic group [ Indian or Pakistani ] , and number of participants in the family [ one vs more than one ] ) to intervention or control . Participants in the same family were not r and omised separately . The intervention group received 15 visits from a dietitian over 3 years and the control group received four visits in the same period . The primary outcome was weight change at 3 years . Analysis was by modified intention to treat , excluding participants who died or were lost to follow-up . We used linear regression models to provide mean differences in baseline-adjusted weight at 3 years . This trial is registered , number IS RCT N25729565 . FINDINGS Of 1319 people who were screened with an oral glucose tolerance test , 196 ( 15 % ) had impaired glucose tolerance or impaired fasting glucose and 171 entered the trial . Participants were in 156 family clusters that were r and omised ( 78 families with 85 participants were allocated to intervention ; 78 families with 86 participants were allocated to control ) . 167 ( 98 % ) participants in 152 families completed the trial . Mean weight loss in the intervention group was 1.13 kg ( SD 4.12 ) , compared with a mean weight gain of 0.51 kg ( 3.65 ) in the control group , an adjusted mean difference of -1.64 kg ( 95 % CI -2.83 to -0.44 ) . INTERPRETATION Modest , medium-term changes in weight are achievable as a component of lifestyle-change strategies , which might control or prevent adiposity-related diseases . FUNDING National Prevention Research Initiative , NHS Research and Development ; NHS National Services Scotl and ; NHS Health Scotl and OBJECTIVE Educational attainment is inversely associated with type 2 diabetes risk , but it is unknown whether education impacts individuals ' diabetes prevention efforts . We examined the comparative efficacy of intensive lifestyle intervention and metformin by educational attainment among participants in the Diabetes Prevention Program ( DPP ) , an ongoing U.S. multi-site trial beginning in 1996 . METHODS We studied 2,910 DPP participants r and omized to receive lifestyle intervention , metformin , or placebo . Stratifying by educational attainment , diabetes incidence and relative risk reductions by treatment assignment were estimated using Cox proportional hazards regression . RESULTS 47 % of participants had completed college and 53 % had not . Compared to placebo , lifestyle participants who had completed college demonstrated a 68 % reduction in diabetes incidence ( 95 % CI=56 , 77 ) , whereas those with less education experienced a 47 % risk reduction ( 95 % CI=29 , 61 ) . For metformin participants , college graduates experienced a 49 % relative risk reduction ( 95 % CI=33 , 62 ) , compared to 23 % ( 95 % CI=1 , 41 ) among those with lower educational attainment . There was a statistically significant education-by-treatment interaction with incident diabetes ( p=0.03 ) . CONCLUSIONS Intensive lifestyle intervention and metformin have greater efficacy among highly educated individuals . Future efforts to deliver these treatments and study their dissemination may be more effective if tailored to individuals ' educational background OBJECTIVE —In the Indian Diabetes Prevention Programme ( IDPP ) , a 3-year r and omized , controlled trial , lifestyle modification ( LSM ) and metformin helped to prevent type 2 diabetes in subjects with impaired glucose tolerance ( IGT ) . The direct medical costs and cost-effectiveness of the interventions relative to the control group are reported here . RESEARCH DESIGN AND METHODS —Relative effectiveness and costs of interventions ( LSM , metformin , and LSM and metformin ) in the IDPP were estimated from the health care system perspective . Costs of intervention considered were only the direct medical costs . Direct nonmedical , indirect , and research costs were excluded . The cost-effectiveness of interventions was measured as the amount spent to prevent one case of diabetes within the 3-year trial period . RESULTS —The direct medical cost to identify one subject with IGT was Indian rupees ( INR ) 5,278 ( $ 117 ) . Direct medical costs of interventions over the 3-year trial period were INR 2,739 ( $ 61 ) per subject in the control group , INR 10,136 ( $ 225 ) with LSM , INR 9,881 ( $ 220 ) with metformin , and INR 12,144 ( $ 270 ) with LSM and metformin . The number of individuals needed to treat to prevent a case of diabetes was 6.4 with LSM , 6.9 with metformin , and 6.5 with LSM and metformin . Cost-effectiveness to prevent one case of diabetes with LSM was INR 47,341 ( $ 1,052 ) , with metformin INR 49,280 ( $ 1,095 ) , and with LSM and metformin INR 61,133 ( $ 1,359 ) . CONCLUSIONS —Both LSM and metformin were cost-effective interventions for preventing diabetes among high risk-individuals in India and perhaps may be useful in other developing countries as well . The long-term cost-effectiveness of the interventions needs to be assessed OBJECTIVE To investigate the effects of insulin resistance ( IR ) and insulin secretion ( IS ) on the development of diabetes mellitus in individuals with impaired glucose tolerance ( IGT ) who underwent lifestyle interventions . METHODS 284 out of 577 individuals with IGT identified by population -based screening in Da Qing , China , who were r and omized to undergo diet change and /or increased physical activity had baseline fasting and 2 h post-load insulin determinations . They were followed for 6 years for the development of diabetes . IR and IS were assessed using calculated indices based on fasting plasma insulin and glucose . The interactions of IR , IS , obesity and plasma glucose and the effects of the lifestyle interventions were evaluated using Cox Proportional Hazards analysis . RESULTS Both IR and IS were significantly associated with the development of diabetes . Lifestyle interventions were more effective in those with lower IT and higher IS at baseline . Diet plus exercise interventions result ed in significantly lower incidence of diabetes , even after controlling for IR , IS , BMI and 2hrPG . CONCLUSION Both IR and beta-cell function were predictors of diabetes in Chinese with IGT . Lifestyle intervention reduced the incidence of DM and these interventions were more effective in those with less IR The Diabetes Prevention Program ( DPP ) is a multicenter r and omized controlled trial design ed to test whether diet and exercise or medication can prevent or delay the onset of type 2 diabetes in persons with impaired glucose tolerance , who are at increased risk of the disease . This paper describes DPP recruitment methods , strategies , performance , and costs . The DPP developed an organizational structure for comprehensive management and continuous monitoring of recruitment efforts . The DPP utilized a variety of recruitment strategies , alone or in combination , and a stepped informed consent procedure leading to r and omization . Study wide and clinic-specific recruitment data were monitored , analyzed , and used to modify recruitment approaches . DPP recruitment was completed slightly ahead of schedule , meeting goals for the proportion of women enrolled and nearly meeting goals for the proportion of racial/ethnic minorities . Clinics varied widely in the recruitment strategies they used , and these strategies also varied by participant age , gender , and race/ethnicity . Staff time devoted to recruitment averaged 86.8 hours per week per clinic , with the majority of effort by staff specifically assigned to recruitment . The number of staff hours required to recruit a participant varied by recruitment strategy . Recruitment cost ( excluding staff cost ) was about 1075 US dollars per r and omized participant . The DPP experience offers lessons for those planning similar efforts : ( 1 ) a method for ongoing assessment and revision of recruitment strategies is valuable ; ( 2 ) a range of recruitment strategies may be useful ; ( 3 ) the most effective methods for recruiting potential subjects may vary according to the gender , age , and race/ethnicity of those individuals ; ( 4 ) recruitment strategies vary in the amount of staff time required to r and omize a participant ; and ( 5 ) a stepped screening may make it easier to identify and recruit volunteers who underst and the requirements of the study Increases in sub clinical inflammation ( C-reactive protein [ CRP ] ) and impaired coagulation have been associated with increased obesity and insulin resistance . Only a few small studies have examined the effect of lifestyle changes , such as weight loss , increased physical activity , and insulin-sensitizing intervention on inflammation and coagulation . The Diabetes Prevention Program ( DPP ) clinical trial studied the effect of an intensive lifestyle intervention or metformin on progression to diabetes relative to placebo in 3,234 adults with impaired glucose tolerance . The effects of these interventions on CRP and fibrinogen at 12 months are examined in this report . Metformin reduced CRP in women compared with the placebo group . In men , the median changes in CRP from baseline to 1 year were -33 % in the lifestyle group , -7 % in the metformin group , and + 5 % in the placebo group . In women , the changes in CRP from baseline to follow-up were -29 % in the lifestyle group , -14 % in the metformin group , and 0 % in the placebo group . In the lifestyle group weight loss rather than increased physical activity seems to account for most of the changes in CRP . Only modest reductions ( although significant ) were seen in fibrinogen levels in the lifestyle group relative to the metformin and placebo group . Lifestyle intervention reduced levels of nontraditional cardiovascular risk factors relative to both placebo and to a lesser degree to metformin BACKGROUND Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies , but long-term effects on cardiovascular disease remain unknown . We examined whether an intensive lifestyle intervention for weight loss would decrease cardiovascular morbidity and mortality among such patients . METHODS In 16 study centers in the United States , we r and omly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity ( intervention group ) or to receive diabetes support and education ( control group ) . The primary outcome was a composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , nonfatal stroke , or hospitalization for angina during a maximum follow-up of 13.5 years . RESULTS The trial was stopped early on the basis of a futility analysis when the median follow-up was 9.6 years . Weight loss was greater in the intervention group than in the control group throughout the study ( 8.6 % vs. 0.7 % at 1 year ; 6.0 % vs. 3.5 % at study end ) . The intensive lifestyle intervention also produced greater reductions in glycated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors , except for low-density-lipoprotein cholesterol levels . The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group ( 1.83 and 1.92 events per 100 person-years , respectively ; hazard ratio in the intervention group , 0.95 ; 95 % confidence interval , 0.83 to 1.09 ; P=0.51 ) . CONCLUSIONS An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes . ( Funded by the National Institutes of Health and others ; Look AHEAD Clinical Trials.gov number , NCT00017953 . ) We studied cognition in the Finnish Diabetes Prevention Study ( DPS ) , a trial of lifestyle intervention that prevented diabetes in persons with impaired glucose tolerance . Cognition was similar in the r and omization arms 9 years after the intervention in 364 participants , suggesting that the intervention did not benefit cognition Aims /hypothesisThis study aim ed to determine whether lifestyle intervention lasting for 4 years affected diabetes incidence , body weight , glycaemia or lifestyle over 13 years among individuals at high risk of type 2 diabetes . Methods Overweight , middle-aged men ( n = 172 ) and women ( n = 350 ) with impaired glucose tolerance were r and omised in 1993–1998 to an intensive lifestyle intervention group ( n = 265 ) , aim ing at weight reduction , dietary modification and increased physical activity , or to a control group ( n = 257 ) that received general lifestyle information . The primary outcome was a diagnosis of diabetes based on annual OGTTs . Secondary outcomes included changes in body weight , glycaemia , physical activity and diet . After active intervention ( median 4 years , range 1–6 years ) , participants still free of diabetes and willing to continue their participation ( 200 in the intervention group and 166 in the control group ) were further followed until diabetes diagnosis , dropout or the end of 2009 , with a median total follow-up of 9 years and a time span of 13 years from baseline . Results During the total follow-up the adjusted HR for diabetes ( intervention group vs control group ) was 0.614 ( 95 % CI 0.478 , 0.789 ; p < 0.001 ) . The corresponding HR during the post-intervention follow-up was 0.672 ( 95 % CI 0.477 , 0.947 ; p = 0.023 ) . The former intervention group participants sustained lower absolute levels of body weight , fasting and 2 h plasma glucose and a healthier diet . Adherence to lifestyle changes during the intervention period predicted greater risk reduction during the total follow-up . Conclusions /interpretationLifestyle intervention in people at high risk of type 2 diabetes induces sustaining lifestyle change and results in long-term prevention of progression to type 2 diabetes . Trial registration Clinical Trials.gov NCT00518167 Funding The DPS study has been financially supported by the Academy of Finl and ( 128315 , 129330 ) , Ministry of Education , Novo Nordisk Foundation , Yrjö Jahnsson Foundation , Juho Vainio Foundation , Finnish Diabetes Research Foundation , Finnish Foundation for Cardiovascular Research , Unilever , and Competitive Research Funding from Tampere , Kuopio and Oulu University Hospitals . The study sponsors had no role in the design and conduct of the study ; the collection , analysis and interpretation of the data ; or the preparation , review or approval of the manuscript Aims /hypothesisThe aim of this study was to investigate whether lifestyle intervention-induced changes in serum fatty acid profile of cholesteryl esters and estimated desaturase activities are related to improvements in insulin sensitivity in subjects at risk of type 2 diabetes . Material s and methods In the Study on Lifestyle Intervention and Impaired Glucose Tolerance Maastricht ( SLIM ) , 97 men and women with IGT were r and omised to a combined diet and exercise programme ( 47 intervention ) or a control group ( 50 control subjects ) . At baseline and after 1 year the following assessment s were made : an OGTT , an exercise test to determine maximal aerobic capacity , anthropometry , and analysis of the serum fatty acid profile of cholesteryl esters . Results The lifestyle programme was effective in reducing the intake of total and saturated fat , increasing physical activity , reducing obesity and improving insulin sensitivity and glucose tolerance . Regression analysis of the total population showed that an increase in the C20:4 n-6/C20:3 n-6 ratio ( estimated Δ5-desaturase activity ) and reductions in the C18:3 n-6/C18:2 n-6 ratio ( estimated Δ6-desaturase activity ) and the C16:1 n-7/C16:0 ratio ( estimated Δ9-desaturase activity or stearoyl-CoA desaturase-1 ) were significantly associated with a decrease in homeostasis model assessment for insulin resistance . After adjustment for lifestyle changes ( change in percentage body fat , aerobic capacity and saturated fat intake ) , these associations were partly reduced , but remained statistically significant . Conclusions /interpretationLifestyle-induced changes in fatty acid profile of cholesteryl esters and desaturase activities were independently related to changes in insulin sensitivity in subjects at risk of type 2 diabetes Background / Objectives : To evaluate the effect of a 4.1-year ( range 3–6 years ) lifestyle intervention according to general public health recommendations on glucose tolerance and dropout in a Dutch population with impaired glucose tolerance (IGT).Subjects/ Methods : In the Study on Lifestyle intervention and Impaired glucose tolerance Maastricht , 147 Caucasian IGT subjects were r and omized to an intervention group ( INT : n=74 ; 38 male , 36 female ) and control group ( CON : n=73 ; 37 male , 36 female ) . Annually , subjects underwent measurements of body weight , anthropometry , glucose tolerance ( oral glucose tolerance test ) , insulin resistance ( homeostasis model assessment -insulin resistance ) , maximal aerobic capacity ( VO2 max ) , blood lipids and blood pressure . INT received individual advice regarding a healthy diet and physical activity . Results : INT decreased their saturated fat intake , increased their carbohydrate intake ( P<0.05 ) and VO2 max ( P=0.04 ) compared with CON . Body weight did not change significantly ( P=0.20 ) between the groups . After an initial decrease , 2-h glucose levels overall increased in INT ( + 0.11 mmol/l ) , but significantly less than CON ( + 1.18 mmol/l ; P=0.04 ) . Diabetes incidence was lower in INT versus CON ( 30 versus 56 % , P=0.04 ) . Change in body weight was associated with change in 2-h glucose levels ( β=0.399 mmol/l per kg , P=0.02 ) . Dropouts had a lower aerobic fitness and socioeconomic status , and a higher body mass index ( BMI ) and 2-h glucose compared with non-dropouts . Conclusions : Prolonged feasible changes in diet and physical activity prevent deterioration of glucose tolerance and reduce diabetes risk . Low socioeconomic status , low aerobic fitness and high BMI and 2-h glucose are indicative of dropout to the program BACKGROUND Type 2 diabetes is linked with cognitive dysfunction and dementia in epidemiological studies , but these observations are limited by lack of data on the exact timing of diabetes onset . We investigated diabetes , dysglycaemia , and cognition in the Finnish Diabetes Prevention Study , in which the timing and duration of diabetes are well documented . METHODS The Finnish Diabetes Prevention Study comprised middle-aged , overweight participants with impaired glucose tolerance but no diabetes at baseline ( n = 522 ) , r and omized to lifestyle intervention or a control group . After an intervention period ( mean duration 4 years ) and follow-up ( additional 9 years ) , cognitive assessment with the CERAD test battery and Trail Making Test A ( TMT ) was executed twice within a 2-year interval . Of the 364 ( 70 % ) participants with cognitive assessment s , 171 ( 47 % ) had developed diabetes . RESULTS Cognitive function did not differ between those who developed diabetes and those who did not . Lower mean 2-h glucose at an oral glucose tolerance test ( OGTT ) and HbA1C during the intervention period predicted better performance in the TMT ( p = 0.012 and 0.024 , respectively ) . Those without diabetes or with short duration of diabetes improved in CERAD total score between the two assessment s ( p = 0.001 ) whereas those with long duration of diabetes did not ( p = 0.844 ) . CONCLUSIONS Better glycemic control among persons with baseline impaired glucose tolerance predicted better cognitive performance 9 years later in this secondary analysis of the Finnish Diabetes Prevention Study population . In addition , learning effects in cognitive testing were not evident in people with long diabetes duration . Copyright © 2015 John Wiley & Sons , BACKGROUND Childhood obesity has become a growing public health issue in Taiwan . Obese children have risk factors for type 2 diabetes and cardiovascular disease . In this prospect i ve study , we investigated the effect of a twelve-week heart health education and physical activity program on body weight and risk factors for type 2 diabetes and cardiovascular disease . METHODS Subjects were 120 obese fifth grade rs ( 65 boys and 55 girls , aged 10 - 13 years ( mean 10.6 yrs ) , body mass index ( BMI ) at the 95th percentile or more ) and were r and omly assigned to an intervention group ( n=60 ) or control group ( n=60 ) . The intervention group received a twelve-week heart health education and physical activity program , while the control group did not . In both groups , a series of examinations were done at baseline and post-test , including height , weight , BMI , body fat , blood pressure ( BP ) , physical fitness ( 800-meter running test ) , heart health knowledge , and serum biochemistry . Differences for baseline and post-test data were compared between both groups . RESULTS Mean changes in the intervention group versus control group were significant for weight ( P = 0.024 ) , BMI ( P = 0.047 ) , percentage body fat ( P = 0.008 ) , physical fitness ( 800-meter running test ) ( P = 0.025 ) , heart health knowledge ( P = 0.006 ) , total cholesterol ( P = 0.027 ) , triglycerides ( P = 0.018 ) , high-density lipoprotein cholesterol ( HDL-C ) ( P = 0.009 ) , low-density lipoprotein cholesterol ( LDL-C ) ( P = 0.041 ) , sugar ( P = 0.035 ) , insulin ( P = 0.007 ) , and insulin resistance ( HOMA-IR ) ( P = 0.028 ) . At post-test , weight , BMI , body fat , total cholesterol , triglycerides , LDL-C , sugar , insulin and HOMA-IR had decreased , but HDL-C had increased in the intervention group . CONCLUSIONS A classroom-based weight-control intervention provides educational programs to promote cardiovascular health in children . This intervention is simple , practical , and beneficial for elementary school children 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 OBJECTIVES To examine the long-term prevalence and predictors of weekly urinary incontinence in the Diabetes Prevention Program Outcomes Study , a follow-up study of the Diabetes Prevention Program r and omized clinical trial of overweight adults with impaired glucose tolerance . METHODS This analysis included 1778 female participants of the Diabetes Prevention Program Outcomes Study who had been r and omly assigned during the Diabetes Prevention Program to intensive lifestyle intervention ( n = 582 ) , metformin ( n = 589 ) or placebo ( n = 607 ) . The study participants completed semi-annual assessment s after the final Diabetes Prevention Program visit and for 6 years until October 2008 . RESULTS At the study entry , the prevalence of weekly urinary incontinence was lower in the intensive lifestyle intervention group compared with the metformin and placebo groups ( 44.2 % vs 51.8 % , 48.0 % urinary incontinence/week , P = 0.04 ) ; during the 6-year follow-up period , these lower rates in intensive lifestyle intervention were maintained ( 46.7 % , 53.1 % , 49.9 % urinary incontinence/week ; P = 0.03 ) . Statistically adjusting for urinary incontinence prevalence at the end of the Diabetes Prevention Program , the treatment arm no longer had a significant impact on urinary incontinence during the Diabetes Prevention Program Outcomes Study . Independent predictors of lower urinary incontinence during the Diabetes Prevention Program Outcomes Study included lower body mass index ( odds ratio 0.988 , 95 % confidence interval 0.982 - 0.994 ) and greater physical activity ( odds ratio 0.999 , 95 % confidence interval 0.998 - 1.000 ) at the Diabetes Prevention Program Outcomes Study entry , and greater reductions in body mass index ( odds ratio 0.75 , 95 % confidence interval 0.60 - 0.94 ) and waist circumference ( odds ratio 0.998 , 95 % confidence interval 0.996 - 1.0 ) during the Diabetes Prevention Program Outcomes Study . Diabetes was not significantly related to urinary incontinence . CONCLUSIONS Intensive lifestyle intervention has a modest positive and enduring impact on urinary incontinence , and should be considered for the long-term prevention and treatment of urinary incontinence in overweight/obese women with glucose intolerance OBJECTIVE To determine whether improvements in glucose regulation following the PREPARE structured education programme were sustained at 24 months . PATIENTS AND METHODS Ninety-eight overweight or obese individuals with impaired glucose tolerance were r and omized to receive : ( 1 ) advice leaflet , ( 2 ) 3-h structured education programme aim ed at promoting physical activity , ( iii ) 3-h structured education with personalized pedometer use . The primary outcome was change in 2-h post-challenge plasma glucose . RESULTS Seventy-three ( 74 % ) individuals were included for analysis at 24 months ; age 65 ± 8 years , BMI 29.3 ± 4.8 kg/m(2 ) , South Asian ethnicity 21 % . A statistically significant reduction in 2-h glucose of -1.6 mmol/l ( -0.4 to -2.7 ) was seen in the education-with-pedometer group compared with the control group . There is no significant difference in the education-only group . CONCLUSION Improvements in glucose regulation following a pragmatic group-based structured education with pedometer use were sustained at 24 months 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 Summary : Women with impaired glucose tolerance are at high risk of developing noninsulin dependent diabetes mellitus ( NIDDM ) . The Mercy Hospital for Women has a long‐term follow‐up programme for women with gestational diabetes , which identifies many women with impaired glucose tolerance . Two hundred of these women were entered into a r and omized controlled trial of intensive versus routine dietary advice . Seven women were lost to follow‐up . The annual incidence rates of diabetes mellitus for the 2 groups were 6.1 % ( intervention ) and 7.3 % ( control ) , an incident rate ratio of 0.83 , 95 % confidence interval 0.47–1.48 , p = 0.50 . Overall , there was a return to normal glucose tolerance in 44 % of patients . Multivariate analysis showed that body mass index , fasting and 2‐hour plasma glucose levels at trial entry were significantly associated with an increased risk of diabetes mellitus . Impaired glucose tolerance is an important condition that should be treated with advice about lifestyle modification ( diet and /or exercise ) . We consider that future trials in the management of women with previous gestational diabetes who have impaired glucose tolerance should investigate the effect of pharmacological intervention in addition to diet and /or exercise , the latter providing a therapy that it would be unethical to exclude on the evidence presently available CONTEXT Gestational diabetes ( GDM ) confers a high risk of type 2 diabetes . In the Diabetes Prevention Program ( DPP ) , intensive lifestyle ( ILS ) and metformin prevented or delayed diabetes in women with a history of GDM . OBJECTIVE The objective of the study was to evaluate the impact of ILS and metformin intervention over 10 years in women with and without a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study . DESIGN This was a r and omized controlled clinical trial with an observational follow-up . SETTING The study was conducted at 27 clinical centers . PARTICIPANTS Three hundred fifty women with a history of GDM and 1416 women with previous live births but no history of GDM participated in the study . The participants had an elevated body mass index and fasting glucose and impaired glucose tolerance at study entry . INTERVENTIONS Interventions included placebo , ILS , or metformin . OUTCOMES MEASURE Outcomes measure was diabetes mellitus . RESULTS Over 10 years , women with a history of GDM assigned to placebo had a 48 % higher risk of developing diabetes compared with women without a history of GDM . In women with a history of GDM , ILS and metformin reduced progression to diabetes compared with placebo by 35 % and 40 % , respectively . Among women without a history of GDM , ILS reduced the progression to diabetes by 30 % , and metformin did not reduce the progression to diabetes . CONCLUSIONS Women with a history of GDM are at an increased risk of developing diabetes . In women with a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study , both lifestyle and metformin were highly effective in reducing progression to diabetes during a 10-year follow-up period . Among women without a history of GDM , lifestyle but not metformin reduced progression to diabetes AIM To evaluate the effectiveness of lifestyle interventions in people with impaired glucose tolerance ( IGT ) . METHODS Participants with IGT ( n=78 ) , diagnosed on two consecutive oral glucose tolerance tests ( OGTTs ) , were r and omly assigned to a 2-year lifestyle intervention or to a control group . Main outcome measures were changes from baseline in : nutrient intake ; physical activity ; anthropometry , glucose tolerance and insulin sensitivity . Measurements were repeated at 6 , 12 and 24 months follow-up . RESULTS After 24 months follow-up , there was a significant fall in total fat consumption ( difference in change between groups ( Delta intervention-Delta control)= -17.9 , 95 % confidence interval ( CI ) -33.6 to -2.1g/day ) as a result of the intervention . Body mass was significantly lower in the intervention group compared with controls after 6 months ( -1.6 , 95 % CI -2.9 to -0.4 kg ) and 24 months ( -3.3 , 95 % CI -5.7 to -0.89 kg ) . Whole body insulin sensitivity , assessed by the short insulin tolerance test ( ITT ) , improved after 12 months in the intervention group ( 0.52 , 95 % CI 0.15 - 0.89%/min ) . CONCLUSIONS These findings complement the findings of the Finnish Diabetes Prevention Study and the American Diabetes Prevention Study , both of which tested intensive interventions , by showing that pragmatic lifestyle interventions result in improvements in obesity and whole body insulin sensitivity in individuals with IGT , without change in other cardiovascular risk factors BACKGROUND Lifestyle interventions among people with impaired glucose tolerance reduce the incidence of diabetes , but their effect on all-cause and cardiovascular disease mortality is unclear . We assessed the long-term effect of lifestyle intervention on long-term outcomes among adults with impaired glucose tolerance who participated in the Da Qing Diabetes Prevention Study . METHODS The study was a cluster r and omised trial in which 33 clinics in Da Qing , China-serving 577 adults with impaired glucose tolerance-were r and omised ( 1:1:1:1 ) to a control group or lifestyle intervention groups ( diet or exercise or both ) . Patients were enrolled in 1986 and the intervention phase lasted for 6 years . In 2009 , we followed up participants to assess the primary outcomes of cardiovascular mortality , all-cause mortality , and incidence of diabetes in the intention-to-treat population . FINDINGS Of the 577 patients , 439 were assigned to the intervention group and 138 were assigned to the control group ( one refused baseline examination ) . 542 ( 94 % ) of 576 participants had complete data for mortality and 568 ( 99 % ) contributed data to the analysis . 174 participants died during the 23 years of follow-up ( 121 in the intervention group vs 53 in the control group ) . Cumulative incidence of cardiovascular disease mortality was 11.9 % ( 95 % CI 8.8 - 15.0 ) in the intervention group versus 19.6 % ( 12.9 - 26.3 ) in the control group ( hazard ratio [ HR ] 0.59 , 95 % CI 0.36 - 0.96 ; p=0.033 ) . All-cause mortality was 28.1 % ( 95 % CI 23.9 - 32.4 ) versus 38.4 % ( 30.3 - 46.5 ; HR 0.71 , 95 % CI 0.51 - 0.99 ; p=0.049 ) . Incidence of diabetes was 72.6 % ( 68.4 - 76.8 ) versus 89.9 % ( 84.9 - 94.9 ; HR 0.55 , 95 % CI 0.40 - 0.76 ; p=0.001 ) . INTERPRETATION A 6-year lifestyle intervention programme for Chinese people with impaired glucose tolerance can reduce incidence of cardiovascular and all-cause mortality and diabetes . These findings emphasise the long-term clinical benefits of lifestyle intervention for patients with impaired glucose tolerance and provide further justification for adoption of lifestyle interventions as public health measures to control the consequences of diabetes . FUNDING Centers for Disease Control and Prevention , WHO , the China-Japan Friendship Hospital , Da Qing First Hospital Although the Diabetes Prevention Program ( DPP ) developed a lifestyle weight loss intervention that has been demonstrated to prevent type 2 diabetes in high-risk individuals , it has yet to be widely adopted at the community level . The Healthy Living Partnership to Prevent Diabetes study ( HELP PD ) was design ed to translate the DPP approach for use in community setting s as a cost-effective intervention led by Community Health Workers ( CHW 's ) and administered through a Diabetes Care Center ( DCC ) . Approximately 300 overweight and obese ( BMI 25 - 40 kg/m(2 ) ) individuals with prediabetes ( fasting blood glucose 95 - 124 mg/dl ) were r and omly assigned to either a lifestyle weight loss intervention ( LW ) or an enhanced usual care comparison condition ( UC ) . The goal of LW is > or=7 % weight loss achieved through increases in physical activity ( 180 min/wk ) and decreases in caloric intake ( approximately 1500 kcal/day ) . The intervention consists of CHW-led group-mediated cognitive behavioral meetings that occur weekly for 6 months and monthly thereafter for 18 months . UC consists of 2 individual meetings with a registered dietitian and a monthly newsletter . The primary outcome is change in fasting blood glucose . Secondary outcomes include cardiovascular risk factors , health-related quality of life , and social cognitive variables . Outcomes are masked and are collected every 6 months . The cost-effectiveness of the program will also be assessed . A community-based program that is administered through local DCC 's and that harnesses the experience of community members ( CHW 's ) may be a promising strategy for the widespread dissemination of interventions effective at preventing type 2 diabetes in high risk individuals BACKGROUND Previous studies demonstrated that intensive lifestyle modification can prevent type 2 diabetes mellitus among those with impaired glucose tolerance , but similar beneficial results have not been proved among those with impaired fasting glucose levels . We investigated the efficacy of lifestyle modification on type 2 diabetes incidence among those with impaired fasting glucose levels . METHODS The present study was an unmasked , multicenter , r and omized , controlled trial . A total of 641 overweight Japanese ( aged 30 - 60 years ) with impaired fasting glucose levels were recruited nationwide in Japan and r and omly assigned to a frequent intervention group ( n = 311 ) or a control group ( n = 330 ) . For 36 months after r and omization , the frequent intervention group received individual instructions and follow-up support for lifestyle modification from the medical staff 9 times . The control group received similar individual instructions 4 times at 12-month intervals during the same period . The primary outcome was type 2 diabetes incidence in annual 75-g oral glucose tolerance tests , diagnosed according to World Health Organization criteria . RESULTS There were no significant differences between the allocation groups in baseline characteristics and dropout rates . Estimated cumulative incidences of type 2 diabetes were 12.2 % in the frequent intervention group and 16.6 % in the control group . Overall , the adjusted hazard ratio in the frequent intervention group was 0.56 ( 95 % confidence interval , 0.36 - 0.87 ) . In the post hoc subgroup analyses , the hazard ratio reduced to 0.41 ( 95 % confidence interval , 0.24 - 0.69 ) among participants with impaired glucose tolerance at baseline , and to 0.24 ( 0.12 - 0.48 ) among those with baseline hemoglobin A(1c ) levels of 5.6 % or more ( the Japan Diabetes Society method ) . Such risk reduction was not observed among those with isolated impaired fasting glucose findings or baseline hemoglobin A(1c ) levels of less than 5.6 % . CONCLUSIONS Lifestyle modifications can prevent type 2 diabetes among overweight Japanese with impaired fasting glucose levels . In addition , identifying individuals with more deteriorated glycemic status by using 75-g oral glucose tolerance test findings or , especially , measurement of hemoglobin A(1c ) levels , could enhance the efficacy of lifestyle modifications . TRIAL REGISTRATION umin.ac.jp/ctr Identifier : UMIN000001959 OBJECTIVE To provide the specific weight loss outcomes for African-American , Hispanic , and white men and women in the lifestyle and metformin treatment arms of the Diabetes Prevention Program ( DPP ) by race-gender group to facilitate research ers translating similar interventions to minority population s , as well as provide realistic weight loss expectations for clinicians . METHODS AND PROCEDURES Secondary analyses of weight loss of 2,921 overweight participants ( 22 % black ; 17 % Hispanic ; 61 % white ; and 68 % women ) with impaired glucose tolerance r and omized in the DPP to intensive lifestyle modification , metformin or placebo . Data over a 30-month period are examined for comparability across treatment arms by race and gender . RESULTS Within lifestyle treatment , all race-gender groups lost comparable amounts of weight with the exception of black women who exhibited significantly smaller weight losses ( P < 0.01 ) . For example , at 12 months , weight losses for white men ( -8.4 % ) , white women ( -8.1 % ) , Hispanic men ( -7.8 % ) , Hispanic women ( -7.1 % ) , and black men ( -7.1 % ) were similar and significantly higher than black women ( -4.5 % ) . In contrast , within metformin treatment , all race-gender groups including black women lost similar amounts of weight . Race-gender specific mean weight loss data are provided by treatment arm for each follow-up period . DISCUSSION Diminished weight losses were apparent among black women in comparison with other race-gender groups in a lifestyle intervention but not metformin , underscoring the critical nature of examining sociocultural and environmental contributors to successful lifestyle intervention for black women Background : This study aim ed to explore the feasibility and effect of an intervention in clinical practice with isolated physical activity in individuals with IGT , recruited by the FINDRISC question naire . Methods : The question naire was sent to a population of 9734 individuals , 35–75 years old , in Sweden . Those with a risk score ≥15 were encouraged to perform an oral glucose tolerance test . Individuals with IGT were invited to participate in a r and omized controlled trial with a focus on physical activity . The participants were allocated to one of three arms ; basic intervention , intensive intervention or to care as usual . A total of 52 individuals were carefully examined and question naires about diet and lifestyle were completed at baseline and after one year . All analyses were adjusted for differences in age and sex , and calorie intake when relevant . Results : The prevalence of chronic diseases in the study population was high , creating considerable difficulties in conducting a st and ardized test for fitness . Waist circumference ( p=0.020 ) , sagittal diameter ( p=0.035 ) , body weight ( p=0.038 ) and BMI ( p=0.043 ) decreased significantly more in the intensive care group than in care as usual and the basic care group . However , the significance was abolished when differences in energy intake were accounted for . Conclusions : In an intention to treat , prospect i ve lifestyle interventions with physical activity are feasible , but a high prevalence of comorbidities needs to be considered . Also , an intervention focused on isolated physical activity inevitably led to changes in diet with weight loss and significant improvement of essential risk factors in spite of the participants ’ burden of chronic diseases |
13,723 | 21,735,426 | There was currently no evidence to support that TPO receptor agonists are effective in chronic ITP .
Compared to placebo or SOC , despite significantly increased platelet response , there was no evidence to demonstrate that TPO receptor agonists did improve significant bleeding events in chronic ITP .
Although long-term studies are lacking , current data demonstrated adverse effects of TPO receptor agonists were similar to that of placebo and SOC | BACKGROUND Chronic idiopathic thrombocytopenic purpura ( ITP ) is an acquired autoimmune disorder that is characterized predominantly by a low platelet count .
Thrombopoietin ( TPO ) receptor agonists increase production of platelets by stimulating the TPO receptor in people with chronic ITP .
OBJECTIVES To determine the efficacy and safety of TPO receptor agonists in chronic ITP patients . | The CONSORT ( Consoli date d St and ards of Reporting Trials ) statement is used worldwide to improve the reporting of r and omized , controlled trials . Schulz and colleagues describe the latest version , CONSORT 2010 , which up date s the reporting guideline based on new method ological evidence and accumulating experience . Idiopathic thrombocytopenic purpura ( ITP ) is an autoimmune disorder characterized by persistent thrombocytopenia ( peripheral blood platelet count < 150 · 10 ⁄ l ) due to autoantibody binding to platelet antigen(s ) causing their premature destruction by the reticuloendothelial system , and in particular the spleen ( Woods et al , 1984a , b ) . Although the basic underlying pathophysiology of ITP has been known for 50 years ( Harrington et al , 1951 ) , the literature shows that the investigation and management of patients with thrombocytopenia vary widely , and is not evidence -based , due to a lack of clinical trials and quality research . Despite major advances in our underst and ing of the molecular basis of many blood disorders , the diagnosis of ITP remains one of exclusion ; there are currently no robust clinical or laboratory parameters that are able to establish the diagnosis of ITP with accuracy . This guideline aims to assess available diagnostic tests and therapies , and attempts to provide a rational approach to the diagnosis and treatment in adults , children and in pregnancy . Although natural history data are becoming available ( Cohen et al , 2000 ; Djulbegovic & Cohen , 2001 ; Portielje et al , 2001 ) , there are few r and omized trials in ITP and many of the recommendations , like those of the American Society of Hematology ( ASH ) Panel ( George et al , 1996 ) , are based on expert opinion Romiplostim is a thrombopoietin receptor agonist that increases platelet counts in patients with chronic immune thrombocytopenia ( ITP ) . Thrombopoietin receptor agonists are reported to increase the risk for reticulin fiber deposition within bone marrow . This report describes bone marrow findings from romiplostim-treated rats , a retrospective analysis of reticulin observed in romiplostim ITP clinical trials , and a prospect i ve clinical study of the effects of romiplostim on bone marrow morphology . In rats , romiplostim produced a dose-dependent increase in bone marrow fibrosis that resolved after treatment withdrawal . Of 271 ITP patients in romiplostim clinical trials , 10 were reported to have reticulin deposition ; reticulin grade was increased in 4 of 5 patients with both pretreatment and on-treatment bone marrow results . Reticulin grade often decreased soon after romiplostim discontinuation . In the prospect i ve study , reticulin grade during romiplostim treatment remained within the normal range for all patients and was increased in only 1 of 6 patients with pretreatment and on-treatment bone marrow results . This report suggests that romiplostim produces reversible , dose-dependent bone marrow changes in rats and produces modest increases in bone marrow reticulin in some ITP patients that decrease when therapy is discontinued . These studies were registered at www . clinical trials.gov as # NCT00102323 , # NCT00102336 , # NCT00861224 , and # NCT00116688 BACKGROUND Eltrombopag is an oral thrombopoietin receptor agonist for the treatment of thrombocytopenia . We aim ed to compare the response to once daily eltrombopag versus placebo in patients with chronic immune thrombocytopenia during a 6-month period . METHODS We undertook a phase 3 , double-blind , placebo-controlled study in adults with previously treated immune thrombocytopenia of more than 6 months ' duration who had baseline platelet counts lower than 30,000 per μL. Patients were r and omly allocated ( in a 2:1 ratio ) treatment with local st and ard of care plus 50 mg eltrombopag or matching placebo once daily for 6 months . R and omisation was done central ly with a computer-generated r and omisation schedule and was stratified by baseline platelet count ( ≤ 15,000 per μL ) , use of treatment for immune thrombocytopenia , and splenectomy status . Patients , investigators , and those assessing data were masked to allocation . Dose modifications were made on the basis of platelet response . Patients were assessed for response to treatment ( defined as a platelet count of 50,000 - 400,000 per μL ) weekly during the first 6 weeks and at least once every 4 weeks thereafter ; the primary endpoint was the odds of response to eltrombopag versus placebo . Analysis was by intention to treat . This study is registered at Clinical Trials.gov , number NCT00370331 . FINDINGS Between Nov 22 , 2006 , and July 31 , 2007 , 197 patients were r and omly allocated to treatment groups and were included in the intention-to-treat analysis ( 135 eltrombopag , 62 placebo ) . 106 ( 79 % ) patients in the eltrombopag group responded to treatment at least once during the study , compared with 17 ( 28 % ) patients in the placebo group . The odds of responding were greater in patients in the eltrombopag group compared with those in the placebo group throughout the 6-month treatment period ( odds ratio 8·2 , 99 % CI 3·59 - 18·73 ; p<0·0001 ) . 37 ( 59 % ) patients receiving eltrombopag reduced concomitant treatment versus ten ( 32 % ) patients receiving placebo ( p=0·016 ) . 24 ( 18 % ) patients receiving eltrombopag needed rescue treatment compared with 25 ( 40 % ) patients receiving placebo ( p=0·001 ) . Three ( 2 % ) patients receiving eltrombopag had thromboembolic events compared with none in patients on placebo . Nine ( 7 % ) eltrombopag-treated patients and two ( 3 % ) in the placebo group had mild increases in alanine aminotransferase concentration , and five ( 4 % ) eltrombopag-treated patients ( vs none allocated to placebo ) had increases in total bilirubin . Four ( 7 % ) patients taking placebo had serious bleeding events , compared with one ( < 1 % ) patient treated with eltrombopag . INTERPRETATION Eltrombopag is effective for management of chronic immune thrombocytopenia , and could be particularly beneficial for patients who have not responded to splenectomy or previous treatment . These benefits should be balanced with the potential risks associated with eltrombopag treatment . FUNDING GlaxoSmithKline Eltrombopag ( SB-497 115 ) is a first-in-class , oral , small-molecule , nonpeptide agonist of the thrombopoietin receptor ( TpoR ) , being developed as a treatment for thrombocytopenia of various etiologies . In this phase 1 placebo-controlled clinical trial in 73 healthy male subjects , eltrombopag was administered as once-daily oral capsules for 10 days at doses of 5 , 10 , 25 , 30 , 50 , and 75 mg . The pharmacokinetics of eltrombopag were dose dependent and linear , and eltrombopag increased platelet counts in a dose-dependent manner . There were no apparent differences in the incidence or severity of adverse events in subjects receiving active or placebo study medication . These observations indicate that eltrombopag is a once-daily , oral TpoR agonist with demonstrated thrombopoietic activity in human subjects , encouraging further studies in patients with thrombocytopenia BACKGROUND Most current treatments for chronic immune thrombocytopenic purpura ( ITP ) act by decreasing platelet destruction . In a phase 1 - 2 study , we administered a thrombopoiesis-stimulating protein , AMG 531 , to patients with ITP . METHODS In phase 1 , 24 patients who had received at least one treatment for ITP were assigned to escalating-dose cohorts of 4 patients each and given two identical doses of AMG 531 ( 0.2 to 10 microg per kilogram of body weight ) . In phase 2 , 21 patients were r and omly assigned to receive six weekly subcutaneous injections of AMG 531 ( 1 , 3 , or 6 microg per kilogram ) or placebo . The primary objective was to assess the safety of AMG 531 ; the secondary objective was to evaluate platelet counts during and after treatment . RESULTS No major adverse events that could be attributed directly to AMG 531 occurred during the treatment period ; 4 of 41 patients had transient post-treatment worsening of thrombocytopenia . In phase 1 , a platelet count that was within the targeted range ( 50,000 to 450,000 per cubic millimeter ) and at least twice the baseline count was achieved in 4 of 12 patients given 3 , 6 , or 10 mug of AMG 531 per kilogram . Overall , a platelet count of at least 50,000 per cubic millimeter was achieved in 7 of 12 patients , including 3 with counts exceeding 450,000 per cubic millimeter . Increases in the platelet count were dose-dependent ; mean peak counts were 163,000 , 309,000 , and 746,000 per cubic millimeter with 3 , 6 , and 10 microg of AMG 531 per kilogram [ corrected ] , respectively . In phase 2 , the targeted platelet range was achieved in 10 of 16 patients treated with 1 or 3 mug of AMG 531 per kilogram per week for 6 weeks . Mean peak counts were 135,000 , 241,000 , and 81,000 per cubic millimeter in the groups that received the 1-mug dose , the 3-mug dose , and placebo , respectively . CONCLUSIONS AMG 531 caused no major adverse events and increased platelet counts in patients with ITP . ( Clinical Trials.gov number , NCT00111475 [ Clinical Trials.gov ] . ) BACKGROUND Romiplostim , a thrombopoietin mimetic , increases platelet counts in patients with immune thrombocytopenia , with few adverse effects . METHODS In this open-label , 52-week study , we r and omly assigned 234 adult patients with immune thrombocytopenia , who had not undergone splenectomy , to receive the st and ard of care ( 77 patients ) or weekly subcutaneous injections of romiplostim ( 157 patients ) . Primary end points were incidences of treatment failure and splenectomy . Secondary end points included the rate of a platelet response ( a platelet count > 50 × 10(9 ) per liter at any scheduled visit ) , safety outcomes , and the quality of life . RESULTS The rate of a platelet response in the romiplostim group was 2.3 times that in the st and ard-of-care group ( 95 % confidence interval [ CI ] , 2.0 to 2.6 ; P<0.001 ) . Patients receiving romiplostim had a significantly lower incidence of treatment failure ( 18 of 157 patients [ 11 % ] ) than those receiving the st and ard of care ( 23 of 77 patients [ 30 % ] , P<0.001 ) ( odds ratio with romiplostim , 0.31 ; 95 % CI , 0.15 to 0.61 ) . Splenectomy also was performed less frequently in patients receiving romiplostim ( 14 of 157 patients [ 9 % ] ) than in those receiving the st and ard of care ( 28 of 77 patients [ 36 % ] , P<0.001 ) ( odds ratio , 0.17 ; 95 % CI , 0.08 to 0.35 ) . The romiplostim group had a lower rate of bleeding events , fewer blood transfusions , and greater improvements in the quality of life than the st and ard-of-care group . Serious adverse events occurred in 23 % of patients ( 35 of 154 ) receiving romiplostim and 37 % of patients ( 28 of 75 ) receiving the st and ard of care . CONCLUSIONS Patients treated with romiplostim had a higher rate of a platelet response , lower incidence of treatment failure and splenectomy , less bleeding and fewer blood transfusions , and a higher quality of life than patients treated with the st and ard of care . ( Clinical Trials.gov number , NCT00415532 . ) The objective of this study was to evaluate the tolerability , pharmacodynamics , and pharmacokinetics of AMG 531 , a novel thrombopoietin receptor lig and , after a single intravenous or subcutaneous injection in healthy subjects BACKGROUND Chronic immune thrombocytopenic purpura ( ITP ) is characterised by accelerated platelet destruction and decreased platelet production . Short-term administration of the thrombopoiesis-stimulating protein , romiplostim , has been shown to increase platelet counts in most patients with chronic ITP . We assessed the long-term administration of romiplostim in splenectomised and non-splenectomised patients with ITP . METHODS In two parallel trials , 63 splenectomised and 62 non-splenectomised patients with ITP and a mean of three platelet counts 30x10(9)/L or less were r and omly assigned 2:1 to subcutaneous injections of romiplostim ( n=42 in splenectomised study and n=41 in non-splenectomised study ) or placebo ( n=21 in both studies ) every week for 24 weeks . Doses of study drug were adjusted to maintain platelet counts of 50x10(9)/L to 200x10(9)/L. The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response ( platelet count > or = 50x10(9)/L during 6 or more of the last 8 weeks of treatment ) and treatment safety . Analysis was per protocol . These studies are registered with Clinical Trials.gov , numbers NCT00102323 and NCT00102336 . FINDINGS A durable platelet response was achieved by 16 of 42 splenectomised patients given romplostim versus none of 21 given placebo ( difference in proportion of patients responding 38 % [ 95 % CI 23.4 - 52.8 ] , p=0.0013 ) , and by 25 of 41 non-splenectomised patients given romplostim versus one of 21 given placebo ( 56 % [ 38.7 - 73.7 ] , p<0.0001 ) . The overall platelet response rate ( either durable or transient platelet response ) was noted in 88 % ( 36/41 ) of non-splenectomised and 79 % ( 33/42 ) of splenectomised patients given romiplostim compared with 14 % ( three of 21 ) of non-splenectomised and no splenectomised patients given placebo ( p<0.0001 ) . Patients given romiplostim achieved platelet counts of 50x10(9)/L or more on a mean of 13.8 ( SE 0.9 ) weeks ( mean 12.3 [ 1.2 ] weeks in splenectomised group vs 15.2 [ 1.2 ] weeks in non-splenectomised group ) compared with 0.8 ( 0.4 ) weeks for those given placebo ( 0.2 [ 0.1 ] weeks vs 1.3 [ 0.8 ] weeks ) . 87 % ( 20/23 ) of patients given romiplostim ( 12/12 splenectomised and eight of 11 non-splenectomised patients ) reduced or discontinued concurrent therapy compared with 38 % ( six of 16 ) of those given placebo ( one of six splenectomised and five of ten non-splenectomised patients ) . Adverse events were much the same in patients given romiplostim and placebo . No antibodies against romiplostim or thrombopoietin were detected . INTERPRETATION Romiplostim was well tolerated , and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP . Many patients were able to reduce or discontinue other ITP medications . Stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP BACKGROUND Conflicting reports exist in the medical literature regarding the association between industry funding and published research findings . In this study , we examine the association between industry funding and the statistical significance of results in recently published medical and surgical trials . METHODS We examined a consecutive series of 332 r and omized trials published between January 1999 and June 2001 in 8 leading surgical journals and 5 medical journals . Each eligible study was independently review ed for method ological quality using a 21-point index with 5 domains : r and omization , outcomes , eligibility criteria , interventions and statistical issues . Our primary analysis included studies that explicitly identified the primary outcome and reported it as statistically significant . For studies that did not explicitly identify a primary outcome , we defined a " positive " study as one with at least 1 statistically significant outcome measure . We used multivariable regression analysis to determine whether there was an association between reported industry funding and trial results , while controlling for study quality and sample size . RESULTS Among the 332 r and omized trials , there were 158 drug trials , 87 surgical trials and 87 trials of other therapies . In 122 ( 37 % ) of the trials , authors declared industry funding . An unadjusted analysis of this sample of trials revealed that industry funding was associated with a statistically significant result in favour of the new industry product ( odds ratio [ OR ] 1.9 , 95 % confidence interval [ CI ] 1.3 - 3.5 ) . The association remained significant after adjustment for study quality and sample size ( adjusted OR 1.8 , 95 % CI 1.1 - 3.0 ) . There was a nonsignificant difference between surgical trials ( OR 8.0 , 95 % CI 1.1 - 53.2 ) and drug trials ( OR 1.6 , 95 % CI 1.1 - 2.8 ) , both of which were likely to have a pro-industry result ( relative OR 5.0 , 95 % CI 0.7 - 37.5 , p = 0.14 ) . INTERPRETATION Industry-funded trials are more likely to be associated with statistically significant pro-industry findings , both in medical trials and surgical interventions The objective of this open label , phase 1–2 , multicentre trial was to evaluate the safety of AMG 531 , a novel thrombopoiesis‐stimulating peptibody , and its effect on platelet counts in adults with immune thrombocytopenic purpura . Four patients were assigned to each of four unit‐dose cohorts : 30 , 100 , 300 or 500 μg , administered subcutaneously on days 1 and 15 ( or day 22 if the day 15 platelet count was > 50 × 109/l ) . Safety was assessed by adverse event ( AE ) monitoring , clinical laboratory studies and antibody assays . Platelet response was defined as a platelet count double the baseline value and between 50 and 450 × 109/l . Sixteen patients ( 10 women ) were enrolled . The 500‐μg cohort was discontinued because the first patient 's platelet count became unacceptably high . AEs were generally expected and mild or moderate ; the most frequent was headache ( eight of 16 patients ) . Two patients experienced serious AEs related to AMG 531 ( severe headache and elevated serum lactic dehydrogenase ; thrombocytopenia ) . Platelet responses occurred with all doses and with a dose equivalent to ≥1 μg/kg in eight of 11 patients . In summary , patients tolerated AMG 531 well at the doses tested . No anti‐AMG or antithrombopoietin antibodies were detected . Doses equivalent to ≥1 μg/kg increased platelet counts BACKGROUND The pathogenesis of chronic idiopathic thrombocytopenic purpura ( ITP ) involves antibody-mediated platelet destruction and reduced platelet production . Stimulation of platelet production may be an effective treatment for this disorder . METHODS We conducted a trial in which 118 adults with chronic ITP and platelet counts of less than 30,000 per cubic millimeter who had had relapses or whose platelet count was refractory to at least one st and ard treatment for ITP were r and omly assigned to receive the oral thrombopoietin-receptor agonist eltrombopag ( 30 , 50 , or 75 mg daily ) or placebo . The primary end point was a platelet count of 50,000 or more per cubic millimeter on day 43 . RESULTS In the eltrombopag groups receiving 30 , 50 , and 75 mg per day , the primary end point was achieved in 28 % , 70 % , and 81 % of patients , respectively . In the placebo group , the end point was achieved in 11 % of patients . The median platelet counts on day 43 for the groups receiving 30 , 50 , and 75 mg of eltrombopag were 26,000 , 128,000 , and 183,000 per cubic millimeter , respectively ; for the placebo group the count was 16,000 per cubic millimeter . By day 15 , more than 80 % of patients receiving 50 or 75 mg of eltrombopag daily had an increased platelet count . Bleeding also decreased during treatment in these two groups . The incidence and severity of adverse events were similar in the placebo and eltrombopag groups . CONCLUSIONS Eltrombopag increased platelet counts in a dose-dependent manner in patients with relapsed or refractory ITP . ( Clinical Trials.gov number , NCT00102739 . BACKGROUND Eltrombopag is an oral , non-peptide , thrombopoietin-receptor agonist that stimulates thrombopoiesis , leading to increased platelet production . This study assessed the efficacy , safety , and tolerability of once daily eltrombopag 50 mg , and explored the efficacy of a dose increase to 75 mg . METHODS In this phase III , r and omised , double-blind , placebo-controlled study , adults from 63 sites in 23 countries with chronic idiopathic thrombocytopenic purpura ( ITP ) , platelet counts less than 30 000 per muL of blood , and one or more previous ITP treatment received st and ard care plus once-daily eltrombopag 50 mg ( n=76 ) or placebo ( n=38 ) for up to 6 weeks . Patients were r and omly assigned in a 2:1 ratio of eltrombopag : placebo by a vali date d r and omisation system . After 3 weeks , patients with platelet counts less than 50 000 per microL could increase study drug to 75 mg . The primary endpoint was the proportion of patients achieving platelet counts 50 000 per microL or more at day 43 . All participants who received at least one dose of their allocated treatment were included in the analysis . This study is registered with Clinical Trials.gov , number NCT00102739 . FINDINGS 73 patients in the eltrombopag group and 37 in the placebo group were included in the efficacy population and were evaluable for day-43 analyses . 43 ( 59 % ) eltrombopag patients and six ( 16 % ) placebo patients responded ( ie , achieved platelet counts > /=50 000 per microL ; odds ratio [ OR ] 9.61 [ 95 % CI 3.31 - 27.86 ] ; p<0.0001 ) . Response to eltrombopag compared with placebo was not affected by predefined study stratification variables ( baseline platelet counts , concomitant ITP drugs , and splenectomy status ) or by the number of previous ITP treatments . Of the 34 patients in the efficacy analysis who increased their dose of eltrombopag , ten ( 29 % ) responded . Platelet counts generally returned to baseline values within 2 weeks after the end of treatment . Patients receiving eltrombopag had less bleeding at any time during the study than did those receiving placebo ( OR 0.49 [ 95 % CI 0.26 - 0.89 ] ; p=0.021 ) . The frequency of grade 3 - 4 adverse events during treatment ( eltrombopag , two [ 3 % ] ; placebo , one [ 3 % ] ) and adverse events leading to study discontinuation ( eltrombopag , three [ 4 % ] ; placebo , two [ 5 % ] ) , were similar in both groups . INTERPRETATION Eltrombopag is an effective treatment for managment of thrombocytopenia in chronic ITP The goal of treatment for idiopathic ( immune ) thrombocytopenic purpura ( ITP ) is to prevent serious bleeding . Traditionally , corticosteroids have been used as first-line therapy followed by splenectomy . Experience with splenectomy over 60 years shows that approximately two thirds of patients achieve normal platelet counts during the initial observation , but that thrombocytopenia often recurs with longer follow-up . We know that long-term use of corticosteroids can lead to significant morbidities ; there is no consensus regarding the appropriate timing or indications for splenectomy . To address the Issue of appropriate use of splenectomy , we design ed a multicenter clinical trial that will r and omize patients to either st and ard care , involving prednisone followed by splenectomy , or to a novel regimen of limited prednisone treatment followed by WinRho SDF ( Nabi , Boca Raton , FL ) ( anti-D ) therapy to maintain the platelet count in a safe range for 1 year . Anti-D can be administered easily in an outpatient setting with few side effects and can provide predictable , transient increases in platelet count . The hypothesis is that prolonged maintenance therapy with a nontoxic regimen may increase the percentage of patients who will experience a spontaneous remission from thrombocytopenia , thereby avoiding an invasive and permanent surgical procedure , splenectomy , and its potentially life-threatening sequelae Chronic immune thrombocytopenic purpura ( ITP ) is characterized by low platelet counts and mucocutaneous bleeding . In previous studies romiplostim ( AMG531 ) , a thrombopoiesis-stimulating protein , increased platelet counts in most patients with chronic ITP . This ongoing , long-term open-label , single-arm study investigated safety and efficacy in patients who completed a previous romiplostim study and had platelet counts less than or equal to 50 [ corrected ] x 10(9)/L. One hundred forty-two patients were treated for up to 156 weeks ( mean , 69 weeks ) . Platelet responses ( platelet count > or = 50 x 10(9)/L and double baseline ) were observed in 87 % of all patients and occurred on average 67 % of the time in responding patients . In 77 % of patients , the romiplostim dose remained within 2 microg/kg of their most frequent dose at least 90 % of the time . Ninety patients ( 63 % ) received treatment by self-administration . Treatment-related serious adverse events were reported in 13 patients ( 9 % ) . Bone marrow reticulin was observed in 8 patients ; marrows were not routinely performed in this study , so the true incidence of this event can not be determined . Severe bleeding events were reported in 12 patients ( 9 % ) . Thrombotic events occurred in 7 patients ( 5 % ) . In conclusion , romiplostim increased platelet counts in most patients for up to 156 weeks without tachyphylaxis and had an acceptable safety profile . ( Clinical Trials.gov Identifier NCT00116688 ) The CONSORT statement is used worldwide to improve the reporting of r and omised controlled trials . Kenneth Schulz and colleagues describe the latest version , CONSORT 2010 , which up date s the reporting guideline based on new method ological evidence and accumulating |
13,724 | 15,899,051 | Compared with placebo , celecoxib had fewer discontinuations for any cause or for lack of efficacy , fewer serious adverse events , and less nausea .
It had more patients with dyspepsia , diarrhoea , oedema , more adverse events that were gastrointestinal or treatment related , and more patients experiencing an adverse event .
There were no differences for hypertension , gastrointestinal tolerability , or discontinuations for adverse events .
Compared with paracetamol , celecoxib had fewer discontinuations for any cause , for lack of efficacy , or diarrhoea , but no other differences .
Compared with rofecoxib , celecoxib had fewer patients with abdominal pain and oedema , but no other differences .
Compared with NSAIDs , celecoxib had fewer symptomatic ulcers and bleeds , endoscopically detected ulcers , and discontinuations for adverse events or gastrointestinal adverse events .
Fewer patients had any , or a gastrointestinal , or a treatment-related adverse event , or vomiting , abdominal pain , dyspepsia , or reduced haemoglobin or haematocrit .
Discontinuations for lack of efficacy were higher .
No differences were found for all-cause discontinuations , serious adverse events , hypertension , diarrhoea , nausea , oedema , myocardial infa rct ion , cardiac failure , or raised creatinine . | The objective was to improve underst and ing of adverse events occurring with celecoxib in the treatment of osteoarthritis and rheumatoid arthritis . | BACKGROUND Paracetamol is a recommended symptomatic treatment of osteoarthritis ( OA ) , but in clinical trials sample sizes have been relatively small and variable daily doses of paracetamol have been used . OBJECTIVES To determine the therapeutic efficacy of paracetamol in OA of the knee and identify predictive factors of clinical response to treatment . METHODS A double blind , parallel group , placebo controlled trial of analgesic efficacy and safety of paracetamol versus placebo including 779 patients with OA of the knee . Patients were r and omly assigned to receive paracetamol 4 g/day ( n = 405 ) or placebo ( n = 374 ) for 6 weeks . Symptomatic OA of the knee was required at inclusion with global pain intensity of the knee during physical activities for the past 24 hours of > or=30 mm on a 100 mm visual analogue scale . The primary end point was a 30 % decrease of global pain intensity of the knee . Intention to treat analyses were performed . RESULTS The percentage of responders did not differ significantly between groups : 52.6 % and 51.9 % in paracetamol and placebo groups , respectively ( p = 0.840 ) . In a subgroup of patients with chronic mechanical knee pain without signs of inflammation ( n = 123 ) , the mean change in pain intensity from baseline was 25.2 mm v 15.2 mm , in the paracetamol ( n = 63 ) and placebo ( n = 60 ) groups , respectively-mean difference 10.0 mm ; 95 % CI 1.0 to 19.0 ; p = 0.0294 . No serious adverse events were attributable to treatment . CONCLUSION A statistically significant symptomatic effect of oral paracetamol 4 g/day over placebo was not found , suggesting that paracetamol use in symptomatic OA of the knee should be further explored . The tolerability and safety of paracetamol , at the recommended maximum dose of 4 g/day , was confirmed over 6 weeks 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 SUMMARY Objectives : To compare patient and physician attitudes to osteoarthritis ( OA ) treatment with rofecoxib or traditional non-steroidal anti-inflammatory drugs ( tNSAIDs ) . Methods : A 6-month prospect i ve study involving 562 OA patients enrolled at 29 Spanish primary -care centres . Patients were continued on established tNSAID therapy for the first 3 months then switched to rofecoxib 12.5 or 25 mg/day . Results : Both patients and physicians were significantly more likely to be satisfied with rofecoxib treatment than with tNSAIDs ( p < 0.001 ) and assessment s of overall health status improved significantly during rofecoxib therapy ( p < 0.001 ) . Adherence to therapy was significantly better with rofecoxib than during tNSAID treatment ( p < 0.001 ) . Use of rofecoxib was associated with a significant reduction in the proportion of discontinuations attributed to lack of effectiveness ( p < 0.001 ) or gastrointestinal ( GI ) adverse events ( p < 0.001 compared with tNSAIDs ) . Rofecoxib was also associated with a > 60 % reduction in the proportion of patients experiencing a GI adverse event and a halving in the proportion of patients who received GI co-medications ; concomitant analgesic use decreased by one-third during rofecoxib therapy . Conclusions : Use of rofecoxib was associated with marked improvements in several indices of treatment effectiveness and tolerability , and in patient and physician satisfaction and perception of general health status compared with tNSAIDs . Rofecoxib is a valuable additional medication for relieving the symptoms of OA and its use in place of tNSAIDs may lead to a reduction in the prescription of concomitant medications BACKGROUND Chronic pain is recognised as an important problem in the community but our underst and ing of the epidemiology of chronic pain remains limited . We undertook a study design ed to quantify and describe the prevalence and distribution of chronic pain in the community . METHODS A r and om sample of 5036 patients , aged 25 and over , was drawn from 29 general practice s in the Grampian region of the UK and surveyed by a postal self-completion question naire . The question naire included case-screening questions , a question on the cause of the pain , the chronic pain grade question naire , the level of expressed needs question naire , and sociodemographic questions . FINDINGS 3605 question naires were returned completed . 1817 ( 50.4 % ) of patients self reported chronic pain , equivalent to 46.5 % of the general population . 576 reported back pain and 570 reported arthritis ; these were the most common complaints and accounted for a third of all complaints . Backward stepwise logistic-regression modelling identified age , sex , housing tenure , and employment status as significant predictors of the presence of chronic pain in the community . 703 ( 48.7 % ) individuals with chronic pain had the least severe grade of pain , and 228 ( 15.8 % ) the most severe grade . Of those who reported chronic pain , 312 ( 17.2 % ) reported no expressed need , and 509 ( 28.0 % ) reported the highest expressed need . INTERPRETATION Chronic pain is a major problem in the community and certain groups within the population are more likely to have chronic pain . A detailed underst and ing of the epidemiology of chronic pain is essential for efficient management of chronic pain in primary care CONTEXT Conventional nonsteroidal anti-inflammatory drugs ( NSAIDs ) are associated with a spectrum of toxic effects , notably gastrointestinal ( GI ) effects , because of inhibition of cyclooxygenase (COX)-1 . Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown . OBJECTIVE To determine whether celecoxib , a COX-2-specific inhibitor , is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs . DESIGN The Celecoxib Long-term Arthritis Safety Study ( CLASS ) , a double-blind , r and omized controlled trial conducted from September 1998 to March 2000 . SETTING Three hundred eighty-six clinical sites in the United States and Canada . PARTICIPANTS A total of 8059 patients ( > /=18 years old ) with osteoarthritis ( OA ) or rheumatoid arthritis ( RA ) were enrolled in the study , and 7968 received at least 1 dose of study drug . A total of 4573 patients ( 57 % ) received treatment for 6 months . INTERVENTIONS Patients were r and omly assigned to receive celecoxib , 400 mg twice per day ( 2 and 4 times the maximum RA and OA dosages , respectively ; n = 3987 ) ; ibuprofen , 800 mg 3 times per day ( n = 1985 ) ; or diclofenac , 75 mg twice per day ( n = 1996 ) . Aspirin use for cardiovascular prophylaxis ( < /=325 mg/d ) was permitted . MAIN OUTCOME MEASURES Incidence of prospect ively defined symptomatic upper GI ulcers and ulcer complications ( bleeding , perforation , and obstruction ) and other adverse effects during the 6-month treatment period . RESULTS For all patients , the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76 % vs 1.45 % ( P = .09 ) and 2 . 08 % vs 3.54 % ( P = .02 ) , respectively . For patients not taking aspirin , the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44 % vs 1.27 % ( P = .04 ) and 1.40 % vs 2.91 % ( P = .02 ) . For patients taking aspirin , the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01 % vs 2.12 % ( P = .92 ) and 4.70 % vs 6.00 % ( P = .49 ) . Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss , GI intolerance , hepatotoxicity , or renal toxicity . No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs , irrespective of aspirin use . CONCLUSIONS In this study , celecoxib , at dosages greater than those indicated clinical ly , was associated with a lower incidence of symptomatic ulcers and ulcer complications combined , as well as other clinical ly important toxic effects , compared with NSAIDs at st and ard dosages . The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly . JAMA . 2000;284:1247 - Renal prostagl and in inhibition by nonsteroidal antiinflammatory drugs ( NSAIDs ) may decrease renal function , especially under conditions of low effective circulating volume . To evaluate the risk of important deterioration of renal function due to this effect , the authors performed a nested case-control study using Tennessee Medicaid enrollees aged > or = 65 years in 1987 - 1991 . Cases were patients who had been hospitalized with community-acquired acute renal failure ; they were selected on the basis of medical record review of Medicaid enrollees with selected discharge diagnoses . Information on the timing , duration , and dose of prescription NSAIDs used , demographic factors , and comorbidity was gathered from computerized Medicaid-Medicare data files . Of the 1,799 patients with acute renal failure ( 4.51 hospitalizations per 1,000 person-years ) , 18.1 % were current users of prescription NSAIDs as compared with 11.3 % of 9,899 r and omly selected population controls . After control for demographic factors and comorbidity , use of NSAIDs increased the risk of acute renal failure 58 % ( adjusted odds ratio = 1.58 ; 95 % confidence interval ( CI ) : 1.34 , 1.86 ) . For ibuprofen , which accounted for 35 % of NSAID use , odds ratios associated with dosages of < or = 1,200 mg/day , > 1,200-<2,400 mg/day , and > or = 2,400 mg/day were 0.94 ( 95 % CI : 0.58 , 1.51 ) , 1.89 ( 95 % CI : 1.34 , 2.67 ) , and 2.32 ( 95 % CI : 1.45 , 3.71 ) , respectively ( test for linear trend : p = 0.009 ) . Prescription NSAID use result ed in an estimated 25 excess hospitalizations associated with renal failure per 10,000 years of use . Thus , NSAIDs represent a relatively uncommon but avoidable cause of acute renal failure in frail elderly persons Abstract Objective : To compare rates of upper gastrointestinal haemorrhage among elderly patients given selective cyclo-oxygenase-2 ( COX 2 ) inhibitors and non-selective non-steroidal anti-inflammatory drugs ( NSAIDs ) . Design : Observational cohort study . Setting : Administrative data from Ontario , Canada , used from 17 April 2000 to 31 March 2001 to identify population based , NSAID-naive cohorts of patients . Patients : Subjects aged ≥ 66 years who started taking non-selective NSAIDs ( n=5391 ) , diclofenac plus misoprostol ( n=5087 ) , rofecoxib ( n=14 583 ) , or celecoxib ( n=18 908 ) and a r and omly selected control cohort not exposed to NSAIDs ( n=100 000 ) . Main outcome measures : Rate ratios of hospital admission for upper gastrointestinal haemorrhage in each drug cohort with adjustment for potential confounders . Results : Relative to controls , the multivariate model revealed an increased short term risk of upper gastrointestinal haemorrhage for users of non-selective NSAIDs ( adjusted rate ratio 4.0 ( 95 % confidence intervals 2.3 to 6.9 ) ) , diclofenac plus misoprostol ( 3.0 ( 1.7 to 5.6 ) ) , and rofecoxib ( 1.9 ( 1.3 to 2.8 ) ) but not celecoxib ( 1.0 ( 0.7 to 1.6 ) ) . Relative to celecoxib , significantly higher risks of upper gastrointestinal haemorrhage were observed for non-selective NSAIDs ( 4.4 ( 2.3 to 8.5 ) ) , diclofenac plus misoprostol ( 3.2 ( 1.6 to 6.5 ) ) , and rofecoxib ( 1.9 ( 1.2 to 2.8 ) ) . Relative to rofecoxib , non-selective NSAID users were at significantly higher risk of upper gastrointestinal haemorrhage ( 1.9 ( 1.0 to 3.5 ) ) . Conclusions : This population based observational study found a lower short term risk of upper gastrointestinal haemorrhage for selective COX-2 inhibitors compared with non-selective NSAIDs 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 & AIMS We assessed the risk of ulcers with low-dose aspirin and the interaction of low-dose aspirin with a COX-2 selective inhibitor in a double-blind trial that compared placebo , low-dose aspirin , rofecoxib + low-dose aspirin , and ibuprofen . METHODS Osteoarthritis patients > or = 50 years of age without ulcers or erosive esophagitis at baseline endoscopy were assigned r and omly to placebo , enteric-coated aspirin 81 mg/day , rofecoxib 25 mg combined with aspirin 81 mg/day , or ibuprofen 800 mg 3 times a day . Repeat endoscopies were performed at 6 and 12 weeks . RESULTS The 12-week cumulative incidence of ulcers was placebo ( N = 381 ) 5.8 % , aspirin ( N = 387 ) 7.3 % , rofecoxib combined with aspirin ( N = 377 ) 16.1 % , and ibuprofen ( N = 374 ) 17.1 % ( P < 0.001 for rofecoxib combined with aspirin and for ibuprofen vs. each of placebo and aspirin ) . Over 12 weeks , mean increases in the number of erosions were placebo 0.17 , aspirin 0.85 ( P = 0.002 vs. placebo ) , rofecoxib combined with aspirin 1.67 , and ibuprofen 1.91 ( both P < 0.001 vs. aspirin and placebo ) . CONCLUSIONS Low-dose aspirin alone did not significantly increase ulcer incidence . Addition of a cyclooxygenase-2 ( COX-2 ) selective inhibitor to low-dose aspirin increased ulcer incidence , to a rate not significantly less than a nonselective nonsteroidal anti-inflammatory drug ( NSAID ) alone . Determining the relative impact of COX-2 selective inhibitors and nonselective NSAIDs on gastrointestinal mucosal injury in low-dose aspirin users will require further study To determine the prevalence of hip problems in the population aged 55 + , a postal question naire was sent to a multistage stratified r and om sample of residents of a health district with an over-55 population of 210,000 . An initial four page postal question naire produced an 86 % response rate from 18,827 eligible cases . A subsequent detailed question naire ( with a response rate of 78 % ) then determined the prevalence of severe pain and severe disability amongst those with hip problems . The prevalence of those with existing hip replacements is estimated at 32.1/1000 ( 95 % CI 29.5 - 34.9 ) . An estimated 13.5/1000 ( 95 % CI 12.4 - 14.7/1000 ) displayed levels of pain and disability consistent with a current need to consider arthroplasty . In addition , it appears that the over 75s are less likely to have access to appropriate surgery . Unless health authorities and , increasingly , general practitioners consider purchasing more hip replacements , the prevalence pool of those who could benefit will inexorably rise To determine whether the cyclooxygenase-2 ( COX-2 ) inhibitor celecoxib affects cardiovascular thrombotic risk , we analyzed the incidence of cardiovascular events for celecoxib , placebo , and nonsteroidal anti-inflammatory drugs ( NSAIDs ) in the entire controlled , arthritis clinical trial data base for celecoxib . The primary analysis used the Antiplatelet Trialists ' Collaboration end points , which include : ( 1 ) cardiovascular , hemorrhagic , and unknown deaths , ( 2 ) nonfatal myocardial infa rct ion , and ( 3 ) nonfatal stroke . Other secondary thrombotic events were also examined . Separate analyses were performed for all patients and for those not taking aspirin . Data from all controlled , completed arthritis trials of > or = 4 weeks duration , including 13 new drug application studies and 2 large post-marketing trials ( CLASS and SUCCESS ) were included for analyses . Patients were r and omized to celecoxib at doses from 100 to 400 mg twice daily ( 18,942 patients ; 5,668.2 patient-years of exposure ) , diclofenac 50 to 75 mg twice daily , ibuprofen 800 mg thrice daily , naproxen 500 mg twice daily ( combined NSAID exposure of 11,143 patients ; 3,612.2 patient-years ) , or placebo ( 1,794 subjects ; 199.9 subject-years ) . Data from a long-term uncontrolled trial with 5,209 patients ( 6,950 patients -years ) treated with celecoxib were included in a supplemental analysis . The entire 15-trial data base was search ed for possible serious thrombotic events as well as to identify all deaths . For these patients , detailed clinical data were obtained and review ed by 2 of the investigators ( WBW and JSB ) , who were independently and blinded to exposure , to classify the event as primary , secondary , or neither . All analyses were done using the intent-to-treat population , and time-to-event analyses were performed using per-patient data . To examine heterogeneity of results among studies , tests of interaction were performed using the Cox model . Incidences of the primary and secondary events were not significantly different between the celecoxib and placebo groups , nor for the celecoxib group compared with the NSAIDs group , regardless of aspirin use and NSAID type . The relative risks comparing celecoxib with the NSAIDs for the primary events were 1.06 ( 95 % confidence interval 0.70 to 1.61 , p = 0.79 ) for all patients , and 0.86 ( 95 % confidence interval 0.48 to 1.56 , p = 0.62 ) for the subgroup not taking aspirin . Similarly , for secondary cardiovascular end points , all relative risks were < or = 1 for celecoxib compared with either placebo or NSAIDs . These comparative analyses demonstrate no evidence of increased risk of cardiovascular thrombotic events associated with celecoxib compared with either conventional NSAIDs or placebo OBJECTIVE This r and omized , double-blind study tested the hypothesis that rofecoxib , a drug that specifically inhibits cyclooxygenase 2 , would cause fewer gastroduodenal ulcers than ibuprofen ( in a multicenter trial ) , and its side effects would be equivalent to those of placebo ( in a prespecified analysis combining the results with another trial of identical design ) . METHODS Seven hundred seventy-five patients with osteoarthritis were r and omized to receive rofecoxib at a dosage of 25 mg or 50 mg once daily , ibuprofen 800 mg 3 times daily , or placebo . Gastroduodenal ulceration was assessed by endoscopy at 6 , 12 , and ( for active treatment ) 24 weeks . The primary and secondary end points were the incidence of gastroduodenal ulcers at 12 and 24 weeks , respectively . RESULTS Ulcers were significantly less common ( P < 0.001 ) following treatment with rofecoxib ( 25 mg or 50 mg ) than with ibuprofen after 12 weeks ( 5.3 % and 8.8 % versus 29.2 % , respectively ) or 24 weeks ( 9.9 % and 12.4 % versus 46.8 % , respectively ) . In the combined analysis , the 12-week ulcer incidence with 25 mg rofecoxib ( 4.7 % ) and with placebo ( 7.3 % ) satisfied prespecified criteria for equivalence . CONCLUSION At 2 - 4 times the therapeutically effective dose , rofecoxib caused fewer endoscopically detected ulcers than did ibuprofen . Rofecoxib at a dose of 25 mg ( the highest dose recommended for osteoarthritis ) satisfied prespecified criteria for equivalence to placebo In an investigation into how chance might influence the distribution of deaths in a r and omised trial and the time of those deaths , and to highlight the possible dangers of subgroup analyses , 100 r and omised controlled trials were simulated and 50 subgroup pairs were simulated for some of these trials . Each of 580 control patients from a colorectal cancer trial was r and omly coded to simulate allocation to treatment or control , the main outcome measure being time to death . Not surprisingly , most of the 100 trials gave non-significant results . Four were conventionally significant with logrank 2p-values of less than 0.05 . The most extreme result was associated with a logrank 2p-value of 0.003 , showing an absolute reduction in four-year mortality of 40 % ( SD 15 ) for patients allocated to treatment . One of the simulated prognostic factors for this trial ( subgroup 13 ) showed that mortality for one type of patient was non-significantly slightly increased by treatment , whereas treatment reduced four-year mortality by 64 % ( SD 16 ) among the other patients in the trial ( 2p = 0.00006 ) . Similar , extreme results were found for a trial of borderline statistical significance overall . Chance can influence the overall results of any r and omised controlled trial , regardless of how well it is conducted , and can play an even more powerful role in the results of subgroup analyses . This should be borne in mind both by trialists when reporting their results and by readers and review ers of those reports OBJECTIVE : The aim of this study was to assess the rate of upper gastrointestinal ( UGI ) ulcer complications ( bleeding , perforation , or gastric outlet obstruction ) associated with celecoxib , a specific COX-2 inhibitor , compared with the rate associated with nonspecific , nonsteroidal anti-inflammatory drugs ( NSAIDs ) . METHODS : A pooled analysis was conducted of 14 multicenter , double-blind , r and omized , controlled trials ( RCTs ) and a separate analysis of one long-term open label trial that assessed the efficacy and safety of celecoxib for symptomatic treatment of arthritis . The RCTs enrolled 11,008 patients with osteoarthritis or rheumatoid arthritis treated for 2–24 wk ; the long-term open label trial enrolled 5,155 patients receiving celecoxib for a maximum of 2 yr . In the RCTs , patients were r and omly assigned to receive placebo ( n = 1,864 ; 208 patient-years ) , celecoxib 25–400 mg b.i.d . ( n = 6,376 ; 1,020 patient-years ) , or a comparator NSAID ( n = 2,768 ; 535 patient-years ) ; NSAIDs were naproxen 500 mg b.i.d . , diclofenac 50 or 75 mg b.i.d . , or ibuprofen 800 mg t.i.d . ) . In the long-term , open-label trial , patients received celecoxib 100–400 mg b.i.d . for up to 2 yr ( n = 5,155 ; 5,002 patient-years ) . The principal outcome measure of this analysis was development of a UGI ulcer complication , which was prospect ively defined as bleeding , perforation , or gastric outlet obstruction . Ulcer complications were assessed and adjudicated by persons blinded to the patient 's treatment assignment or the study in which the patient participated . RESULTS : In the RCTs , UGI ulcer complications occurred in no placebo patients ( 0 of 1,864 patients ) , in 2 of 6,376 celecoxib patients ( 0.03 % ) , and in 9 of 2,768 patients receiving an NSAID ( 0.33 % ) , corresponding to annual incidences of 0.20 % for celecoxib ( p > 0.05vs placebo ) and 1.68 % for NSAIDs ( p = 0.002vs celecoxib and placebo ) . In the long-term open-label trial , nine UGI ulcer complications occurred , for an incidence of 0.17 % and an annualized incidence of 0.18 % . CONCLUSIONS : The incidence of UGI ulcer complications associated with celecoxib was 8-fold lower than with nonspecific NSAIDs . The incidence of ulcer complications observed in celecoxib-treated patients was similar to that in patients receiving placebo in the RCTs , and to that in non-NSAID users reported in the literature OBJECTIVE To determine whether discontinuation patterns differed among nonsteroidal antiinflammatory drugs ( NSAID ) prescribed to treat osteoarthritis ( OA ) . METHODS In a retrospective cohort study of Health Maintenance Organization enrollees , 1405 patients with OA aged 45 and older who received a new prescription for one of 4 NSAID were followed for 12 months . Survival analysis was used to evaluate time to discontinuation , used here as a relative measure of both drug efficacy and tolerability . RESULTS Rates of NSAID discontinuation during the study period were high ; only 15 to 20 % of those started on a study NSAID were still using the same drug at the end of the 12 month followup period . Using a proportional hazards model to adjust for covariates , the risk of discontinuation did not differ when comparing the agent with the longest duration of use , piroxicam ( the referent ) , to enteric coated aspirin [ relative risk ( RR ) 1.10 , 95 % confidence interval ( CI ) 0.93 to 1.30 ] . Adjusted rates of discontinuation were significantly higher for ibuprofen ( RR 1.43 , 95 % CI 1.22 to 1.69 ) and for naproxen ( RR 1.40 , 95 % CI 1.19 to 1.65 ) when compared to piroxicam . CONCLUSION NSAID discontinuation rates are high among patients with OA and risk of discontinuation differed between NSAID , even after controlling for the effects of such variables as age , disease severity , and concomitant therapy Abstract R and omised controlled trials ( RCTs ) alone are unlikely to provide reliable estimates of the incidence of rare events because of their limited size . Cohort , case control , and other observational studies have large numbers but are vulnerable to various kinds of bias . Wanting to estimate the risk of death from bleeding or perforated gastroduodenal ulcers with chronic usage of non‐steroidal anti‐inflammatory drugs ( NSAIDs ) with greater precision , we developed a model to quantify the frequency of rare adverse events which follow a biological progression . The model combined data from both RCTs and observational studies . We search ed systematic ally for any report of chronic ( ≥2 months ) use of NSAIDs which gave information on gastroduodenal ulcer , bleed or perforation , death due to these complications , or progression from one level of harm to the next . Fifteen RCTs ( 19 364 patients exposed to NSAIDs for 2–60 months ) , three cohort studies ( 215 076 patients redeeming a NSAID prescription over a 3–12 month period ) , six case‐control studies ( 2957 cases ) and 20 case series ( 7406 ) , and case reports ( 4447 ) were analysed . In RCTs the incidence of bleeding or perforation in 6822 patients exposed to NSAIDs was 0.69 % ; two deaths occurred . Of 11 040 patients with bleeding or perforation with or without NSAID exposure across all reports , 6–16 % ( average 12 % ) died ; the risk was lowest in RCTs and highest in case reports . Death from bleeding or perforation in all controls not exposed to NSAIDs occurred in 18 out of 849 489 ( 0.002 % ) . From these numbers we calculated the number‐needed‐to‐treat for one patient to die due to gastroduodenal complications with chronic ( ≥2 months ) NSAIDs as 1/((0.69 × {6–16 % , average 12%})−0.002%))=909–2500 ( average 1220 ) . On average 1 in 1200 patients taking NSAIDs for at least 2 months will die from gastroduodenal complications who would not have died had they not taken NSAIDs . This extrapolates to about 2000 deaths each year in the UK |
13,725 | 20,878,942 | Chlorhexidine should be used preferentially for preoperative antisepsis in clean-contaminated surgery | BACKGROUND Surgical-site infection increases morbidity , mortality and financial burden .
The preferred topical antiseptic agent ( chlorhexidine or povidone-iodine ) for preoperative skin cleansing is unclear . | BACKGROUND Mild perioperative hypothermia , which is common during major surgery , may promote surgical-wound infection by triggering thermoregulatory vasoconstriction , which decreases subcutaneous oxygen tension . Reduced levels of oxygen in tissue impair oxidative killing by neutrophils and decrease the strength of the healing wound by reducing the deposition of collagen . Hypothermia also directly impairs immune function . We tested the hypothesis that hypothermia both increases susceptibility to surgical-wound infection and lengthens hospitalization . METHODS Two hundred patients undergoing colorectal surgery were r and omly assigned to routine intraoperative thermal care ( the hypothermia group ) or additional warming ( the normothermia group ) . The patient 's anesthetic care was st and ardized , and they were all given cefam and ole and metronidazole . In a double-blind protocol , their wounds were evaluated daily until discharge from the hospital and in the clinic after two weeks ; wounds containing culture-positive pus were considered infected . The patients ' surgeons remained unaware of the patients ' group assignments . RESULTS The mean ( + /- SD ) final intraoperative core temperature was 34.7 + /- 0.6 degrees C in the hypothermia group and 36.6 + /- 0.5 degrees C in the normothermia group ( P < 0.001 ) Surgical-wound infections were found in 18 of 96 patients assigned to hypothermia ( 19 percent ) but in only 6 of 104 patients assigned to normothermia ( 6 percent , P = 0.009 ) . The sutures were removed one day later in the patients assigned to hypothermia than in those assigned to normothermia ( P = 0.002 ) , and the duration of hospitalization was prolonged by 2.6 days ( approximately 20 percent ) in hypothermia group ( P = 0.01 ) . CONCLUSIONS Hypothermia itself may delay healing and predispose patients to wound infections . Maintaining normothermia intraoperatively is likely to decrease the incidence of infectious complications in patients undergoing colorectal resection and to shorten their hospitalizations OBJECTIVE To compare the effectiveness for prevention of central venous and arterial catheter colonization of 3 skin antisepsis with 1 of 3 antiseptic solutions : 10 % aqueous povidone iodine ( aqueous PI ) , 2 % aqueous chlorhexidine gluconate ( aqueous CG ) , and 0.5 % alcoholic chlorhexidine gluconate ( alcoholic CG ) . DESIGN Prospect i ve , r and omized controlled trial . SETTING Intensive care unit in a teaching hospital . METHODS Patients were r and omly assigned to 1 of the 3 skin antisepsis groups . The distal tips of catheters were semiquantitatively cultured when the catheters were no longer necessary or if there was a suspicion of catheter-related infection . Rates of catheter colonization , catheter-related sepsis , and catheter-related bacteremia were compared among the 3 groups . RESULTS A total of 631 catheters were included in the study ( 194 from the aqueous PI group , 211 from the aqueous CG group , and 226 from the alcoholic CG group ) . The incidence of catheter colonization was significantly lower in the alcoholic CG than in the aqueous PI group ( 14.2 % vs 24.7 % ; relative risk , 0.5 [ 95 % confidence interval , 0.3 - 0.8 ; P < .01 ] ) ; it was also significantly lower in the aqueous CG group than in the aqueous PI group ( 16.1 % vs 24.7 % ; relative risk , 0.6 [ 95 % confidence interval , 0.4 - 0.9 ; P = .03 ] ) . There were no significant differences between the aqueous CG and the alcoholic CG groups . Incidences of catheter-related bacteremia were similar for all 3 groups . The aqueous and alcoholic CG solutions were superior to the aqueous PI solution in preventing catheter colonization due to gram-positive bacteria . CONCLUSIONS The aqueous and alcoholic CG solutions for cutaneous antisepsis were similarly effective in preventing colonization of central venous catheters and arterial catheters . Both had significantly lower incidences of colonization than did the aqueous PI solution ; this effect seems to be related to the CG solutions ' more efficacious prevention of colonization with gram-positive bacteria BACKGROUND Orthopedic surgical procedures involving the foot and ankle are associated with high rates of infection . The optimal method of preparing the skin and nails for foot and ankle surgery remains unknown . OBJECTIVE This study was conducted to compare the efficacy of 4 different methods of skin and nail preparation of the foot using various antiseptic solutions . METHODS In this prospect i ve , r and omized study , 4 methods of skin and nail preparation were compared in terms of their efficacy in eliminating bacteria from the hallux nailfold and first web space of the normal foot in 28 healthy adult volunteers . Efficacy was determined by evaluating the difference in the total bacterial load before and after skin preparation . The foot-preparation solutions evaluated were 4 % chlorhexidine gluconate , 70 % isopropyl alcohol , and 7.5 % to 10 % povidone-iodine . RESULTS The addition of alcohol to povidone-iodine was found to increase the efficacy of the preparation method . The nailfold remained contaminated after any of the preoperative skin- and nail-preparation methods studied . LIMITATIONS This study did not measure clinical ly relevant infections , and the results may not correlate with decreased rates of infection after surgery . CONCLUSION Incorporation of alcohol and povidone-iodine into the preoperative skin- and nail-preparation process may help reduce the bacterial load . Every effort should be made to lower the risk of contamination from the nail The effects of alcohol , chlorhexidine cream and iodophor cream on the infectious complications associated with intravenous catheters were studied . One hundred and fifty patients were r and omly allocated into each antiseptic group . Daily cleansing and disinfecting the cut down wounds were done with the above antiseptics . Minor surgical wound infections were found in one patient in the alcohol and iodophor group compared to five in the chlorhexidine group . Phlebitis complicated four patients , two in the iodophor group and one in each of the remaining groups . Only one patient in the chlorhexidine group had septicaemia due to A. antitratus . Thirty-four catheter tips ( 22.7 % ) yielded bacteria on culture . Incidence of positive tip cultures was significantly higher in the chlorhexidine group than in the other two . The rates of positive tip cultures correlated with duration of catheterization . It is concluded that alcohol is the antiseptic of choice for cut down wounds . Application of antiseptic cream to the wounds was less effective than alcohol and this practice should be discouraged The optimum duration of antimicrobial prophylaxis in elective gastric cancer surgery is still open to question . This multicentre r and omized clinical trial compared a single‐dose with a multiple‐dose regimen of antimicrobial prophylaxis for prevention of surgical‐site infection Estimating the cost of hospital infection has become a matter of increasing interest in terms of health economics . This study aim ed to assess the accuracy of economic studies on hospital infections , using surgical site infection ( SSI ) as an example . A search was performed for original articles reporting the cost of SSI , published in the English language between 1996 and 2005 . For the critical review , the period of cost tracking , classification of costs and cost counting methods were noted . Fifteen articles met the inclusion criteria . The costs of SSI vary according to surgical procedures , country , publication year , study design and accounting method . Only two studies estimated the additional cost of SSI after discharge . All 15 studies included healthcare costs and none measured patient/family re sources . In 10 studies , the costs were calculated based on accounting . Three studies used estimated costs from the ratio of costs to charges and two studies used charge data in place of cost data . It will become increasingly important for future studies to perform multi-centre prospect i ve surveys , establish a st and ard method for cost accounting , include the cost of healthcare services following hospitalization and consider the morbidity cost to patients themselves from a societal perspective OBJECTIVE The purpose of this study was to compare the efficacy of chlorhexidine and povidone iodine for cleansing the operative field for vaginal surgery . STUDY DESIGN This was a r and omized controlled trial that compared 10 % povidone iodine and 4 % chlorhexidine gluconate as surgical scrubs . Our primary end point was the proportion of contaminated specimens ( defined as total bacterial colony counts of > /=5000 colony-forming units ) per group found throughout the surgical procedures . All patients received st and ard infection prophylaxis that included preoperative intravenous antibiotics . Immediately before antibiotic administration and baseline aerobic and anaerobic cultures of the vaginal flora were obtained , which were followed by cultures at 30 minutes after the surgical scrub and hourly thereafter throughout each patient 's surgery . RESULTS A total of 50 patients were enrolled between October 2002 and September 2003 . There were no differences between the povidone iodine ( n = 27 ) and chlorhexidine ( n = 23 ) groups with respect to age , race , exogenous hormone use , body mass index , gravity , parity , preoperative mean colony counts , or operative time . Among the first set of intraoperative specimens ( which were obtained 30 minutes after the surgical scrub ) , 63 % of the cultures ( 17/27 ) from the povidone iodine group and 22 % of the cultures ( 5/23 ) from the chlorhexidine group were classified as contaminated ( P = .003 ; relative risk , 6.12 ; 95 % CI , 1.7 , 21.6 ) . Subsequent cultures failed to demonstrate significant differences . CONCLUSION Chlorhexidine gluconate was more effective than povidone iodine in decreasing the bacterial colony counts that were found in the operative field for vaginal hysterectomy BACKGROUND Previous studies have demonstrated higher infection rates following orthopaedic procedures on the foot and ankle as compared with procedures involving other areas of the body . Previous studies also have documented the difficulty of eliminating bacteria from the forefoot prior to surgery . The purpose of the present study was to evaluate the efficacy of three different surgical skin-preparation solutions in eliminating potential bacterial pathogens from the foot . METHODS A prospect i ve study was undertaken to evaluate 125 consecutive patients undergoing surgery of the foot and ankle . Each lower extremity was prepared with one of three r and omly selected solutions : DuraPrep ( 0.7 % iodine and 74 % isopropyl alcohol ) , Techni-Care ( 3.0 % chloroxylenol ) , or ChloraPrep ( 2 % chlorhexidine gluconate and 70 % isopropyl alcohol ) . After preparation , quantitative culture specimens were obtained from three locations : the hallux nailfold ( the hallux site ) , the web spaces between the second and third and between the fourth and fifth digits ( the toe site ) , and the anterior part of the tibia ( the control site ) . RESULTS In the Techni-Care group , bacteria grew on culture of specimens obtained from 95 % of the hallux sites , 98 % of the toe sites , and 35 % of the control sites . In the DuraPrep group , bacteria grew on culture of specimens obtained from 65 % of the hallux sites , 45 % of the toe sites , and 23 % of the control sites . In the ChloraPrep group , bacteria grew on culture of specimens from 30 % of the hallux sites , 23 % of the toe sites , and 10 % of the control sites . ChloraPrep was the most effective agent for eliminating bacteria from the halluces and the toes ( p < 0.0001 ) . CONCLUSIONS The use of effective preoperative preparation solution is an important step in limiting surgical wound contamination and preventing infection , particularly in foot and ankle surgery . Of the three solutions tested in the present study , the combination of chlorhexidine and alcohol ( ChloraPrep ) was most effective for eliminating bacteria from the forefoot prior to surgery BACKGROUND Currently , there are various antiseptics used for cleaning the skin before surgery , but there is no st and ard procedure in practice . Chlorhexidine and povidone-iodine are the most preferred compounds among antiseptics . Both are proved to be safe and effective for skin disinfection . In this study , our aim was to investigate the combined effects of chlorhexidine and povidone-iodine on the skin 's flora before neurosurgical intervention , consecutively . METHODS R and omly , 50 cranial and 50 spine neurosurgery cases were assigned to the study . The first culture was obtained after hair removal and before cleaning the skin with any antiseptic . The second culture was obtained after the skin had been cleaned with chlorhexidine for 3 minutes . Then , the skin was cleaned twice with povidone-iodine for 30 seconds , and the third and fourth cultures were taken from the skin incision area . Bacteria were identified by means of st and ard laboratory identification methods . Positive culture results were compared statistically among order of cultures obtained . RESULTS In the first culture evaluation , 39 ( 33 cnS , 6 Stapylococcus aureus ) of 50 cranial sample s and 37 ( 33 cnS , 4 S aureus ) of 50 spine sample s showed reproduction . In the second culture , 9 cranial and 5 spine sample s showed reproduction of cnS. In the third and fourth cultures , no growth was observed ( P < .001 ) . CONCLUSION Three minutes ' cleaning of the incision area with chlorhexidine , followed by 30-second cleaning with povidone-iodine , could be a sufficient disinfection procedure for preoperative preparation of the skin in patients undergoing a neurosurgical procedure Contamination of blood cultures is common because microflora are usually present on the skin . The misinformation that results from contamination of blood cultures may have deleterious consequences . Therefore , it is important that blood cultures be collected by using a procedure that minimizes contamination ( 1 ) . In general , preparation of the skin with one or more antiseptic agents should permit satisfactory antisepsis , provided that a suitable period ( 0.5 to 2 minutes ) is allowed for the antiseptic to take effect ( 2 ) . In many hospitals , however , the personnel collecting blood cultures do not carefully follow the recommended procedures , leading to an excessively high rate of blood culture contamination . This is especially true in the intensive care unit , possibly because of the high workload of nurses ( 2 ) . A recent trial comparing povidone-iodine and iodine tincture antiseptics showed a substantially lower rate of blood culture contamination with use of iodine tincture ; this finding was related to the fact that iodine tincture acts faster than povidone-iodine ( 1 ) . However , use of iodine tincture in the intensive care unit is limited because repeated exposure to high concentrations of iodine can be toxic ( 3 ) . Alternately , chlorhexidine has been found to be superior to povidone-iodine and alcohol when it is used for catheter care ( 3 - 5 ) , but its value in preventing blood culture contamination remains unknown . We assumed that the decreased effectiveness of aqueous 10 % povidone-iodine in previous studies could be related to the time required to achieve skin antisepsis with this agent . We examined whether the use of alcoholic chlorhexidine decreased the rate of blood culture contamination in hospitals in which personnel did not consistently allow antiseptics to act for the recommended time period before collection . Methods Patients The study was conducted between 1 December 1997 and 24 April 1998 in three adult intensive care units ( medical , surgical , and neurosurgical ) at Hpital Bictre , a 1000-bed teaching hospital in France . All adult patients without apparent skin infection who had blood cultures drawn through a peripheral vein were eligible for the study . Because we compared two well-accepted interventions , institutional review board approval was not sought , in accordance with the policy at our institution . Study Design We assigned patients to one of two groups according to type of antiseptic solution used for skin preparation before blood culture . Computerized r and omization lists were generated in blocks of four and were stratified by unit of hospitalization . We used an alcoholic solution of 0.5 % chlorhexidine gluconate ( Hibitane Champ , Zeneca Pharma , Cergy , France ) or an aqueous solution of 10 % povidone-iodine ( Btadine , Asta Medica , Marignane , France ) . Skin antisepsis was done by vigorously applying the assigned antiseptic solution once . Blood was obtained 15 to 30 seconds after the application . The 20-mL blood sample s , which the nurses collected according to a previously determined procedure ( dictated by the hospital ) , were inoculated simultaneously into aerobic and anaerobic vials of blood culture media ( Vital , bioMrieux , Mary-l'Etoile , France ) . Blood cultures were incubated at 37 C and were monitored for 5 days . Isolated organisms and their susceptibilities to antibiotics were determined by using st and ard methods and criteria . Evaluation of Efficacy The primary end point was the number of blood cultures considered to be contaminated . Two independent review ers who were blinded to the patients ' study group assignment classified each blood culture isolate as a contaminant or a true pathogen . Contaminant isolates were defined as isolates of several organismscoagulase-negative staphylococci , Propionibacterium acnes , Streptococcus viridans , Corynebacterium species ( excluding group JK ) , Micrococcus species , or Bacillus speciesthat were obtained from one set of blood cultures and an identical organism ( that is , an organism of the same species with the same antibiotic susceptibility and the same pulsed-field gel electrophoresis pattern [ 6 ] ) that was not obtained from another potentially infected site ( for example , blood culture , catheter tip , or urine ) 5 days before or 5 days after blood culture collection . In all other cases , blood culture isolates were considered to be true pathogens . We defined positive blood culture as a positive bacterial culture obtained from any aerobic or anaerobic vials ; such a culture was considered to be contaminated when it yielded a contaminant and was considered to be truly positive when it yielded a true pathogen . In cases of polymicrobic cultures , the positive blood culture was considered to be a single contaminated or truly bacteremic culture when all bacteria were interpreted as contaminants or true pathogens . A positive blood culture was considered to be a single concomitantly contaminated and truly bacteremic culture when some isolates were interpreted as contaminants and others were interpreted as true pathogens . Statistical Analysis Our study was design ed to determine whether skin preparation with alcoholic chlorhexidine reduced the risk for blood culture contamination . We computed the sample size necessary to detect a twofold decrease in the incidence of contaminated blood cultures . We assumed that the incidence of contaminated blood cultures in the povidone-iodine group would be 5 % ; therefore , 1900 blood cultures would be required to detect a difference of this magnitude ( power , 0.8 ; type I error , 5 % ) . Statistical analysis ( odds ratio estimation ) was performed by using generalized estimating equations that took into account a possible clustering effect of multiple cultures by patient ( PROC GENMOD , SAS software , version 6.12 , SAS Institute , Inc. , Cary , North Carolina ) . All tests were two-tailed . A P value of 0.05 or less was considered statistically significant . Role of the Funding Source The funding agencies ( Zeneca Pharma and Universit Paris XI [ UPRES JE 2227 ] ) were not involved in the design , conduct , or reporting of this study or in the decision to su bmi t the manuscript for publication . Results A total of 2041 blood cultures were collected in 403 patients . The two study groups were similar with regard to distribution among the three intensive care units ( Table 1 ) . Of these 2041 cultures , 124 yielded pathogens and were interpreted as contaminated ( 45 cultures ) , truly positive ( 76 cultures ) , or concomitantly contaminated and truly positive ( 3 cultures ) . Chlorhexidine significantly reduced the rate of blood culture contamination compared with povidone-iodine ( 14 of 1019 cultures [ 1.4 % ] compared with 34 of 1022 cultures [ 3.3 % ] ; odds ratio , 0.40 [ 95 % CI , 0.21 to 0.75 ] ; P=0.004 ) . The chlorhexidine group and the povidone-iodine group were similar with regard to incidence of true bacteremias ( 43 of 1019 cultures [ 4.2 % ] compared with 36 of 1022 cultures [ 3.5 % ] ; odds ratio , 1.09 [ CI , 0.79 to 1.51 ] ; P>0.2 ) and sterile blood cultures ( 963 of 1019 cultures [ 94.5 % ] compared with 954 of 1022 cultures [ 93.3 % ] ; odds ratio , 1.28 [ CI , 0.93 to 1.75 ] ; P=0.13 ) . Coagulase-negative staphylococci were the main organisms recovered , accounting for about 98 % of contaminants and 22 % of true pathogens ( Table 2 ) . Table 1 . Distribution of Patients and Blood Cultures among the Three Intensive Care Units Table 2 . Microorganisms That Were Recovered and Classified as Contaminants or as True Pathogens Discussion Contamination of blood cultures considerably increases the cost of patient care , particularly laboratory and pharmacy expenses , and prolongs hospital stay ( 7 - 9 ) . Lack of good skin preparation is the most common cause of contaminants in blood cultures ( 7 ) . Povidone-iodine solutions have greater in vitro microbicidal activity than chlorhexidine solutions ( 10 ) . However , in a r and omized trial comparing 10 % povidone-iodine , 2 % aqueous chlorhexidine , and 70 % isopropyl alcohol applied once for the prevention of infection associated with central venous and arterial catheters , substantially fewer infections occurred with chlorhexidine ( 3 ) . The superiority of chlorhexidine over povidone-iodine for skin antisepsis in preventing catheter infection , even when the antiseptics were applied serially , was confirmed ( 4 , 5 ) . Chlorhexidine is a potent , broad-spectrum germicide that is effective against all nosocomial pathogens ( 3 ) . Primary bacterial resistance to chlorhexidine is rare ( 11 ) , and acquired resistance is detected only when diluted aqueous solutions are used ( 12 ) . In addition , although blood , fat , and other protein-rich bio material s of the skin surface neutralize the germicidal activity of iodine-containing disinfectants , proteinaceous solutions have little effect on the antibacterial activity of chlorhexidine ( 13 ) . Finally , the in vivo bactericidal effect of chlorhexidine on gram-positive cocci is dramatically improved by the addition of alcohol and is superior to that of aqueous povidone-iodine ( 14 - 16 ) . Coagulase-negative staphylococci are the organisms most frequently found in normal skin flora and are also predominant among contaminants ( 17 ) . Such gram-positive organisms tend to be resistant to multiple drugs and often remain susceptible only to glycopeptides . In critically ill patients who are predisposed to nosocomial infections , reflexive use of vancomycin after reports of gram-positive cocci in blood cultures is common , even when contamination is recognized ( 17 ) . In an era of emerging vancomycin-resistant enterococci ( 18 ) and , more recently , vancomycin-intermediate Staphylococcus aureus ( 19 ) , prudent use of vancomycin is necessary to limit the spread of vancomycin-resistant gram- positive cocci ( 20 ) . Our trial has several limitations . The two antiseptics were different colors ; this lack of blinding may have introduced bias . However , because these antiseptics were widely used in the three intensive care units before our study began , we do not believe that the nurses who obtained the cultures knew BACKGROUND Ertapenem , a long-acting carbapenem , may be an alternative to the recommended prophylactic antibiotic cefotetan . METHODS In this r and omized , double-blind trial , we assessed the efficacy and safety of antibiotic prophylaxis with ertapenem , as compared with cefotetan , in patients undergoing elective colorectal surgery . A successful outcome was defined as the absence of surgical-site infection , anastomotic leakage , or antibiotic use 4 weeks postoperatively . All adverse events were collected until 14 days after the administration of antibiotic prophylaxis . RESULTS Of the 1002 patients r and omly assigned to study groups , 901 ( 451 in the ertapenem group and 450 in the cefotetan group ) qualified for the modified intention-to-treat analysis , and 672 ( 338 in the ertapenem group and 334 in the cefotetan group ) were included in the per- protocol analysis . After adjustment for strata , in the modified intention-to-treat analysis , the rate of overall prophylactic failure was 40.2 % in the ertapenem group and 50.9 % in the cefotetan group ( absolute difference , -10.7 % ; 95 % confidence interval [ CI ] , -17.1 to -4.2 ) ; in the per- protocol analysis , the failure rate was 28.0 % in the ertapenem group and 42.8 % in the cefotetan group ( absolute difference , -14.8 % ; 95 % CI , -21.9 to -7.5 ) . Both analyses fulfilled statistical criteria for the superiority of ertapenem . In the modified intention-to-treat analysis , the most common reason for failure of prophylaxis in both groups was surgical-site infection : 17.1 % in the ertapenem group and 26.2 % in the cefotetan group ( absolute difference , -9.1 ; 95 % CI , -14.4 to -3.7 ) . In the treated population , the overall incidence of Clostridium difficile infection was 1.7 % in the ertapenem group and 0.6 % in the cefotetan group ( P=0.22 ) . CONCLUSIONS Ertapenem is more effective than cefotetan in the prevention of surgical-site infection in patients undergoing elective colorectal surgery but may be associated with an increase in C. difficile infection . ( Clinical Trials.gov number , NCT00090272 [ Clinical Trials.gov ] . ) Feet are prone to bacterial contamination . We hypothesized that chlorhexidine scrub and isopropyl alcohol paint provide superior local flora reduction than povidone-iodine scrub and paint . Patients with intact , uninfected skin having clean elective foot and ankle surgery were prospect ively enrolled and r and omly assigned to skin preparation with povidone-iodine ( Group 1 ) or chlorhexidine scrub and isopropyl alcohol paint ( Group 2 ) . Culture swabs ( aerobic , anaerobic , acid fast , fungus , and routine antibiotic sensitivity ) were taken from all web spaces , nail folds , toe surfaces , and proposed surgical incision sites . One-hundred twenty-seven patients were enrolled ( mean age , 46 years ; range , 16–85 years ) . Sixty-seven patients were assigned to Group 1 ; 60 patients were assigned to Group 2 . In Group 1 , 53 of 67 patients ( 79 % ) had positive cultures ; in Group 2 , 23 of 60 patients ( 38 % ) had positive cultures . These data indicate that chlorhexidine and alcohol provide better reduction in bacterial carriage than povidone-iodine . Based on these data , we recommended chlorhexidine as the surgical preparatory agent for the foot and ankle . Level of Evidence : Therapeutic study , Level I-1a ( significant difference ) . See the Guidelines for Authors for a complete description of levels of evidence Objective Central venous catheter (CVC)-related infections may be caused by micro-organisms introduced from the skin surface into deeper tissue at the time of CVC insertion . The optimal disinfection regimen to avoid catheter-related infections has not yet been defined . This study compares three different approaches . Design Prospect i ve r and omised trial . Setting A tertiary care hospital . Patients and participants One hundred nineteen patients scheduled electively to receive 140 CVCs . Interventions Skin disinfection was performed with either povidone-iodine 10 % ( PVP-iodine ) , chlorhexidine 0.5%/propanol 70 % , or chlorhexidine 0.5%/propanol 70 % followed by PVP-iodine 10 % . Prior to disinfection , a swab from the site of insertion was taken for culture . CVCs were removed if no longer needed or infection was suspected . All catheters were cultured quantitatively after removal . Measurement and results Bacteria could be isolated from 20.7 % of the catheter tips . Bacterial growth was found in 30.8 % of the catheters placed after skin disinfection with povidone-iodine , in 24.4 % after disinfection with propanol/chlorhexidine and in 4.7 % after disinfection with propanol/chlorhexidine followed by povidone-iodine ( p=0.006 ) . In 15 cases , the same organism was isolated from the skin swab and the catheter tip . Ten of these paired isolates showed the same pattern in a pulsed-field gel electrophoresis analysis . Conclusions Skin disinfection with propanol/chlorhexidine followed by PVP-iodine was superior in the prevention of microbial CVC colonisation compared to either of the regimens alone . These results support the concept that catheter infections can originate from bacterial translocation at the time of catheter insertion More than 90 % of all intravascular device-related septicaemias are due to central venous or arterial catheters . To assess the efficacy of cutaneous antisepsis to prevent catheter-associated infection , we prospect ively studied three antiseptics for disinfection of patients ' central venous and arterial catheter insertion sites in a surgical intensive care unit . 668 catheters were r and omised to 10 % povidone-iodine , 70 % alcohol , or 2 % aqueous chlorhexidine disinfection of the site before insertion and for site care every other day thereafter . Chlorhexidine was associated with the lowest incidence of local catheter-related infection ( 2.3 per 100 catheters vs 7.1 and 9.3 for alcohol and povidone-iodine , respectively , p = 0.02 ) and catheter-related bacteraemia ( 0.5 vs 2.3 and 2.6 ) . Of the 14 infusion-related bacteraemias ( 4 due to contaminated infusate or catheter hub , 10 due to infected catheters ) , 1 was in the chlorhexidine group and 13 were in the other two groups ( odds ratio 0.16 , p = 0.04 ) . We conclude that use of 2 % chlorhexidine , rather than 10 % povidone-iodine or 70 % alcohol , for cutaneous disinfection before insertion of an intravascular device and for post-insertion site care can substantially reduce the incidence of device-related infection BACKGROUND Antiseptic preoperative skin site preparation is used to prepare the operative site before making a surgical incision . The goal of this preparation is a reduction in postoperative wound infection . The most straightforward technique necessary to achieve this goal remains controversial . STUDY DESIGN A prospect i ve r and omized trial was design ed to prove equivalency for two commonly used techniques of surgical skin site preparation . Two hundred thirty-four patients undergoing nonlaparoscopic abdominal operations were consented for the trial . Exclusion criteria included presence of active infection at the time of operation , neutropenia , history of skin reaction to iodine , or anticipated insertion of prosthetic material at the time of operation . Patients were r and omized to receive either a vigorous 5-minute scrub with povidone-iodine soap , followed by absorption with a sterile towel , and a paint with aqueous povidone-iodine or surgical site preparation with a povidone-iodine paint only . The primary end point of the study was wound infection rate at 30 days , defined as presence of clinical signs of infection requiring therapeutic intervention . RESULTS Patients r and omized to the scrub- and -paint arm ( n = 115 ) and the paint-only arm ( n = 119 ) matched at baseline with respect to age , comorbidity , wound classification , mean operative time , placement of drains , prophylactic antibiotic use , and surgical procedure ( all p > 0.09 ) . Wound infection occurred in 12 ( 10 % ) scrub- and -paint patients , and 12 ( 10 % ) paint-only patients . Based on our predefined equivalency parameters , we conclude equivalence of infection rates between the two preparations . CONCLUSIONS Preoperative preparation of the abdomen with a scrub with povidone-iodine soap followed by a paint with aqueous povidone-iodine can be ab and oned in favor of a paint with aqueous povidone-iodine alone . This change will result in reductions in operative times and costs Background : Chlorhexidine is better than povidone-iodine for skin preparation before intravascular device insertion or blood culture collection , but it is not known whether chlorhexidine is superior in reducing the colonization of continuous epidural catheters . Methods : Patients requiring an epidural catheter for postoperative analgesia were r and omly assigned to receive skin preparation with 0.5 % chlorhexidine ethanol ( CE group ) or 10 % povidone-iodine ( PI group ) before catheter insertion . Using surgical aseptic techniques , catheters were inserted into either the lumbar or the thoracic epidural space . Gloves used at catheter insertion , swabs of insertion site skin and the catheter tip at catheter removal were qualitatively cultured . Results : Of 70 r and omly assigned patients , 62 were evaluable . The clinical characteristics of the patients and the risk factors for infection were similar in the two groups . Catheters were kept in place for 49 ± 7 h ( mean ± SD ) . Seven cultures from gloves yielded microorganisms . In 1 case , the leak test of gloves was positive . Fifteen cultures of catheter insertion sites yielded microorganisms : 7/28 ( 25 % ) in the PI group and 8/34 ( 24 % ) in the CE group . Six cultures of catheter tips yielded microorganisms : 3/28 ( 11 % ) in the PI group and 3/34 ( 9 % ) in the CE group . As for the incidence of isolation of bacteria , no difference was seen between the two groups . In none of these 62 cases was any inflammatory reaction seen in the skin locally at catheter removal . Conclusions : The effect of 0.5 % chlorhexidine ethanol is not different from that of 10 % povidone-iodine in reducing catheter colonization associated with short-term epidural catheter placement A multicenter prospect i ve , r and omized , controlled trial , with 0.5 % tincture of chlorhexidene versus 10 % povidone-iodine as cutaneous antisepsis for central venous catheter ( CVC ) insertion , was conducted for patients in intensive care units . Of 374 patients , 242 had a CVC inserted for > 3 days and were used for the primary analysis . Outcomes included catheter-related bacteremia , significant catheter colonization ( > or = 15 colony-forming units [ cfu ] ) , exit-site infection , serial quantitative exit-site culture ( every 72 h ) , and molecular subtyping of all isolates . Patients in both study groups were comparable with respect to age , sex , underlying disease , length of hospitalization , reason for line insertion , and baseline APACHE II score . Documented catheter-related bacteremia rates were 4.6 cases per 1000 catheter-days in the chlorhexidine group ( n=125 ) and 4.1 cases per 1000 catheter-days in the povidone-iodine group ( n=117 ; not significant [ NS ] ) . Significant catheter-tip colonization occurred in 24 ( 27 % ) of 88 patients in the povidone-iodine group and in 31 ( 34 % ) of 92 patients in the chlorhexidine group ( NS ) . A mean exit-site colony count of 5.9 x 10(5 ) cfu/mL per 25 cm(2 ) of the surface area of skin in the povidone-iodine group versus 3.1 x 10(5 ) cfu/mL per 25 cm(2 ) in the chlorhexidine group ( NS ) was found . There was a trend toward fewer exit-site infections in the chlorhexidine group ( 0 of 125 patients ) versus those in the povidone-iodine group ( 4 of 117 patients ; P=.053 ) . Results of an intention-to-treat analysis were unchanged from the primary analysis . No difference was demonstrable between 0.5 % tincture of chlorhexidine and 10 % povidone-iodine when used for cutaneous antisepsis for CVC insertion in patients in the intensive care unit OBJECTIVES To compare the efficacy of a newly available antiseptic solution ( composed of 0.25 % chlorhexidine gluconate , 0.025 % benzalkonium chloride , and 4 % benzyl alcohol ) , with 10 % povidone iodine , on the prevention of central venous or arterial catheter colonization and infection . DESIGN Prospect i ve , r and omized clinical trial . SETTING Surgical-trauma intensive care unit ( ICU ) in a university hospital . PATIENTS All patients admitted to the ICU and requiring the insertion of a central venous and /or an arterial catheter from July 1 , 1992 to October 31 , 1993 . INTERVENTIONS Patients were r and omly assigned to one of two groups according to the antiseptic solution used for insertion and catheter care . The same solution was used for skin disinfection from the time of catheter insertion to the time of removal of each catheter . MEASUREMENTS AND MAIN RESULTS Catheter distal tips were quantitatively cultured when catheters were no longer necessary , if there was a suspicion of catheter-related infection , and routinely after 7 days of use for arterial catheters , or after 15 days of use for central venous catheters . The rate of significant catheter colonization ( i.e. , > or = 10(3 ) colony-forming units [cfu]/mL by quantitative culture ) , and catheter-related sepsis ( as defined by sepsis abating following catheter removal per 1,000 catheter-days ) , were significantly lower in the chlorhexidine group ( 12 vs. 31 [ relative risk 0.4 , 95 % confidence interval 0.1 to 0.9 , p < .01 ] and 6 vs. 16 [ relative risk 0.4 , 95 % confidence interval 0.1 to 1 , p = 0.5 ] , respectively ) . The rate of central venous catheter colonization and central venous catheter-related sepsis per 1,000 catheter-days were also significantly lower in the chlorhexidine group ( 8 vs. 31 [ relative risk 0.3 , 95 % confidence interval 0.1 to 1 , p = .03 ] and 5 vs. 19 [ relative risk 0.3 , 95 % confidence interval 0.1 to 1 , p = .02 ] , respectively ) . Finally , the rate of arterial catheter colonization per 1,000 catheter-days was significantly lower in the chlorhexidine group ( 15 vs. 32 [ relative risk 0.5 , 95 % confidence interval 0.1 to 1 , p = .05 ] ) , whereas the rate of arterial catheter-related sepsis per 1,000 catheter-days was similar for the two study groups ( 8 in the chlorhexidine group vs. 10 in the povidone iodine group [ relative risk 0.8 , 95 % confidence interval 0.1 to 2.2 , p = .6 ] ) . The 0.25 % chlorhexidine solution was superior to the 10 % povidone iodine solution in preventing catheter colonizations and catheter-related sepsis due to Gram-positive bacteria ( 5 vs. 20 [ p < .001 ] , and 2 vs. 10 [ p < .001 ] , respectively ) , whereas the activity of the 0.25 % chlorhexidine solution was nonsignificantly superior in preventing Gram-negative infections ( 7 vs. 4 [ p = .5 ] , and 4 vs. 2 [ p = .8 ] , respectively ) . CONCLUSIONS The 4 % alcohol-based solution of 0.25 % chlorhexidine gluconate and 0.025 % benzalkonium chloride was more effective than 10 % povidone iodine for insertion site care of short-term central venous and arterial catheters . This effect appeared related to a more efficacious prevention of infections with Gram-positive bacteria OBJECTIVE To compare the effects of different skin preparation solutions on surgical-site infection rates . DESIGN Three skin preparations were compared by means of a sequential implementation design . Each agent was adopted as the preferred modality for a 6-month period for all general surgery cases . Period 1 used a povidone-iodine scrub-paint combination ( Betadine ) with an isopropyl alcohol application between these steps , period 2 used 2 % chlorhexidine and 70 % isopropyl alcohol ( ChloraPrep ) , and period 3 used iodine povacrylex in isopropyl alcohol ( DuraPrep ) . Surgical-site infections were tracked for 30 days as part of ongoing data collection for the National Surgical Quality Improvement Project initiative . The primary outcome was the overall rate of surgical-site infection by 6-month period performed in an intent-to-treat manner . SETTING Single large academic medical center . PATIENTS All adult general surgery patients . RESULTS The study comprised 3,209 operations . The lowest infection rate was seen in period 3 , with iodine povacrylex in isopropyl alcohol as the preferred preparation method ( 3.9 % , compared with 6.4 % for period 1 and 7.1 % for period 2 ; P = .002 ) . In subgroup analysis , no difference in outcomes was seen between patients prepared with povidone-iodine scrub-paint and those prepared with iodine povacrylex in isopropyl alcohol , but patients in both these groups had significantly lower surgical-site infection rates , compared with rates for patients prepared with 2 % chlorhexidine and 70 % isopropyl alcohol ( 4.8 % vs 8.2 % ; P = .001 ) . CONCLUSIONS Skin preparation solution is an important factor in the prevention of surgical-site infections . Iodophor-based compounds may be superior to chlorhexidine for this purpose in general surgery patients BACKGROUND Deep infection following shoulder surgery is a rare but devastating problem . The use of an effective skin-preparation solution may be an important step in preventing infection . The purpose s of the present study were to examine the native bacteria around the shoulder and to determine the efficacy of three different surgical skin-preparation solutions on the eradication of bacteria from the shoulder . METHODS A prospect i ve study was undertaken to evaluate 150 consecutive patients undergoing shoulder surgery at one institution . Each shoulder was prepared with one of three r and omly selected solutions : ChloraPrep ( 2 % chlorhexidine gluconate and 70 % isopropyl alcohol ) , DuraPrep ( 0.7 % iodophor and 74 % isopropyl alcohol ) , or povidone-iodine scrub and paint ( 0.75 % iodine scrub and 1.0 % iodine paint ) . Aerobic and anaerobic cultures were obtained prior to skin preparation for the first twenty patients , to determine the native bacteria around the shoulder , and following skin preparation for all patients . RESULTS Coagulase-negative Staphylococcus and Propionibacterium acnes were the most commonly isolated organisms prior to skin preparation . The overall rate of positive cultures was 31 % in the povidone-iodine group , 19 % in the DuraPrep group , and 7 % in the ChloraPrep group . The positive culture rate for the ChloraPrep group was lower than that for the povidone-iodine group ( p < 0.0001 ) and the DuraPrep group ( p = 0.01 ) . ChloraPrep and DuraPrep were more effective than povidone-iodine in eliminating coagulase-negative Staphylococcus from the shoulder region ( p < 0.001 for both ) . No significant difference was detected among the agents in their ability to eliminate Propionibacterium acnes from the shoulder region . No infections occurred in any of the patients treated in this study at a minimum of ten months of follow-up . CONCLUSIONS ChloraPrep is more effective than DuraPrep and povidone-iodine at eliminating overall bacteria from the shoulder region . Both ChloraPrep and DuraPrep are more effective than povidone-iodine at eliminating coagulase-negative Staphylococcus from the shoulder Background : Currently a lack of consensus exists on the optimum solution and preparation methods needed to decrease bacteria present during forefoot surgery . We therefore compared the effect of povidine-iodine and chlorhexidine gluconate on lowering bacterial load and to study any additional benefits gained by pre-treatment with the use of a bristled brush . Material s and Methods : Fifty consecutive patients undergoing forefoot surgery were recruited into the study and r and omized to receive one of two surgical skin preparations ( Povidine-iodine 1 % with isopropyl alcohol 23 % or Chlorhexidine gluconate 0.5 % with isopropyl alcohol 70 % ) . In addition to the skin preparation of the foot with the r and omized solution , the subjects other foot was also scrubbed with a sterile surgical bristled brush for three minutes and then painted with the same solution . Swabs were taken from three sites and analyzed via qualitative and quantitative analysis before and after prepping . Results : All four preparation methods significantly decreased ( p < 0.001 ) , in all three sites , the number of colony forming units . Using two-way analysis of variance , no significant interaction was observed between preparation method and number of colony-forming units , suggesting that no difference in bacterial inhibition between preparation methods . Conclusion : We suggest that either povidone - iodine with no more that 23 % isopropyl alcohol or chlorhexidine gluconate with 70 % isopropyl alcohol be used for surgical preparation in forefoot surgery . No additional benefit in reduction in bacterial load was gained by scrubbing the foot with bristles prior to painting |
13,726 | 25,224,106 | The two meta-analyses did not show any significant effect of melatonin .
Although some studies were positive , there was no clear evidence of a therapeutic- or prophylactic effect of melatonin against depression or depressive symptoms | Circadian- and sleep disturbances may be central for underst and ing the pathophysiology and treatment of depression .
The effect of melatonin on depression/depressive symptoms has been investigated previously .
This systematic review assesses the current evidence of a therapeutic- and prophylactic effect of melatonin in adult patients against depression or depressive symptoms . | CONTEXT Cognitive decline , mood , behavioral and sleep disturbances , and limitations of activities of daily living commonly burden elderly patients with dementia and their caregivers . Circadian rhythm disturbances have been associated with these symptoms . OBJECTIVE To determine whether the progression of cognitive and noncognitive symptoms may be ameliorated by individual or combined long-term application of the 2 major synchronizers of the circadian timing system : bright light and melatonin . DESIGN , SETTING , AND PARTICIPANTS A long-term , double-blind , placebo-controlled , 2 x 2 factorial r and omized trial performed from 1999 to 2004 with 189 residents of 12 group care facilities in the Netherl and s ; mean ( SD ) age , 85.8 ( 5.5 ) years ; 90 % were female and 87 % had dementia . INTERVENTIONS R and om assignment by facility to long-term daily treatment with whole-day bright ( + /- 1000 lux ) or dim ( + /- 300 lux ) light and by participant to evening melatonin ( 2.5 mg ) or placebo for a mean ( SD ) of 15 ( 12 ) months ( maximum period of 3.5 years ) . MAIN OUTCOME MEASURES St and ardized scales for cognitive and noncognitive symptoms , limitations of activities of daily living , and adverse effects assessed every 6 months . RESULTS Light attenuated cognitive deterioration by a mean of 0.9 points ( 95 % confidence interval [ CI ] , 0.04 - 1.71 ) on the Mini-Mental State Examination or a relative 5 % . Light also ameliorated depressive symptoms by 1.5 points ( 95 % CI , 0.24 - 2.70 ) on the Cornell Scale for Depression in Dementia or a relative 19 % , and attenuated the increase in functional limitations over time by 1.8 points per year ( 95 % CI , 0.61 - 2.92 ) on the nurse-informant activities of daily living scale or a relative 53 % difference . Melatonin shortened sleep onset latency by 8.2 minutes ( 95 % CI , 1.08 - 15.38 ) or 19 % and increased sleep duration by 27 minutes ( 95 % CI , 9 - 46 ) or 6 % . However , melatonin adversely affected scores on the Philadelphia Geriatric Centre Affect Rating Scale , both for positive affect ( -0.5 points ; 95 % CI , -0.10 to -1.00 ) and negative affect ( 0.8 points ; 95 % CI , 0.20 - 1.44 ) . Melatonin also increased withdrawn behavior by 1.02 points ( 95 % CI , 0.18 - 1.86 ) on the Multi Observational Scale for Elderly Subjects scale , although this effect was not seen if given in combination with light . Combined treatment also attenuated aggressive behavior by 3.9 points ( 95 % CI , 0.88 - 6.92 ) on the Cohen-Mansfield Agitation Index or 9 % , increased sleep efficiency by 3.5 % ( 95 % CI , 0.8%-6.1 % ) , and improved nocturnal restlessness by 1.00 minute per hour each year ( 95 % CI , 0.26 - 1.78 ) or 9 % ( treatment x time effect ) . CONCLUSIONS Light has a modest benefit in improving some cognitive and noncognitive symptoms of dementia . To counteract the adverse effect of melatonin on mood , it is recommended only in combination with light . TRIAL REGISTRATION controlled-trials.com/is rct n Identifier : IS RCT N93133646 The effects of immediate-release melatonin on circadian rest-activity profiles , cognition , and mood were investigated in ten elderly individuals with self-reported sleep-wake disturbances . Melatonin ( 6 mg ) , administered 2 hr before habitual bedtime , enhanced the rest-activity rhythm and improved sleep quality as observed in a reduction in sleep onset latency and in the number of transitions from sleep to wakefulness . However , total sleep time was not significantly increased nor was wake within sleep significantly reduced . The ability to remember previously learned items improved along with a significant reduction in depressed moods . No side effects or contraindications were reported by any of our participants during the 10 day trials . These data suggest that melatonin can safely improve some aspects of sleep , memory , and mood in the elderly in short-term use 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 We used in vitro neurogenesis-based human neural stem cell ( hNSCs ) assays and rodent in vivo behavioral assays to identify potential novel antidepressants . A combination of buspirone and melatonin displayed antidepressant activity in these assays whereas neither buspirone nor melatonin alone showed any antidepressant-like profile . After evaluating numerous combination ratios , we determined that low dose buspirone 15 mg combined with melatonin-SR 3 mg yielded optimal antidepressant efficacy in our pre- clinical platform . The low dose of buspirone suggested that antidepressant efficacy might be achieved with only minimal adverse event liability . Based on these data , we conducted an exploratory 6-week , multi-center , double-blind , r and omized , placebo- and comparator-controlled study of the combination of buspirone and melatonin in subjects with acute Major Depressive Disorder ( MDD ) . The combination treatment revealed a significant antidepressant response in subjects with MDD on several measures ( Clinical Global Impression of Severity and Improvement , Inventory of Depressive Symptomatology ) compared to either placebo or buspirone 15 mg monotherapy . These preliminary findings have clinical implication s and suggest that a platform of pre- clinical neurogenesis matched with confirmatory behavioral assays may be useful as a drug discovery strategy Patients with winter depression ( seasonal affective disorder ( SAD ) ) commonly complain of sleepiness . Sleepiness can be objective ly measured by spectral analysis of the waking electroencephalogram ( EEG ) in the 1–10 Hz b and . The waking EEG was measured every 3 h in 16 female SAD patients and 13 age-matched control women throughout a total sleep deprivation of 30 h. Melatonin ( or placebo ) under double-blind conditions was administered subsequently ( 0.5 mg at 1700 h for 6 days ) , appropriately timed to phase advance circadian rhythms , followed by re assessment in the laboratory for 12 h. The increase in EEG power density in a narrow theta b and ( 5–5.99 Hz , derivation Fz – Cz ) during the 30 h protocol was significantly attenuated in patients compared with controls ( difference between linear trends p=0.037 ) . Sleepiness ( p=0.092 ) and energy ( p=0.045 ) self-ratings followed a similar pattern . Six patients improved after sleep deprivation ( ⩾50 % reduction on SIGH-SAD22 score ) . EEG power density dynamics was correlated with clinical response to sleep deprivation : the steeper the build-up ( as in controls ) , the better the improvement ( p<0.05 ) . There was no differential effect of melatonin or placebo on any measure ; both treatments stabilized the improvement . Overall , patients with winter depression manifest similar wake EEG characteristics as long sleepers or late chronotype with respect to an insufficient build-up of homeostatic sleep pressure . Sleep deprivation was an effective antidepressant treatment for some patients , but evening melatonin was not more efficacious than placebo in sustaining this antidepressant effect Background In many mammals , the duration of the nocturnal melatonin elevation regulates seasonal changes in reproductive hormones such as luteinizing hormone ( LH ) . Melatonin 's effects on human reproductive endocrinology are uncertain . It is thought that the same hypothalamic pulse generator may both trigger the pulsatile release of GnRH and LH and also cause hot flashes . Thus , if melatonin suppressed this pulse generator in postmenopausal women , it might moderate hot flashes . This clinical trial tested the hypothesis that melatonin could suppress LH and relieve hot flashes . Methods Twenty postmenopausal women troubled by hot flashes underwent one week of baseline observation followed by 4 weeks of a r and omized controlled trial of melatonin or matched placebo . The three r and omized treatments were melatonin 0.5 mg 2.5–3 hours before bedtime , melatonin 0.5 mg upon morning awakening , or placebo capsules . Twelve of the women were admitted to the GCRC at baseline and at the end of r and omized treatment for 24-hour sampling of blood for LH . Morning urine sample s were collected twice weekly to measure LH excretion . Subjective responses measured throughout baseline and treatment included sleep and hot flash logs , the CESD and QIDS depression self-ratings , and the SAFTEE physical symptom inventory . Results Urinary LH tended to increase from baseline to the end of treatment . Contrasts among the 3 r and omized groups were statistically marginal , but there was relative suppression combining the groups given melatonin as contrasted to the placebo group ( p < 0.01 one-tailed , Mann-Whitney U = 14 . ) Similar but not significant results were seen in blood LH . There were no significant contrasts among groups in hot flashes , sleep , depression , or side-effect measures and no significant adverse effects of any sort . Conclusion The data are consistent with the hypothesis that melatonin suppresses LH in postmenopausal women . An effect related to the duration of nocturnal melatonin elevation is suggested . Effects of melatonin on reproductive endocrinology should be studied further in younger women and in men . Larger studies of melatonin effects on postmenopausal symptoms would be worthwhile Five patients with winter depression received low doses of melatonin in the afternoon , and five patients received placebo capsules . Melatonin treatment significantly decreased depression ratings compared to placebo . If these findings are replicated in a larger sample with documentation of expected phase shifts , the phase shift hypothesis will be substantially supported Objectives : We sought to report the efficacy of oral melatonin as treatment for chronic tinnitus and to determine whether particular subsets of tinnitus patients have greater benefit from melatonin therapy than others . Methods : This was a prospect i ve , r and omized , double-blind , crossover clinical trial in an ambulatory tertiary referral otology and neurotology practice . Adults with chronic tinnitus were r and omized to 3 mg melatonin or placebo nightly for 30 days followed by a 1-month washout period . Each group then crossed into the opposite treatment arm for 30 days . The tests audiometric tinnitus matching ( TM ) , Tinnitus Severity Index ( TSI ) , Self Rated Tinnitus ( SRT ) , Pittsburgh Sleep Quality Index ( PSQI ) , and Beck Depression Inventory ( BDI ) were administered at the outset and every 30 days thereafter to assess the effects of each intervention . Results : A total of 61 subjects completed the study . A significantly greater decrease in TM and SRT scores ( p < 0.05 ) from baseline was observed after treatment with melatonin relative to the effect observed with placebo . Male gender , bilateral tinnitus , noise exposure , no prior tinnitus treatment , absence of depression and /or anxiety at baseline , and greater pretreatment TSI scores were associated with a positive response to melatonin . Absence of depression and /or anxiety at baseline , greater pretreatment TSI scores , and greater pretreatment SRT scores were found to be positively associated with greater likelihood of improvement in both tinnitus and sleep with use of melatonin ( p < 0.05 ) . Conclusions : Melatonin is associated with a statistically significant decrease in tinnitus intensity and improved sleep quality in patients with chronic tinnitus . Melatonin is most effective in men , those without a history of depression , those who have not undergone prior tinnitus treatments , those with more severe and bilateral tinnitus , and those with a history of noise exposure BACKGROUND Low nighttime levels of melatonin have been demonstrated in patients with insomnia , and melatonin has been shown to have hypnotic properties in some groups of such subjects . Low melatonin levels have also been observed in patients with schizophrenia ; however , there is little literature on the efficacy of exogenous melatonin in treating insomnia associated with schizophrenia . METHOD Stable DSM-IV schizophrenic out patients ( N = 40 ) with initial insomnia of at least 2 weeks ' duration were r and omly assigned to augment their current medications with either flexibly dosed melatonin ( 3 - 12 mg/night ; N = 20 ) or placebo ( N = 20 ) . By use of a question naire , double-blind assessment s of aspects of sleep functioning were obtained daily across the next 15 days . The study was conducted between March and December 2002 . RESULTS The modal stable dose of melatonin was 3 mg . Relative to placebo , melatonin significantly improved the quality and depth of nighttime sleep , reduced the number of nighttime awakenings , and increased the duration of sleep without producing a morning hangover ( p < .05 ) . Subjectively , melatonin also significantly reduced sleep-onset latency , heightened freshness on awakening , improved mood , and improved daytime functioning ( p < .05 ) . CONCLUSION Melatonin may be a useful short-term hypnotic for schizophrenic patients with insomnia . Melatonin could be considered for patients in whom conventional hypnotic drug therapy or higher sedative antipsychotic drug doses may be problematic Sleep disturbance is common in major depressive disorder ( MDD ) , and is often characterized by early-morning waking . Melatonin is a hypnotic and synchronizes circadian rhythms . It may also be an antidepressant . The melatonin agonists , ramelteon and agomelatine , have hypnotic and antidepressant properties , but there is a dearth of trials investigating the use of melatonin in MDD . This r and omized , controlled trial aim ed to determine whether exogenous melatonin is a sleep promoter and antidepressant . Thirty-three participants with a Diagnostic and Statistical Manual of Mental Disorders ( fourth edition ) diagnosis of MDD and early-morning waking were selected for a 4-week , r and omized , double-blind trial of slow-release melatonin ( 6 mg ; vs. placebo ) given at bedtime over 4 weeks . Sleep was measured subjectively using sleep diaries and the Leeds Sleep Evaluation Question naire and objective ly using wrist actigraphy . Of the 33 participants , 31 completed the trial . General Linear Modelling showed significant improvements in depression and sleep over time , but this was not specific to melatonin . However , there was a trend towards an improvement in mood with melatonin , and no adverse side effects were observed . In conclusion , melatonin may be beneficial for treating MDD , it seems to be safe and well tolerated , but its potential for treating depression in people who do not wish to take antidepressants requires further evaluation Patterns of seasonal changes in mood and behavior in Montgomery County , Maryl and , were evaluated in r and omly selected household sample s by lay interviewers using a telephone version of the Seasonal Pattern Assessment Question naire . The method for selecting the sample unit was r and om-digit dialing . We found that 92 % of the survey subjects noticed seasonal changes of mood and behavior to varying degrees . For 27 % of the sample seasonal changes were a problem and 4.3 % to 10 % of subjects , depending on the case-finding definition , rated a degree of seasonal impairment equivalent to that of patients with seasonal affective disorder . The seasonal pattern of " feeling worst " exhibited a bimodal distribution with a greater winter and a substantially lower summer peak ( ratio , 4.5:1 ) . Younger women who have a problem with seasonal changes and who feel worse on short days tended to exhibit the highest seasonality scores . It is apparent from our study that seasonal affective disorder represents the extreme end of the spectrum of seasonality that affects a large percentage of the general population . The influence of environmental factors on mood disorders and mood changes in the general population might provide valuable insight into pathogenesis , treatment , and prevention of affective illness In aging humans , night levels of melatonin ( MEL ) decline progressively . Also thyroid and gonadal functions decline during aging while gonadotropins ( luteotropic hormone ( LH ) and follicle stimulating hormone ( FSH ) ) steadily increase . A desynchronization of pineal circadian cyclicity as expressed by the progressive decrease of the MEL night peak may be permissively linked to the onset and progression of menopause . We studied the effects of exogenous , evening administration of MEL on the level of hormones which are known to be involved in the genesis and progression of menopause . Perimenopausal and menopausal women from 42 to 62years of age with no pathology or medication were selected . MEL was measured in saliva to divide them into low , medium and high-MEL patients . Half of them took 3 mg MEL and half of them Placebo at bedtime ( 10 - 12p.m . ) in a fully r and omized and double-blind fashion . Three and six months later blood was taken for determination of pituitary ( LH , FSH ) , ovarian , and thyroid hormones I(T3 and T4 ) . All women taking MEL with low basal level of MEL and /or Placebo for three and six months showed a significant increase in levels of thyroid hormones . Before initiation of the study , a negative correlation was found in all women between LH , FSH and basal MEL levels . Within six months of treatment , MEL produced a significant diminution of LH in the younger women ( 43 to 49year-old ) , while no effect was seen in the older women ( 50 - 62years old ) . A decrement of FSH was observed in MEL-treated women with low basal MEL levels . In addition , most MEL-treated women reported a general improvement of mood and a significant mitigation of depression . MEL decline during aging may thus signal the derangement of pineal and pituitary-controlled ovarian cyclicity and the progressive quenching of fertility in women . These findings seem to show a recovery of pituitary and thyroid functions in MEL-treated women , towards a more juvenile pattern of regulation Background and aims : The aim of the study was to evaluate the effect of melatonin administration on sleep and behavioral disorders in the elderly and the facilitation of the discontinuation of regular hypnotic drugs . Methods : This was a prospect i ve , r and omized , double-blind , placebo-controlled , crossover trial in a community-living population . Participants were 22 older adults ( 7 men , 15 women over 65 ) with a history of sleep disorder complaints . Fourteen of these subjects were receiving hypnotic drug therapy . Participants received 2 months of melatonin ( 5 mg/day ) and 2 months of placebo . Sleep disorders were evaluated with the Northside Hospital Sleep Medicine Institute ( NHSMI ) test , discarding secondary insomnia and evaluating sleep quality . Behavioral disorders were evaluated with the Yesavage Geriatric Depression Scale ( GDS ) and Goldberg Anxiety Scale ( GAS ) . Patients discontinuing hypnotic drugs were also recorded . Results : Melatonin treatment for two months significantly improved sleep quality scores measured by the NHSMI test ( 1.78± 0.40 ) when compared with both basal ( 3.72± 0.45 ; p=0.001 ) and placebo ( 3.44± 0.56 ; p=0.025 ) groups . Depression measured by GDS and anxiety measured by GAS also improved significantly after melatonin administration ( p=0.043 and p=0.009 , respectively ) . Nine out of 14 subjects receiving hypnotic drugs were able to discontinue this treatment during melatonin but not placebo administration ; one discontinued hypnotic drugs during both melatonin and placebo administration , and four were unable to discontinue hypnotic therapy . Conclusions : The results of this study suggest that melatonin administration significantly improves sleep and behavioral disorders in the elderly and facilitates discontinuation of therapy with conventional hypnotic drugs BACKGROUND Patients with chronic fatigue syndrome ( CFS ) show evidence of circadian rhythm disturbances . We aim ed to determine whether CFS symptoms were alleviated by melatonin and bright-light phototherapy , which have been shown to improve circadian rhythm disorders and fatigue in jet-lag and shift workers . DESIGN Thirty patients with unexplained fatigue for > 6 months were initially assessed using placebo and then received melatonin ( 5 mg in the evening ) and phototherapy ( 2500 Lux for 1 h in the morning ) , each for 12 weeks in r and om order separated by a washout period . Principal symptoms of CFS were measured by visual analogue scales , the Shortform ( SF-36 ) Health Survey , Mental Fatigue Inventory and Hospital Anxiety and Depression Scale . We also determined the circadian rhythm of body temperature , timing of the onset of melatonin secretion , and the relationship between these . RESULTS Neither intervention showed any significant effect on any of the principal symptoms or on general measures of physical or mental health . Compared with placebo , neither body temperature rhythm nor onset of melatonin secretion was significantly altered by either treatment , except for a slight advance of temperature phase ( 0.8 h ; P = 0.04 ) with phototherapy . CONCLUSION Melatonin and bright-light phototherapy appear ineffective in CFS . Both treatments are being prescribed for CFS sufferers by medical and alternative practitioners . Their unregulated use should be prohibited unless , or until , clear benefits are convincingly demonstrated Background and aims : Melatonin , a sleep promoting agent , is involved in the regulation of gastrointestinal motility and sensation . We aim ed to determine if melatonin was effective in improving bowel symptoms and sleep disturbances in irritable bowel syndrome ( IBS ) patients with sleep disturbance . Methods : Forty IBS patients ( aged 20–64 years ; 24 female ) with sleep disturbances were r and omly assigned to receive either melatonin 3 mg ( n = 20 ) or matching placebo ( n = 20 ) at bedtime for two weeks . Immediately before and after the treatment , subjects completed bowel , sleep , and psychological question naires , and underwent rectal manometry and overnight polysomnography . Results : Compared with placebo , melatonin taken for two weeks significantly decreased mean abdominal pain score ( 2.35 v 0.70 ; p<0.001 ) and increased mean rectal pain threshold ( 8.9 v −1.2 mm Hg ; p<0.01 ) . Bloating , stool type , stool frequency , and anxiety and depression scores did not significantly differ after treatment in both groups . Data from sleep question naires and polysomnography showed that the two week course of melatonin did not influence sleep parameters , including total sleep time , sleep latency , sleep efficiency , sleep onset latency , arousals , duration of stages 1–4 , rapid eye movement ( REM ) sleep , and REM onset latency . Conclusions : Administration of melatonin 3 mg at bedtime for two weeks significantly attenuated abdominal pain and reduced rectal pain sensitivity without improvements in sleep disturbance or psychological distress . The findings suggest that the beneficial effects of melatonin on abdominal pain in IBS patients with sleep disturbances are independent of its action on sleep disturbances or psychological profiles In order to test the efficacy of the pineal neurohumor melatonin on depression , the hormone was administered in varying doses to six moderately to severely depressed patients and two patients with Huntington 's chorea in double-blind crossover study . Melatonin exacerbated symptoms of dysphoria in these patients , as well as causing a loss of sleep and weight and a drop in oral temperature . Melatonin increased cerebrospinal fluid 5-hydroxyindoleacetic acid and calcium in three of four patients studied . The authors discuss the implication s of this finding BACKGROUND Depression is a common problem in patients with Delayed Sleep Phase Syndrome ( DSPS ) . This study used a r and omized , double-blind , crossover , placebo-controlled approach to test the hypothesis that exogenous melatonin ( 5 mg ) can attenuate depressive symptomatology in DSPS patients . METHODS Twenty patients with an established diagnosis of DSPS were dichotomized into DSPS with depressive symptoms ( Group I ; n=8 ) and without depressive symptoms ( Group II ; n=12 ) based on structured clinical interviews and a score greater than 17 on Center for Epidemiologic Studies Depression Scale ( CES-D ) . Both groups received melatonin and placebo treatment for 4 weeks with a 1-week washout period in between . Participants underwent a clinical interview and psychometric evaluation to assess depression , and overnight polysomnographic sleep studies were carried out at baseline and at the end of melatonin and placebo treatments . Furthermore , melatonin secretion rhythm as a circadian phase marker was assessed by measuring urinary 6-sulphatoxymelatonin levels . RESULTS Melatonin treatment significantly reduced depression scores in the depressed patients as measured by the CES-D and Hamilton Depression Rating Scale--17 . Melatonin treatment improved sleep continuity in both groups compared to placebo and baseline conditions . Group I individuals showed marked alterations in melatonin rhythms compared to Group II individuals . CONCLUSION Exogenous melatonin treatment may be an effective treatment modality for individuals with circadian rhythm sleep disorders and associated comorbid depressive symptomatology PURPOSE Prior studies have suggested that melatonin , a frequently used integrative medicine , can attenuate weight loss , anorexia , and fatigue in patients with cancer . These studies were limited by a lack of blinding and absence of placebo controls . The primary purpose of this study was to compare melatonin with placebo for appetite improvement in patients with cancer cachexia . PATIENTS AND METHODS We performed a r and omized , double-blind , 28-day trial of melatonin 20 mg versus placebo in patients with advanced lung or GI cancer , appetite scores ≥ 4 on a 0 to 10 scale ( 10 = worst appetite ) , and history of weight loss ≥ 5 % . Assessment s included weight , symptoms by the Edmonton Symptom Assessment Scale , and quality of life by the Functional Assessment of Anorexia/Cachexia Therapy ( FAACT ) question naire . Differences between groups from baseline to day 28 were analyzed using one-sided , two- sample t tests or Wilcoxon two- sample tests . Interim analysis halfway through the trial had a Lan-DeMets monitoring boundary with an O'Brien-Fleming stopping rule . Decision boundaries were to accept the null hypothesis of futility if the test statistic z < 0.39 ( P ≥ .348 ) and reject the null hypothesis if z > 2.54 ( P ≤ .0056 ) . RESULTS After interim analysis of 48 patients , the study was closed for futility . There were no significant differences between groups for appetite ( P = .78 ) or other symptoms , weight ( P = .17 ) , FAACT score ( P = .95 ) , toxicity , or survival from baseline to day 28 . CONCLUSION In cachectic patients with advanced cancer , oral melatonin 20 mg at night did not improve appetite , weight , or quality of life compared with placebo |
13,727 | 19,468,050 | RESULTS There is some evidence for a beneficial effect of estrogen alone on verbal memory in younger naturally post-menopausal women and more consistent evidence from small-n studies of surgically post-menopausal women .
There is stronger evidence of a detrimental effect of conjugated equine estrogen plus medroxyprogesterone acetate on verbal memory in younger and older post-menopausal women .
Observational studies and pharmacological models of menopause provide initial evidence of improvements in executive function with hormone therapy .
Future studies should include measures of executive function and should address pressing clinical questions ; including what formulation of combination hormone therapy is cognitively neutral/beneficial , yet effective in treating hot flashes in the early post-menopause | BACKGROUND Clinical trials yield discrepant information about the impact of hormone therapy on verbal memory and executive function .
This issue is clinical ly relevant because declines in verbal memory are the earliest predictor of Alzheimer 's disease and declines in executive function are central to some theories of normal , age-related changes in cognition . | Memory performance by four age groups ( 30 - 45 years , 46 - 60 years , 61 - 75 years , and 76 - 90 years ) was compared on a multi-trial verbal recall task with 20-minute and 1-day delay free recall and recognition trials . The rate of acquisition across 5 learning trials was similar for all ages except the youngest group whose performance was constrained by a ceiling effect . The level of acquisition achieved was less in the two oldest groups . Words gained across trials and words lost across trials made similar contributions to the shape of the learning curve for the acquisition trials . Subjective organization decreased with age , but remained strongly related to the number of words recalled during acquisition for all age groups . The two oldest age groups demonstrated significant declines in words recalled on the 20-minute and 1-day delay trials . A subset of the oldest group demonstrated more rapid forgetting at the 1-day delay when participants from all age conditions were matched on acquisition . Thus , many aspects of free recall were impaired with age , and variance measurement of recall showed greater inter-individual differences with increasing age . This increase in individual differences could reflect a single form of age-related memory impairment , or it could indicate that memory impairment in the elderly is due to multiple processes . The importance of testing across the life span and using tests that examine a variety of memory components and processes for establishing norms and clarifying age-related deficits are discussed This study describes the neural circuitry underlying temporally separated components of working memory ( WM ) performance-stimulus encoding , maintenance of information during a delay , and the response to a probe . While other studies have applied event-related fMRI to separate epochs of WM tasks , this study differs in that it employs a methodology that does not make any a priori assumptions about the shape of the hemodynamic response ( HDR ) . This is important because no one model of the HDR is valid across the range of activated brain regions and stimulus types . Systematic modeling inaccuracies may lead to the misattribution of activity to adjacent events . Twelve healthy subjects performed a numerical version of the Sternberg Item Recognition Paradigm adapted for rapid presentation event-related fMRI . This paradigm emphasized maintenance rather than manipulative WM processes and used a subcapacity WM load . WM trials with different delay lengths were compared to fixation . The HDR of the entire WM trial for each trial type was estimated using a finite impulse response ( FIR ) . Regional activity associated with the Encode , Delay , and Probe epochs was identified using contrasts that were based on the FIR estimates and by examining the HDRs . Each epoch was associated with a distinct but overlapping pattern of regional activity . Activation of the dorsolateral prefrontal cortex , thalamus , and basal ganglia was exclusively associated with the probe . This suggests that frontostriatal neural circuitry participates in selecting an appropriate response based on the contents of WM Estrogen Therapy ( ET ) may protect against age-related cognitive decline and neuropsychiatric disorders ( e.g. Alzheimer 's disease ) . The biological basis for this putative neuroprotective effect is not fully understood , but may include modulation of cholinergic systems . Cholinergic dysfunction has been implicated in age-related memory impairment and Alzheimer 's disease . However , to date no one has investigated the effect of long-term ET on brain cholinergic muscarinic receptor aging , and related this to cognitive function . We used Single Photon Emission Tomography ( SPET ) and (R , R)[(123)I]-I-QNB , a novel lig and with high affinity for m(1)/m(4 ) muscarinic receptors , to examine the effect of long-term ET and age on brain m(1)/m(4 ) receptors in healthy females . We included 10 younger premenopausal subjects and 22 postmenopausal women ; 11 long-term ET users ( all treated following surgical menopause ) and 11 ET never-users ( surgical menopause , n=2 ) . Also , verbal memory and executive function was assessed in all postmenopausal subjects . Compared to young women , postmenopausal women ( ET users and never-users combined ) had significantly lower muscarinic receptor density in all brain regions examined . ET users also had higher muscarinic receptor density than ET never-users in all the brain regions , and this reached statistical significance in left striatum and hippocampus , lateral frontal cortex and thalamus . Moreover , in ET users , (R , R)[(123)I]-I-QNB binding in left hippocampus and temporal cortex was significantly positively correlated with plasma estradiol levels . We also found evidence for improved executive function in ET users as compared to ET never-users . However , there was no significant relationship between receptor binding and cognitive function within any of the groups . In healthy postmenopausal women use of long-term ET is associated with reduced age-related differences in muscarinic receptor binding , and this may be related to serum estradiol levels Estradiol has been shown to interact with the cholinergic system to affect cognition in postmenopausal women . This study further investigated the interaction of estradiol and cholinergic system functioning on verbal memory and attention in two groups of healthy younger ( ages 50 - 62 ) and older ( ages 70 - 81 ) postmenopausal women . Twenty-two postmenopausal women were r and omly and blindly placed on 1 mg of 17-beta estradiol orally for 1 month then 2 mg for 2 months or matching placebo pills after which they participated in three anticholinergic challenge sessions when verbal memory and attention were assessed . Subjects were administered either the antimuscarinic drug scopolamine ( SCOP ) , the antinicotinic drug mecamylamine ( MECA ) , or placebo . After the first challenge phase , they were crossed over to the other hormone treatment for another 3 months and repeated the challenges . Results showed that estradiol pretreatment significantly attenuated the anticholinergic drug-induced impairments on a test of episodic memory ( the Buschke Selective Reminding Task ) for the younger group only , while estradiol treatment impaired performance of the older group . The results suggest that younger subjects may experience more cholinergic benefit from estradiol treatment than older subjects , supporting the concept of a critical period for postmenopausal estrogen use CONTEXT Postmenopausal women have a greater risk than men of developing Alzheimer disease , but studies of the effects of estrogen therapy on Alzheimer disease have been inconsistent . On July 8 , 2002 , the study drugs , estrogen plus progestin , in the Women 's Health Initiative ( WHI ) trial were discontinued because of certain increased health risks in women receiving combined hormone therapy . OBJECTIVE To evaluate the effect of estrogen plus progestin on the incidence of dementia and mild cognitive impairment compared with placebo . DESIGN , SETTING , AND PARTICIPANTS The Women 's Health Initiative Memory Study ( WHIMS ) , a r and omized , double-blind , placebo-controlled clinical trial , began enrolling participants from the Women 's Health Initiative ( WHI ) estrogen plus progestin trial in May 1996 . Of the 4894 eligible participants of the WHI study , 4532 ( 92.6 % ) postmenopausal women free of probable dementia , aged 65 years or older , and recruited from 39 of 40 WHI clinical centers were enrolled in the WHIMS . INTERVENTION Participants received either 1 daily tablet of 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate ( n = 2229 ) , or a matching placebo ( n = 2303 ) . MAIN OUTCOME MEASURES Incidence of probable dementia ( primary outcome ) and mild cognitive impairment ( secondary outcome ) were identified through a structured clinical assessment . RESULTS The mean ( SD ) time between the date of r and omization into WHI and the last Modified Mini-Mental State Examination ( 3MSE ) for all WHIMS participants was 4.05 ( 1.19 ) years . Overall , 61 women were diagnosed with probable dementia , 40 ( 66 % ) in the estrogen plus progestin group compared with 21 ( 34 % ) in the placebo group . The hazard ratio ( HR ) for probable dementia was 2.05 ( 95 % confidence interval [ CI ] , 1.21 - 3.48 ; 45 vs 22 per 10 000 person-years ; P = .01 ) . This increased risk would result in an additional 23 cases of dementia per 10 000 women per year . Alzheimer disease was the most common classification of dementia in both study groups . Treatment effects on mild cognitive impairment did not differ between groups ( HR , 1.07 ; 95 % CI , 0.74 - 1.55 ; 63 vs 59 cases per 10 000 person-years ; P = .72 ) . CONCLUSIONS Estrogen plus progestin therapy increased the risk for probable dementia in postmenopausal women aged 65 years or older . In addition , estrogen plus progestin therapy did not prevent mild cognitive impairment in these women . These findings , coupled with previously reported WHI data , support the conclusion that the risks of estrogen plus progestin outweigh the benefits UNLABELLED The aim of the double-blind , placebo-controlled study was to investigate the effects of a continuous combined estrogen-progestogen treatment ( Climodien , Lafamme ) as compared with estrogen alone on vigilance in insomniac postmenopausal syndrome patients , objectified by EEG mapping . METHODS In a 3-arm , 2-month parallel group design phase , patients received a combination of estradiol valerate 2 mg and the novel progestogen dienogest 3 mg ( Climodien 2/3 ) or estradiol valerate 2 mg alone or placebo . In a subsequent open-label phase , all patients received estradiol valerate 2 mg+dienogest 2 mg ( Climodien 2/2 ) . EEG mapping was carried out before and after the 2-month double-blind phase as well as after the 2-month open-label treatment . RESULTS As compared with placebo , Climodien 2/3 induced a marked and highly significant increase in absolute power in all frequency b and s , specifically in alpha-2 activity . Moreover , a significant increase in relative alpha-2 power , a decrease in relative delta and beta power as well as an acceleration of the dominant frequency and of the delta and alpha centroids suggested a marked improvement in vigilance . In contrast , under estradiol valerate 2 mg alone , only a slight augmentation of alpha and attenuation of relative delta and beta power occurred , suggesting only a slight vigilance improvement as compared with placebo . Thus , dienogest 2 mg increased the estrogen effect , which was also confirmed by a statistical evaluation of the differences between Climodien 2/3 and estradiol valerate alone ( augmentation of alpha-2 , attenuation of relative beta , acceleration of the dominant frequency ) . Moreover , Climodien 2/2 also markedly increased alpha-2 power , decreased relative beta-2 power and accelerated the alpha centroid . Finally , comparing Climodien 2/3 with Climodien 2/2 , there was even a dose-efficacy relation . CONCLUSIONS Estradiol valerate 2 mg improves vigilance slightly , thereby confirming previous findings . The additional administration of dienogest does not minimize the effect of estrogen , but on the contrary increases it , which makes the combination superior to both placebo and estradiol valerate alone . Vigilance improvement may be of great therapeutic benefit to menopausal syndrome patients at a time when increased adaptability is needed to adjust to increasing sexual , marital , occupational and social difficulties known to occur specifically in this period of life Recent research in rodents suggests that extended and chronic hormone therapy can exacerbate memory impairments and irreversibly damage cells . However , aerobic fitness regimens have been shown to spare brain tissue and cognitive function . In addition , interactions between estrogen treatment and exercise have been reported in rodents . However , whether aerobic fitness and hormone treatments show interactive effects on human brain tissue and cognition has yet to be determined . Here we report two unique and important results : ( a ) HRT treatment up to 10 years in duration spares gray matter in prefrontal cortex and is associated with better performance on measures of executive function , whereas HRT treatment beyond 10 years in duration increases the degree of prefrontal deterioration and amplifies the decline on measures of executive functioning ( b ) higher fitness levels augment the effects of shorter duration s of hormone treatment and ameliorate the declines associated with prolonged hormone treatment In the last ten years , numerous mechanisms by which sex steroids modify cortical function have been described . For example , estrogen replacement improves verbal memory in women , and animal studies have shown effects of estrogen on hippocampal synaptogenesis and function . Little is known about sex steroid effects on other aspects of memory , such as frontal lobe-mediated working memory . We examined the relationships between working memory and sex steroid concentrations and whether sex steroid supplementation would modify age-related loss of working memory in older men and women . Before hormone supplementation , working memory , tested with the Subject Ordered Pointing Test ( SOP ) , was worse in older subjects than younger subjects , and there was no evidence of gender differences at either age . Testosterone supplementation improved working memory in older men , but a similar enhancement of working memory was not found in older women supplemented with estrogen . In men , testosterone and estrogen effects were reciprocalwith better working memory related to a higher testosterone to estrogen ratio . These results suggest that sex steroids can modulate working memory in men and can act as modulators of cognition throughout life The present r and omized double blind study investigated the effects of a 2 week transdermal estradiol treatment on memory performance in 38 healthy elderly women . Cognitive performance was tested at baseline and after 2 weeks of estradiol or placebo treatment using verbal , semantic , and spatial memory tests as well as a mental rotation task and the Stroop . Initial results showed no differences after treatment between placebo or estradiol treated subjects . However , within treatment group analysis revealed that estradiol treated subjects who reached higher estradiol levels ( larger than 29 pg/ml ) performed significantly better after treatment in the delayed recall of the paired associate test ( verbal memory ) than subjects who reached lower estradiol levels ( P < 0.05 ) . A nonsignificant trend was observed for the immediate recall condition ( P < 0.10 ) . These findings were strengthened by correlations between treatment-induced estradiol levels and changes in verbal memory performance . In addition , there was an association between estradiol levels and mood changes . However mood changes were not significantly associated with changes in verbal memory performance ( P > 0.20 ) . The present study supports the idea that estradiol replacement has specific effects on verbal memory in healthy postmenopausal women , with delayed recall being more affected . It suggests that these effects can occur relatively rapidly , and that there may be a dose response relationship of estradiol to memory enhancement . Furthermore , the fact that these results were obtained in women who had been menopausal for an average of 17 years before entering the study indicates that the brain maintains a sensitivity for estrogens even after years of low estradiol plasma concentrations We used event-related functional MRI to investigate the neural bases of two categories of mental processes believed to contribute to performance of an alphabetization working memory task : memory storage and memory manipulation . Our delayed-response tasks required memory for the identity and position-in-the-display of items in two- or five-letter memory sets ( to identify load-sensitive regions ) or memory for the identity and relative position-in-the-alphabet of items in five-letter memory sets ( to identify manipulation-sensitive regions ) . Results revealed voxels in the left perisylvian cortex of five of five subjects showing load sensitivity ( as contrasted with alphabetization-sensitive voxels in this region in only one subject ) and voxels of dorsolateral prefrontal cortex in all subjects showing alphabetization sensitivity ( as contrasted with load-sensitive voxels in this region in two subjects ) . This double dissociation was reliable at the group level . These data are consistent with the hypothesis that the nonmnemonic executive control processes that can contribute to working memory function are primarily prefrontal cortex-mediated whereas mnemonic processes necessary for working memory storage are primarily posteriorly mediated . More broadly , they support the view that working memory is a faculty that arises from the coordinated interaction of computationally and neuroanatomically dissociable processes Estrogen has been shown to interact with the cholinergic system and influence cognition in animal models . This study investigated the interaction of estrogen and cholinergic system functioning and the effects of this interaction on cognitive task performance in healthy older women . Fifteen post-menopausal women were r and omly and blindly placed on 1 mg of 17-β estradiol or placebo for 3 months after which they participated in five anticholinergic challenge sessions , where they were administered one of two doses of the antimuscarinic drug scopolamine ( SCOP ) or the antinicotinic drug mecamylamine ( MECA ) or placebo . After the first challenge phase , they were crossed over to the other hormone treatment for another 3 months and repeated the challenges . Performance in multiple domains of cognition was assessed during anticholinergic drug challenge , including attention and verbal and nonverbal learning and memory . Results showed that estrogen pretreatment attenuated the anticholinergic drug-induced impairments on tests of attention and tasks with speed components . This study is the first to demonstrate the interaction of estrogen and the cholinergic system and the effects on cognitive performance in humans . The results suggest that estrogen status may affect cholinergic system tone and may be important for cholinergic system integrity Among the identified risks and benefits of hormone-replacement therapy , the effects of treatment on cognitive function in postmenopausal women have proved difficult to define . Here we conducted a controlled , prospect i ve analysis in a nonhuman primate model to test whether surgical menopause and estrogen replacement influence the cognitive outcome of normal aging . Sixteen aged rhesus monkeys were ovariectomized , and throughout the course of subsequent neuropsychological assessment , half received a regimen of low-dose , cyclic estradiol replacement . Hormone treatment substantially reversed the marked age-related impairment vehicle-injected monkeys exhibited on a delayed response test of spatial working memory . Modest improvement was also observed on a delayed nonmatching-to- sample recognition memory task . In contrast , ovariectomy exacerbated age-related deficits in object discrimination learning ; the magnitude of this effect was equivalent among vehicle- and estrogen-treated monkeys . Together , these results demonstrate that ovarian hormone status can broadly influence normal cognitive aging in monkeys , affecting capacities mediated by multiple brain regions , including the prefrontal cortex and the medial temporal lobe memory system . The animal model established here should enable progress toward defining the neurobiological mechanisms that mediate the beneficial effects of estrogen on age-related cognitive decline in primates Objective : To examine how menopausal symptoms and estrogen therapy (ET)-induced symptom relief affect cognition in early menopause . Design : : There were two components . Part 1 was a cross-sectional study of 37 healthy , recently postmenopausal women with diverse menopausal symptoms . Women were categorized as having low ( n = 20 ) or high symptoms ( n = 17 ) based on a vali date d symptom question naire . Women completed mood and sleep question naires and underwent cognitive testing , which included verbal memory , visual memory , emotional memory , and verbal fluency . Thirty-two of these women went on to part 2 of the study . Fourteen were r and omly assigned to receive ET and 18 to receive placebo for 8 weeks . Before treatment and at 4 and 8 weeks , women completed the same measures as in part 1 of the study . Results : High symptom women had more negative mood ( P = 0.01 ) and lower quality sleep ( P < 0.001 ) than low symptom women . Despite suffering from more menopausal symptoms , worse mood , and poorer sleep , women in the high symptom group performed the same on cognitive testing as women in the low symptom group . Women receiving ET had greater improvements in menopausal symptoms and sleep compared with those receiving the placebo ( P ≤ 0.05 ) . ET did not improve mood compared with placebo . Women receiving ET did not have any improvement in cognitive performance compared with those receiving the placebo . Conclusions : Menopausal symptoms do not impair cognition . ET does not improve cognition despite alleviating symptoms and improving sleep in recently naturally menopausal women with diverse menopausal symptoms The potential role of estrogen in protecting women from cognitive decline and reducing depressive symptoms is of great therapeutic interest . In a pilot r and omised placebo controlled cross-over study , we aim ed to determine the short-term effects of transdermal estradiol therapy on cognition and depressive symptoms in healthy cognitively normal post-menopausal women over 60 years of age . Nineteen cognitively normal women , without clinical depression whom had undergone a hysterectomy in the past were recruited . Women were r and omised to receive either transdermal estradiol 50 microg/24 h ( Femseven ) or transdermal placebo for 12 weeks before crossing over to the other medication for a further 12 weeks . Cognition was assessed every 6 weeks by the cognitive drug research ( CDR ) computerised assessment which recorded both accuracy and speed in the following cognitive tests ; simple reaction time , choice reaction time , digit vigilance , visual tracking , spatial working memory , immediate and delayed word recall and delayed face and picture recall . Depressive symptoms were measured using the brief assessment scale depression card ( BASDEC ) depression rating scale at baseline , 12 and 24 weeks . Participants had a mean age of 71 , IQ of 115 and MMSE of 29 . Simple reaction time and the BASDEC depression rating scale improved after 12 weeks of estradiol use . All other tests were unaltered by estradiol . Twelve weeks of transdermal estradiol therapy did not consistently improve the speed or accuracy of older women in various cognitive tests . However , the results do support the concept that depressive symptoms may be reduced by estradiol , and not simply due to the relief of climacteric symptoms Observational studies suggest that estrogen replacement therapy ( ERT ) may protect against age-related memory decline and lower the risk of Alzheimer 's disease ( AD ) . This study aim ed to characterize the neural substrates of those effects by comparing 2-year longitudinal changes in regional cerebral blood flow ( rCBF ) in 12 ERT users and 16 nonusers . Positron emission tomography ( PET ) measurements of rCBF were obtained under three conditions : rest , and verbal and figural recognition memory tasks . Groups showed different patterns of change in rCBF over time in a number of brain areas . These group differences , for the most part , reflected regions of increased rCBF over time in users compared to nonusers . The greatest differences between ERT users and nonusers were in the hippocampus , parahippocampal gyrus , and temporal lobe , regions that form a memory circuit and that are sensitive to pre clinical AD . Across a battery of st and ardized neuropsychological tests of memory , users obtained higher scores than did nonusers of comparable intellect . Group differences in longitudinal change in rCBF patterns may reflect one way through which hormones modulate brain activity and contribute to enhanced memory performance among ERT users The effects of estrogen ( E ) on memory were assessed in 19 women who required a hysterectomy and bilateral oophorectomy for benign disease . Blood sample s were drawn and memory tests were administered before surgery and again after 2 mo of postoperative treatment consisting of either monthly E or placebo ( PL ) injections . Scores on the immediate and delayed recall of paired-associates stayed at the same level in E-treated women , whereas they decreased significantly pre- to post-operatively in the PL-treated subjects . In the immediate recall of paragraphs , the scores of those given E improved postoperatively compared to baseline ; scores remained unchanged in the PL group . No hormonal effects were apparent on the immediate or delayed recall of visual material , delayed recall of paragraphs , or digit span scores . These findings suggest that variations in specific aspects of memory function may occur in surgically menopausal women coincident with changes in plasma estrone and estradiol levels The goal of this study was to assess the influence of sex steroid hormone suppression on performance on tests of prefrontal cortex ( PFC ) and working memory function ( WM ) in premenopausal women . Twenty-five women were treated with leuprolide acetate depot ( LAD ) , a gonadotropin releasing hormone ( GnRH ) analog that chemically suppressed ovarian function as treatment of various benign gynecologic disorders . Performance on tests of PFC and WM of the LAD-treated women was assessed at pretreatment baseline and , again , following 4 weeks of treatment and their performance was compared to that of 25 healthy , control participants matched on age , education , and general intelligence . Following 4 weeks of LAD treatment , estrogen levels decreased to the postmenopausal range whereas progesterone levels fell to the lower limit of the menstrual cycle range of values . Furthermore , the LAD-treated women also experienced a significant deterioration in mood , in health-related symptoms and in performance on two tests of WM following 4 weeks of treatment . It was determined that only the post-treatment declines in estrogen , but not those in progesterone , in mood , or in health-related symptoms were associated with the worsening of performance on the WM tests . These findings provide new evidence that estrogen is influential in the maintenance of WM processes in premenopausal women CONTEXT Some studies of hormone treatment in postmenopausal women suggest benefits on specific cognitive functions , particularly memory . OBJECTIVE The objective of this study was to determine whether hormone therapy influences changes in specific cognitive functions and affect in older women . DESIGN This study was a r and omized , double-blind , placebo-controlled clinical trial . SETTING Participants were women from 14 of 40 clinical centers of the Women 's Health Initiative ( WHI ) . PARTICIPANTS Postmenopausal women ( 1416 ) aged 65 yr and older , free of probable dementia , and enrolled in WHI and the WHI Memory Study ( WHIMS ) trial of combination estrogen and progestin for a mean of 3 yr and followed for a mean of 1.35 yr , were studied . INTERVENTION Intervention was conjugated equine estrogen ( CEE ; 0.625 mg ) with 2.5 mg medroxyprogesterone acetate ( MPA ) in one daily tablet ( CEE + MPA ) or placebo . MAIN OUTCOME MEASURES Annual rates of change in specific cognitive functions and affect , adjusted for time since r and omization , were measured . RESULTS CEE + MPA had a negative impact on verbal memory ( P < or= 0.01 ) and a trend to a positive impact on figural memory ( P = 0.012 ) over time compared with placebo , but other cognitive domains were not affected . Both effects on memory were evident only after long-term therapy . CEE + MPA did not significantly influence positive affect , negative affect , or depressive symptoms . CONCLUSIONS The effect of CEE + MPA on cognitive function varies across cognitive domains in older women , reflecting both possible beneficial and detrimental actions of ovarian steroids on the aging brain . Our results extend prior findings about dementia and global cognitive function to age-related changes in specific cognitive functions and suggest directions for future research The results of several observational studies suggest that the use of estrogen replacement is associated with better mood , cognitive function and quality of life . Such findings are consistent with those of laboratory-based research showing that estrogen promotes neuronal sprouting , enhances cholinergic activity in the brain , decreases brain and plasma levels of beta-amyloid , increases serotonin postsynaptic responsivity and the turnover of noradrenaline , and inhibits monoamine oxidase activity . However , the findings from the Women 's Health Initiative controlled trial showed that hormone replacement ( estrogen plus progestin ) not only failed to improve mood , cognition and quality of life but also increased the risk of dementia . At present , there is limited information about the effect of unopposed estradiol replacement therapy ( ERT ) on the mental health outcomes of women at increased risk of cognitive decline ( aged 70 years and over ) . We design ed the present r and omized , double-blind , placebo-controlled trial to clarify this issue . One hundred and fifteen women were r and omized to treatment with estradiol ( n=58 ; 2 mg per day ) or placebo for a total period of 20 weeks . The outcomes of interest in this study included changes in the Beck Depression Inventory ( BDI ) scores between baseline and week 20 , as well as changes in quality of life scores ( as measured by the SF-36 ) and cognitive function ( CAMCOG , Block Design , Memory for Faces , California Verbal Learning Test ( CVLT ) and verbal fluency ( VF ) ) . Nineteen women treated with estradiol and 10 of those treated with placebo discontinued the use of the medication during trial , most frequently due to adverse reactions ( OR=4.11 , 95 % CI=1.29 - 15.37 ) . Intention-to-treat analysis showed that the active and placebo groups did not differ in their response to treatment in any of the outcome measures ( p>0.05 ) . A separate analysis restricted to women who completed the 20-week-trial produced similar negative results . The results of this trial indicate that the use of a relatively high dosage of unopposed estrogen replacement for 20 weeks is not associated with significant changes in cognitive function , mood and quality of life . Other more efficacious and safer interventions need to be devised with the aim of improving the mental state and quality of life of older women Objective : To characterize the relationship between age-related memory change and repeat testing using serial administrations of the California Verbal Learning Test ( CVLT ) in 385 nondemented Baltimore Longitudinal Study of Aging participants aged 55 and older with two or more memory assessment s. Methods : The authors investigated longitudinal change and the effects of age , sex , education , and repeat testing on new learning and recall by analyzing measures of learning and interference , short- and long-delay free and cued recall , and recognition hits in separate mixed-effects regressions . Results : The authors found cross-sectional effects of age ( p ≤ 0.001 ) and sex ( p ≤ 0.05 ) on learning and interference , regardless of baseline performance . Younger adults outperformed older adults , and women outperformed men . Longitudinal age changes were documented across total learning and long-delay free and cued recall regardless of baseline scores ( p ≤ 0.05 ) . In addition , controlling for baseline scores enhanced the sensitivity for detection of longitudinal age changes on Trial 5 , short-delay cued recall and recognition hits ( p ≤ 0.05 ) . The influence of repeated administrations changed with advancing baseline age for total learning and short- and long-delay recall such that younger baseline age was associated with improvement over time whereas older baseline age was associated with decline over time . Conclusion : Longitudinal declines in CVLT performance exist in normal aging and are influenced by baseline age . Furthermore , failure to account for the influence of repeat testing with aging may decrease sensitivity to detect pathologic decline BACKGROUND Several small trials and many observational studies suggest that estrogen treatment in postmenopausal women improves cognition , but 2 large r and omized trials have shown harm . The effect of an ultra-low- dose of unopposed transdermal estradiol on cognition and health-related quality of life is unknown . OBJECTIVE To investigate the effect of unopposed ultra-low-dose transdermal estradiol on cognitive function and quality of life in postmenopausal women . DESIGN R and omized , placebo-controlled , double-blind trial with 2-year follow-up . The main outcome of the trial was change in bone density . Changes in cognitive function and quality of life were preplanned secondary outcomes of the trial . SETTING Nine clinical centers in the United States . PARTICIPANTS Postmenopausal women ( N = 417 ) , aged 60 to 80 years , with a normal bone density for age and an intact uterus . INTERVENTION A weekly transdermal patch that delivers estradiol , 0.014 mg/d ( n = 208 ) , or placebo ( n = 209 ) . MAIN OUTCOME MEASURES Seven st and ardized cognitive tests ( a total of 10 scores ) administered at baseline and years 1 and 2 to test global cognitive function , verbal and visuospatial memory , language , executive function , and semantic memory . The 36-Item Short-Form General Health Survey was administered to assess health-related quality of life in physical and mental domains . The sample size provided 80 % power to detect a st and ardized effect of 0.29 SD , a small-to-moderate difference . RESULTS Baseline characteristics were similar in the 2 treatment groups . At 2 years of follow-up , we found no statistically significant differences between treatment groups in change on any of the cognitive test scores or on the 36-Item Short-Form General Health Survey ( P > .12 for all ) . There was no consistent evidence that the effect of treatment on change in cognitive or 36-Item Short-Form General Health Survey scores depended on the level of baseline endogenous estradiol . CONCLUSION Postmenopausal treatment with ultra-low-dose unopposed transdermal estradiol for 2 years had no effect on change in cognitive function or in health-related quality of life over 2 years of treatment The influence of a combined estrogen-progestin regimen ( Climodien ) on noopsyche , thymopsyche , personality and psychophysiological measures of menopausal syndrome patients was investigated in a double-blind , placebo-controlled , comparative , r and omized 3-arm trial phase ( Climodien 2/3 = estradiol valerate ( CAS 979 - 32 - 8 ) 2 mg + the progestin dienogest ( CAS 65928 - 58 - 7 ) 3 mg = regimen A , estradiol valerate 2 mg = regimen EV , and placebo = regimen P ) followed by an open-label phase in which all patients received Climodien 2/2 ( estradiol valerate 2 mg + dienogest 2 mg ) = regimen A*. 49 women ( 16 , 17 , 16 valid patients per arm ) aged between 46 and 67 years ( mean 58 , 58 , 56 years , respectively ) with the diagnoses of insomnia ( G 47.0 ) related to postmenopausal syndrome ( N 95.1 ) were included in the analysis of the double-blind phase . Both the double-blind and the open-label phase lasted 2 months . Noopsychic investigations demonstrated an improvement in associative verbal memory after 2 months of regimen A , which was significant as compared with both baseline and placebo . Regarding visual memory , regimen A * induced an improvement , which was significantly different from the decline in correct reproductions in the Benton Test observed under estradiol . Errors in the Benton Test decreased significantly after regimen A * as compared with regimen EV . These findings suggest that hormone replacement therapy with estradiol , and even more in combination with dienogest , improves verbal and visual memory , which is in line with the improvement in information processing speed and capacity objectified by event-related potentials ( ERP ) . Thymopsychic investigations demonstrated a significant improvement in somatic complaints and trait anxiety after both regimen A and regimen EV as compared with baseline . State anxiety decreased significantly under regimen A * as compared with EV . The Freiburger Personality Inventory showed an improvement in aggressivity after regimen A * as compared with the preceding placebo as well as an improvement in striving after dominancy after both regimen A and regimen EV as compared with pre-treatment , but also after regimen A * as compared with regimen EV . Extraversion increased after 2 months of regimen A as compared to regimen P. Psychophysiological findings including pupillary and skin conductance variables were not significant There is considerable evidence from animal studies that gonadal steroid hormones modulate neuronal activity and affect behavior . To study this in humans directly , we used H215O positron-emission tomography to measure regional cerebral blood flow ( rCBF ) in young women during three pharmacologically controlled hormonal conditions spanning 4 - 5 months : ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate ( Lupron ) , Lupron plus estradiol replacement , and Lupron plus progesterone replacement . Estradiol and progesterone were administered in a double-blind cross-over design . On each occasion positron-emission tomography scans were performed during ( i ) the Wisconsin Card Sorting Test , a neuropsychological test that physiologically activates prefrontal cortex ( PFC ) and an associated cortical network including inferior parietal lobule and posterior inferolateral temporal gyrus , and ( ii ) a no-delay matching-to- sample sensorimotor control task . During treatment with Lupron alone ( i.e. , with virtual absence of gonadal steroid hormones ) , there was marked attenuation of the typical Wisconsin Card Sorting Test activation pattern even though task performance did not change . Most strikingly , there was no rCBF increase in PFC . When either progesterone or estrogen was added to the Lupron regimen , there was normalization of the rCBF activation pattern with augmentation of the parietal and temporal foci and return of the dorsolateral PFC activation . These data directly demonstrate that the hormonal milieu modulates cognition-related neural activity in humans Abstract Rationale : Estrogen concentrations decline with age and menopause is often followed by an acceleration of the age effects on cognition . It is suggested that replacement of estrogen would reinstate , at least in part , cognitive abilities . Effects of estrogens on memory have been reported in studies with women in a clinical setting who either needed or wished to have the estrogen replacement and are mostly in the perimenopausal age-b and . Objective : The present study investigated the effects of estradiol on memory and on frontal lobe function in elderly female subjects who did not suffer any of the postmenopausal symptoms and had never taken estrogen hormone replacement ( EHR ) previously . Methods : EHR ( Progynova TS , transdermal estradiol ; n=19 ) or placebo ( n=18 ) was given for a period of 3 weeks to elderly healthy female subjects . Memory , frontal lobe functions ( inhibition and planning ) and visuospatial abilities ( mental rotation ) were tested before and after treatment . Estrogen plasma levels were measured to confirm the result of EHR . Cortisol plasma levels were also measured before and after cognitive performance in order to evaluate the effects of EHR on the sensitivity of the hypothalamo- pituitary-adrenal ( HPA ) axis to mild mental stress . Results : Plasma estradiol levels in the drug group increased to levels equivalent to that of a fertile woman ( 0.21± 0.5 nmol/l ) . Memory function as well as visuospatial abilities as measured by a mental rotation task improved significantly with EHR . However , there was no effect of EHR on frontal lobe functions . The cognitive effects were not dependent on an improvement in mood or general well-being as may be the case with EHR in women at peri- or post-menopausal stage . EHR was found to increase the HPA response to task-induced stress , as indicated by an increase in cortisol plasma levels . Conclusions : The present study has provided evidence of a beneficial effect of EHR on cognitive abilities given for first time to healthy elderly women . Furthermore , the present study has demonstrated a differential effect of EHR on memory , visuospatial abilities and frontal lobe function Previous studies indicated an enhanced capability of divergent creative thinking in young women during the ovulatory phase , which expressed itself also by an increased dimensional complexity of ongoing electroencephalographic ( EEG ) activity . Considering the enhanced plasma levels of estrogen and testosterone characterizing the ovulatory phase , we tested whether short-term administration of estrogen or testosterone in postmenopausal women with constantly low levels of gonadal steroids induces similar changes in divergent thinking . In two placebo-controlled cross-over studies , healthy postmenopausal women ( n=12 , in each study , mean age 58 years , range 47–65 years ) were treated transdermally over 3 days with estrogen and testosterone , respectively , at doses inducing plasma hormone concentrations comparable with those observed in young women around ovulation . Capabilities of divergent thought and convergent analytical thought , performance on motor perseveration , and verbal memory were examined . EEG activity was recorded while subjects performed on tasks of thinking and during mental relaxation . Estrogen impaired divergent thinking ( p<0.01 ) and enhanced convergent thinking , motor perseveration , and memory for the initial word list ( p<0.05 for all tests ) . In parallel , EEG dimensional complexity was reduced ( p<0.05 ) . Overall , these changes indicate an estrogen-induced shift from a ‘ divergent ’ towards a more ‘ convergent ’ mode of processing . However , overall less consistent , effects of testosterone were opposite to those of estrogen . It increased performance on some of the divergent thinking tasks ( p<0.05 ) , and tended to increase EEG dimensional complexity during divergent thinking . Data indicate a differential sensitivity of modes of thinking to short-term treatment with estrogen and testosterone in postmenopausal women OBJECTIVE This study was undertaken to assess whether estrogen therapy ( ET ) reduces the risk of cognitive decline in women with cerebrovascular disease . STUDY DESIGN We conducted a r and omized , double-blind trial of estradiol 17beta versus placebo for secondary stroke prevention in 664 postmenopausal women with a recent stroke or transient ischemic attack . The Mini-Mental State Examination ( MMSE ) and 5 domain measures were obtained at baseline and exit . RESULTS Among 461 women withdrawn alive without stroke , ET did not have a significant effect on cognitive measures after an average of 3 years ( relative risk of MMSE decline : 0.74 , 95 % CI , 0.49 - 1.13 ) . In women with normal MMSE at entry , estrogen was associated with less decline ( relative risk , 0.46 , 95 % CI , 0.24 - 0.87 ) . CONCLUSION In this study , estradiol did not have significant effects on cognitive measures . However , in women with normal function at baseline , there may be a benefit for ET in reducing the risk for cognitive decline The effect of estrogen and /or and rogen replacement therapy on several aspects of cognitive functioning in surgically menopausal women was tested in a prospect i ve , crossover design . Women who received either a combined estrogen- and rogen preparation , estrogen alone , or and rogen alone had scores on two tests of short-term memory , a test of long-term memory and a test of logical reasoning that were not different during the postoperative treatment phase compared to their preoperative performance . However , oophorectomized women who received placebo had lower scores on all four measures of cognitive functioning postoperatively , coincident with their significantly lower concentrations of plasma estradiol and testosterone . Patients who had a hysterectomy but whose ovaries were retained showed stability both in cognitive performance and in circulating sex steroid concentrations . These findings suggest that the drastic change in endocrine milieu following surgical menopause may have a direct , albeit modest , effect on aspects of cognitive functioning . Possible mechanisms of action of the sex hormones on cognitive functioning in women are discussed OBJECTIVE To determine the effects of 9 months of hormone replacement therapy ( HRT ) on cognitive performance in women aged 75 years and older . METHODS A 9-month r and omized , double-blinded , placebo-controlled parallel trial . Fifty-two elderly postmenopausal women ( age range 75 - 91 years ) without known contraindications to HRT or evidence of dementia or depression were enrolled . Participants were r and omly assigned in a 1:2 ratio to placebo or conjugated estrogens at 0.625 mg/d plus trimonthly medroxyprogesterone acetate at 5 mg/d for 13 days ( HRT ) . Main outcome measures were change from baseline and rate of change from baseline for the following psychometric tests : Verbal Fluency Test , Weschler Paired Associate Learning and 20 min Delayed Recall , Trailmaking A and B Tests , Cancellation R and om Letter and R and om Form Tests . RESULTS At baseline , women in the HRT group reported a younger age of onset of menopause and a higher prevalence of hysterectomy , but otherwise did not differ from women in the placebo group . After 9 months of treatment , there were no significant group differences for any of the cognitive performance measures . The lack of an observed group-by-time difference for all cognitive tests remained after controlling for age of onset of menopause , education , and previous hysterectomy . CONCLUSIONS Although conclusions are limited by small sample size and the relatively short duration of treatment , results suggest that 9 months of estrogen replacement in combination with trimonthly progestin does not improve cognitive performance in women over 75 years who do not have dementia or depression BACKGROUND Oestrogen use by postmenopausal women has many health benefits , but findings on the effect of oestrogen in Alzheimer 's disease are conflicting . Oestrogen promotes the growth and survival of cholinergic neurons and could decrease cerebral amyloid deposition , both of which may delay the onset or prevent Alzheimer 's disease . To investigate whether use of oestrogen during the postmenopausal period affects the risk of Alzheimer 's disease , we studied 1124 elderly women who were initially free of Alzheimer 's disease , Parkinson 's disease , and stroke , and who were taking part in a longitudinal study of ageing and health in a New York City community . METHODS Relative risks and age-at-onset distributions were calculated from simple and adjusted Cox proportional hazards models . St and ard annual clinical assessment s and criterion-based diagnoses were used in follow-up ( range 1 - 5 years ) . FINDINGS Overall , 156 ( 12.5 % ) women reported taking oestrogen after onset of menopause . The age at onset of Alzheimer 's disease was significantly later in women who had taken oestrogen than in those who did not and the relative risk of the disease was significantly reduced ( 9/156 [ 5.8 % ] oestrogen users vs 158/968 [ 16.3 % ] nonusers ; 0.40 [ 95 % Cl 0.22 - 0.85 ] , p < 0.01 ) , even after adjustment for differences in education , ethnic origin , and apolipoprotein-E genotype . Women who had used oestrogen for longer than 1 year had a greater reduction in risk ; none of 23 women who were taking oestrogen at study enrolment has developed Alzheimer 's disease . INTERPRETATION Oestrogen use in postmenopausal women may delay the onset and decrease the risk of Alzheimer 's disease . Prospect i ve studies are needed to establish the dose and duration of oestrogen required to provide this benefit and to assess its safety in elderly postmenopausal women The question of whether estrogen replacement therapy ( ERT ) is beneficial to cognitive functioning in postmenopausal women has become controversial in the past several years . Early studies suggested that ERT improved cognitive functioning and decreased the risk of Alzheimer 's disease , but recent studies have failed to find any benefit . However , studies have varied in terms of the age of participants , the estrogen preparation used , whether progesterone is administered concurrently , and the study design . The present study used a r and omized , placebo-controlled design and a transdermal estrogen preparation composed of 17-beta estradiol . A neuropsychological battery was administered at baseline and after completion of the 10-week trial , and test scores were grouped into four composite scores using psychometric techniques . Baseline to follow-up change was analyzed using multiple regression techniques . Results indicate that while little overall beneficial effect of estrogen was found , years since menopause was significantly related to change in executive functioning in the estrogen but not the placebo group , such that more recently postmenopausal women demonstrated greater positive change than older women . Body mass index , a gross estimate of circulating estrogen , was significantly positively related to change in attentional and psychomotor processes regardless of treatment group , and to a weaker extent , verbal memory , but only in the estrogen-treated group . These results suggest that reproductive events and levels of endogenous estrogen are related to the clinical response to ERT , but larger studies with longer follow-up periods are needed to determine the strength of these effects Objective : To evaluate the effects of hormone therapy ( HT ) on cognition and subjective quality of life ( QoL ) in recently postmenopausal women with cognitive complaints . Methods : Cognitive Complaints in Early Menopause Trial ( COGENT ) was a r and omized , double-blind , placebo-controlled , multicenter , pilot study of 180 healthy postmenopausal women aged 45 to 55 years , r and omly assigned to receive either placebo or conjugated equine estrogen 0.625 mg/medroxyprogesterone acetate 2.5 mg for 4 months . Outcome measures included memory , subjective cognition , QoL , sexuality , and sleep , which were assessed at baseline and month 4 . Results : The study was terminated before the expected final sample size of 275 due to a decrease in enrollment coinciding with the publication of findings from the Women ’s Health Initiative . There were no differences between groups on any cognitive or QoL measures , except for an increase in sexual interest and thoughts with HT . Modest negative effects on short- and long-term verbal memory approached significance ( p < 0.10 ) . Women with baseline vasomotor symptoms ( VMS ) showed a decrease in VMS and an improvement in general QoL , but no cognitive benefit vs placebo . Conclusions : With the power to detect an effect size of ≥0.45 , this study suggests potential modest negative effects on verbal memory that are consistent with previous hormone therapy trials in older women . GLOSSARY : BTA = Brief Test of Attention ; BVRT = Benton Visual Retention Test ; COGENT = Cognitive Complaints in Early Menopause Trial ; CRT = Educational Testing Service Card Rotation Test ; CVLT = California Verbal Learning ; FAS = Letter Fluency Test ; HERS = Heart and Estrogen/progestin Replacement Study ; HT = hormone therapy ; MFSQ = McCoy Female Sexuality Scale Question naire ; MFQ = The Memory Functioning Question naire ; PANAS = Positive and Negative Affect Scale ; PSQI = The Pittsburgh Sleep Quality Index ; QoL = subjective quality of life ; SWAN = Study of Women ’s Health Across the Nation ; UQoL = Utian Quality of Life ; VMS = vasomotor symptoms Test ; WHI = Women ’s Health Initiative ; WHISCA = WHI Study of Cognitive Aging ; WMS-R/DGT-F , MS-R/DGT-B = Digit Span Forward and Backward Subtests of the Wechsler Memory Scale – Revised Article abstract —We attempted to characterize the changes in cognition associated with the earliest , or pre clinical , stages of Alzheimer 's disease ( AD ) by administering a comprehensive neuropsychological test battery to a group of initially nondemented older adults participating in a prospect i ve epidemiologic study of dementia . Using Cox regression analyses , we examined the associations between baseline neuropsychological test scores and subsequent development of AD . Results confirmed preliminary findings that baseline scores on the Boston Naming Test , Immediate Recall on the Selective Reminding Test , and the Similarities subtest of the Wechsler Adult Intelligence Scale-Revised were significantly and independently associated with later diagnosis of AD . Analyses controlled for the effects of age , education , sex , and language of test administration . These results lend support to the notion of a pre clinical phase of AD and indicate that this very early stage of AD is characterized by poor word-finding ability , abstract reasoning , and memory Studies were conducted on the effect of estrogen on the mental and psychosomatic disorders and mental performance in 27 patients with climacteric symptoms and 25 postmenopausal women who had been amenorrheic for at least 1 year . Both groups were treated with estrogen and a progestogen cyclically for 6 months . A group of 21 postmenopausal women were divided into 2 subgroups 11 were treated with estrogen and 10 received placebo in a double-blind procedure . Social status parity education and occupation were similar in all groups . All patients received a general physical and gynecological examination and metabolic screening . Each patient was examined by means of a series of psychological tests inventories and rating scales for degree of neuroticism distress depression sexual function information-processing capacity and psychosomatic complaints . There was a decrease of follicle stimulating hormone and luteinizing hormone in the estrogen-treated postmenopausal women at 3 and 6 months of treatment ; levels in estrogen-treated premenopausal women and in the placebo group were unchanged . Climacteric and postmenopausal patients initially showed a higher than st and ard degree of neuroticism as measured by the Eysenck Personality Inventory . Estrogen-treated patients showed a statistically significant decrease in contrast to an increase in placebo patients . In the Hamilton Rating Scale for Depression and Sabbatsberg Distress Self-Rating Scale estrogen-treated groups improved significantly while the placebo group showed a deterioration . Performance tests of estrogen-treated patients particularly in complex tasks showed improved information-processing capacity . An improvement was noted on the Sabbatsberg General Symptoms Rating Scale and Sabbatsberg Sexual Self Rating Scale . In self-report estrogen-treated patients considered themselves improved while placebo patients reported the opposite . These findings suggest that estrogen deficiency should be treated to restore somatic mental and social well-being We examined the hypothesis that changes in memory performance of older normal participants are due to frontal lobe dysfunction by comparing three groups of normal individuals ( young , middle-aged , and older ) with three groups of patients who had documented lesions in specific frontal regions : unilateral right , unilateral left , and bilateral . All participants were given 4 successive learning trials on each of 3 lists of words : unrelated , related but presented in a pseudo-r and om order , and related and presented in a blocked format . We found significant correspondences in performance between the older normal participants and the ( younger ) frontal damaged groups . The qualitative nature of recall performance , particularly as measured by indices of organizational control processes , was similar between older normals and patients with frontal damage , particularly those with right frontal damage , but different from that normally exhibited by patients with focal limbic/memory dysfunction . These results add to the evidence that at least some of the decline in older people in tasks which measure executive or supervisory abilities is due to frontal system dysfunction Reports that estrogen may protect against age-associated memory decline and Alzheimer 's Disease have kindled interest in the effects of estrogen replacement therapy ( ERT ) on cognition and brain function . As part of a 9-year study in the Baltimore Longitudinal Study of Aging , we are performing annual magnetic resonance imaging , positron emission tomography ( PET ) , and neuropsychological assessment s to examine brain structure and function in individuals aged 55 and older . PET measurements of regional cerebral blood flow ( rCBF ) are obtained under 3 conditions : rest and verbal and figural delayed recognition memory tasks . Fifteen women receiving ERT ( with or without the addition of progesterone ) were compared with a matched sample of 17 untreated women . There were no significant differences between groups in regional brain volumes or ventricular size . However , ERT users and nonusers showed significant differences in PET-rCBF relative activation patterns during the memory tasks . During verbal memory processing , there were significant interactions in rCBF activations for the right parahippocampal gyrus , right precuneus , right frontal regions , and left hypothalamus . During figural memory processing , significant interactions were observed for right parahippocampal and inferior parietal regions and for left visual association and anterior thalamic regions . ERT users also showed better performance on neuropsychological tests of figural and verbal memory and on some aspects of the PET activation tests , although the two groups did not differ in education , overall verbal ability , or performance on other neuropsychological tests . These findings confirm our previous observation of the beneficial effects of ERT on figural memory . Moreover , differences in rCBF activation patterns between ERT users and nonusers suggest an area for future research to examine mechanisms through which ERT may influence memory and other cognitive abilities Postural instability and falls in the elderly patient constitute a major health care problem . The etiology is often multifactorial , involving abnormal sensory input ( visual , vestibular , and somatosensory ) , poor central processing , and suboptimal musculoskeletal biomechanics . Estrogen replacement therapy has been shown to prevent Alzheimer 's disease and to improve cognitive performance in women with dementia . It was , therefore , postulated that estrogen replacement may improve central processing speed , which would result in improved postural stability . In this prospect i ve , r and omized , double-blinded study , 87 elderly female subjects ( age > 69 ) were examined by repeated dynamic platform posturography , to measure the effect of estrogen therapy versus placebo upon postural stability . Results indicate that those receiving estrogen had no significant improvement in postural stability at 2 and 8 months of treatment relative to those receiving placebo . Trail Making B test was used as the psychometric test of central processing speed . There was no significant effect of estrogen on this measure over the 8 months of observations . It is concluded that 8 months of estrogen replacement therapy has no significant effect on central processing speed or postural stability in a healthy older female population Estrogen treatment of postmenopausal women has been suggested to improve mood and psychological function . However , this remains controversial because previous studies involved heterogeneous groups , were not double blind , and included women who were also experiencing somatic symptoms that were relieved by estrogen . A r and omized double-blind study was carried out comparing the effects of placebo and conjugated equine estrogens ( 0.625 and 1.25 mg ) on psychological function over 3 months in 36 asymptomatic women , aged 45 - 60 . The tests included the Minnesota Multiphasic Personality Inventory-168 , the Profile of Adaptation to Life , and the Beck Depression Inventory . Memory was assessed directly by the Wechsler Adult Intelligence Scales , measuring both digit span and digit symbol . All women were well-adjusted psychologically . The income management scale of the Profile of Adaptation to Life improved ( P<.05 ) with estrogen , as did the Beck Depression Inventory ( P<.05 ) , but these results were not dose-related . Memory assessed prospect ively by the Wechsler Adult Intelligence Scales was not affected significantly . These results suggest that estrogen use may improve the overall quality of life in postmenopausal women OBJECTIVES To evaluate the effect of ultra-low-dose ( 0.25 mg/d ) micronized 17beta-estradiol on cognitive function in older postmenopausal women . DESIGN R and omized , placebo-controlled trial conducted for 3 years . SETTING Academic health center in greater Hartford , Connecticut . PARTICIPANTS Fifty-seven healthy , community-dwelling , older postmenopausal women . INTERVENTION Women received 0.25 mg/d of micronized 17beta-estradiol ( estrogen therapy ( ET ) , n=32 ) or placebo ( n=25 ) ; all women who had not had a hysterectomy received 100 mg/d of oral micronized progesterone for 2-week periods every 6 months . MEASUREMENTS Neuropsychological measures of memory , language , mood , and executive function were collected at baseline , 3 months , and 36 months . Measures of executive function included the Controlled Oral Word Association Test , the Trail Making Test , and the Wisconsin Card Sorting Test . The Boston Naming Test was used to measure language skills . The Symbol Digit Modalities Test was used as a measure of sustained attention . Measures of memory included the Complex Figure Test , Fuld Object Memory Test , and a selected subtest from the Wechsler Memory Scale . Scores from the Geriatric Depression Scale and the Beck Anxiety Inventory were used to assess symptoms of depression . RESULTS No differences were found between ET and placebo on any of the neurocognitive measures or depression instruments , nor were there any differences when the groups were stratified according to age . CONCLUSION This small study , which had adequate power to detect change in some but not all domains of cognition tested , revealed that low-dose estrogen neither benefits nor harms cognitive function in older women after 3 years of treatment , but confirmation is needed from larger trials Objective Considerable controversy surrounds the issue of whether estrogen influences cognitive function in postmenopausal women , and the results are far from consistent . For the most part , the cognitive processes studied have involved memory ; to our knowledge , no previous studies have specifically examined the effects of estrogen on women 's reading ability . Design To investigate reading and short-term memory in postmenopausal women treated with conjugated equine estrogens , we carried out a r and omized , double-blind , placebo-controlled trial of 21 days in 60 midlife , postmenopausal women aged 32.8 to 64.9 years ( mean 51.2 years , SD 5.0 years ) . Women were evaluated for oral reading measured by Gray Oral Reading Tests ( third edition ) and for verbal memory using immediate and delayed recall on the Logical Memory and Paired Associate Learning subtests of the Wechsler Memory Scale and by a Sentence Span task . Results The group receiving daily treatment with conjugated equine estrogens ( Premarin , 1.25 mg ; Wyeth-Ayerst Labs , Philadelphia , PA , USA ) showed better oral reading and verbal memory performance than the placebo group . Conclusion Estrogen may have positive effects on oral reading and verbal memory in midlife , postmenopausal women ABSTRACT The present study was design ed to explore whether the frontal lobe hypothesis of cognitive aging may be extended to describe the cognitive effects associated with estrogen use in postmenopausal women . Postmenopausal estrogen-only users , estrogen + progesterone users , and non-users ( 60–80 years old ) , as well as young , regularly cycling women ( 18–30 years old ) completed an item and source memory task . Since source memory is thought to rely more on executive processes than item memory , we hypothesized that aging and estrogen effects would be greater for source memory than for item memory . Neuropsychological tests explored whether the effects of aging and estrogen use were revealed on other tests of frontal lobe function . Results from the experimental task revealed greater aging and estrogen effects for source memory than for item memory , and neuropsychological results revealed aging and estrogen effects on a subset of tests of executive function . Women on estrogen + progesterone therapy did not outperform non-users , suggesting that the addition of progesterone to hormone therapy may mitigate the benefits induced by estrogen use alone . Overall , findings support the hypothesis that estrogen use may temper age-related cognitive decline by helping to maintain functions subserved by the frontal lobes Objective : Estrogen therapy ( ET ) seems to differentially effect cognitive processes in younger versus older postmenopausal women , suggesting a window of opportunity when ET is most beneficial . Cognitive improvement in younger postmenopausal women has been attributed to ET 's influence on hot flushes and sleep , but empiric examination of the mediating role of menopause symptoms versus direct effects of ET on the brain is limited . Design : In a double-blind trial , 52 women were r and omly assigned to estradiol 0.05 mg/day ( n = 26 ) or placebo transdermal patches ( n = 26 ) for 12 weeks . Women completed tests of memory , learning , and executive functioning , and hot flush and sleep assessment s at baseline and study end . A subset of women ( five ET treated , six placebo treated ) also underwent blood oxygenation level-dependent ( BOLD ) functional magnetic resonance imaging ( fMRI ) studies . Results : Nondepressed perimenopausal and postmenopausal women were studied . The majority had hot flushes and sleep impairment . Compared with placebo , ET selectively reduced errors of perseveration during verbal recall ( P = 0.03 ) , a frontal system-mediated function , but did not influence other cognitive processes . Women with baseline hot flushes had greater cognitive benefit with ET ( P < 0.05 ) . Cognitive benefit was not associated with sleep problems or its improvement . Measures of fMRI BOLD activation during tests of verbal and spatial working memory showed significant increases in frontal system activity with ET ( P < 0.001 ) . Conclusions : Estrogen therapy selectively improves executive functioning as demonstrated by reduced perseverative errors and prefrontal cortex activation during verbal recall tasks . Cognitive improvement with ET is associated with hot flushes , but not with sleep , suggesting that ET has a direct central nervous system effect , rather than an indirect effect mediated through improvement of sleep A formal memory test was administered to 18 female patients with signs or symptoms of oestrogen deficiency taking part in a double-blind study of piperazine oestrone sulphate . A significant improvement in memory was seen in the treated group compared with the placebo group . The findings are discussed OBJECTIVE To evaluate the interval between the onset of detectable cognitive impairment and clinical diagnosis in individuals with probable Alzheimer 's disease ( AD ) , and to identify the pattern of the earliest changes in cognition in probable AD . DESIGN Longitudinal follow-up of a community-based cohort sample . In 1976 through 1978 , a screening neuropsychological examination was administered to Framingham Study participants . These subjects were then followed up prospect ively for development of probable AD for up to 13 years . SETTING This study was conducted at a community-based center for epidemiologic research . PARTICIPANTS The surveillance sample consisted of 1045 participants in the Framingham Study aged 65 to 88 years who were free of dementia at the time of the neuropsychological screening examination . MAIN OUTCOME MEASURES Scores on a group of neuropsychological tests were entered into a series of age- and education-adjusted multiple regression procedures , with the presence or absence of probable AD as the outcome variable . RESULTS Considered individually , most of the screening neuropsychological measures were significantly related to later AD diagnosis . When stepwise regression procedures were employed , only measures of verbal memory and immediate auditory attention span remained significantly related to AD diagnosis . Of note , subjects later diagnosed with probable AD performed at higher levels than normal subjects on the Digit Span test at initial screening . Regression results were essentially unchanged even when the AD sample was restricted to those individuals for whom the screening examination preceded the clinical onset of dementia by 7 years or more . CONCLUSIONS These findings support previous contentions that a " pre clinical phase " of detectable cognitive deficits can precede the clinical diagnosis of probable AD by many years , and they also support the hypothesis that problems with secondary verbal memory are among the first signs of AD CONTEXT Observational studies have suggested that postmenopausal hormone treatment may improve cognitive function , but data from r and omized clinical trials have been sparse and inconclusive . The Women 's Health Initiative Memory Study ( WHIMS ) is an ancillary study of the Women 's Health Initiative ( WHI ) hormone therapy trials . On July 8 , 2002 , the estrogen plus progestin therapy in the WHI trial was discontinued because of certain increased health risks for women . OBJECTIVE To determine whether estrogen plus progestin therapy protects global cognitive function in older postmenopausal women . DESIGN , SETTING , AND PARTICIPANTS A r and omized , double-blind , placebo-controlled clinical trial , WHIMS is an ancillary study of geographically diverse , community-dwelling women aged 65 years or older from 39 of 40 clinical centers within the WHI estrogen plus progestin trial that started in June 1995 . Of 4894 eligible postmenopausal women aged 65 years or older and free of probable dementia at baseline , 4532 ( 92.6 % ) were enrolled in the estrogen plus progestin component of WHIMS . A total of 4381 participants ( 96.7 % ) provided at least 1 valid cognitive function score between June 1995 and July 8 , 2002 . INTERVENTIONS Participants received either 1 daily tablet containing 0.625 mg of conjugated equine estrogen with 2.5 mg of medroxyprogesterone acetate ( n = 2145 ) or matching placebo ( n = 2236 ) . MAIN OUTCOME MEASURE Global cognitive function measured annually with the Modified Mini-Mental State Examination . RESULTS The Modified Mini-Mental State Examination mean total scores in both groups increased slightly over time ( mean follow-up of 4.2 years ) . Women in the estrogen plus progestin group had smaller average increases in total scores compared with women receiving placebo ( P = .03 ) , but these differences were not clinical ly important . Removing women by censoring them after adjudicated dementia , mild cognitive impairment , or stroke , and nonadherence to study protocol , did not alter the findings . Prior hormone therapy use and duration of prior use did not affect the interpretation of the results , nor did timing of prior hormone therapy initiation with respect to the final menstrual period . More women in the estrogen plus progestin group had a substantial and clinical ly important decline ( > or = 2 SDs ) in Modified Mini-Mental State Examination total score ( 6.7 % ) compared with the placebo group ( 4.8 % ) ( P = .008 ) . CONCLUSIONS Among postmenopausal women aged 65 years or older , estrogen plus progestin did not improve cognitive function when compared with placebo . While most women receiving estrogen plus progestin did not experience clinical ly relevant adverse effects on cognition compared with placebo , a small increased risk of clinical ly meaningful cognitive decline occurred in the estrogen plus progestin group Recent neurophysiological data suggest that the prefrontal cortex ( PFC ) may be susceptible to modulation by estrogen . In humans , the PFC mediates a number of cognitive processes that contribute to memory function , particularly working memory . The present study examined whether memory tasks that recruit PFC-dependent information processing might exhibit estrogen sensitivity in women . Performance on several memory tasks , including measures of working memory , was evaluated in three groups of postmenopausal women : ( 1 ) women who were tested when taking estrogen only ( n = 38 , M(age ) = 55.1 years ) , ( 2 ) women who were tested when taking estrogen and a progestin concurrently ( n = 23 , M(age ) = 55.9 years ) , and ( 3 ) women who were not taking hormone replacement therapy ( n = 35 , M(age ) = 56.0 years ) . Estrogen users exhibited significantly better performance on a verbal task and on a spatial task , each with a prominent working memory component , but did not differ from nonusers on control tasks involving simple passive recall . These findings are consistent with the hypothesis that estrogen is active within PFC and is capable of influencing functions dependent on this region . The results of this study raise the possibility that estrogen may play a role in maintaining certain frontal lobe functions in women Objective To evaluate the effect of estrogen replacement therapy on cognitive functioning . Methods The study consisted of two 3-month treatment periods , one with estrogen and one with the placebo , in r and om order , separated by a 1-month wash-out period . The study group comprised 70 healthy postmenopausal women , aged 47–65 years , with previous hysterectomy . Sixty-two women completed the study . Cognitive speed and accuracy , attention , and memory were evaluated . Serum estradiol ( E2 ) and FSH levels were controlled at the end of the estrogen , placebo , and wash-out periods . Results Most of the cognitive tests correlated with age : older women were slower and made errors than younger women . Estrogen replacement therapy was not superior to the placebo in any test of cognitive performance . In two out of ten visual detection tasks , recognition thresholds were longer with estrogen than with the placebo ( P < .001 and P = .004 ) . On the most dem and ing test of working memory , the reaction times ( P = .045 ) and error rates ( P = .043 ) differed between treatments , yet this finding proved to be an effect of learning rather than treatment . There was no correlation between cognitive performance and serum E2 levels . Conclusion Cognitive performance decreased with age . Short-term estrogen replacement therapy did not provide any advantage over the placebo in terms of improving the performance PURPOSE To determine if hormone therapy results in better cognitive function in older postmenopausal women . SUBJECTS AND METHODS The Heart and Estrogen/progestin Replacement Study ( HERS ) was a r and omized , placebo-controlled trial involving 2763 women with coronary disease . Women were assigned r and omly to conjugated estrogen ( 0.625 mg ) plus medroxyprogesterone acetate ( 2.5 mg ) in one tablet daily or identical placebo ; they were followed for a mean ( + /- SD ) of 4.2 + /- 0.4 years . Participants at 10 of the 20 HERS centers were invited to enroll in the cognitive function sub study . At the end of the trial , we measured cognitive function in 517 women in the hormone group and 546 in the placebo group using six st and ard tests : the modified Mini-Mental Status Examination , Verbal Fluency , Boston Naming , Word List Memory , Word List Recall , and Trails B. Cognitive function was not measured at baseline . RESULTS The mean age of participants at the time of cognitive function testing was 71 + /- 6 years . There were no differences in age-adjusted cognitive function test scores between the two treatment groups , except that women assigned to hormones scored worse on the Verbal Fluency test than women assigned to placebo ( 15.9 + /- 4.8 vs. 16.6 + /- 4.8 , P = 0.02 ) . Adjustment for other potential confounders and restriction of the analyses to women who had been adherent to study medication did not change the results . CONCLUSION Among older postmenopausal women with coronary disease , 4 years of treatment with postmenopausal hormone therapy did not result in better cognitive function as measured on six st and ardized tests . Whether these results also apply to elderly women without coronary disease can not be determined from this study OBJECTIVE This study examined the effects of hormone-replacement therapy on memory and other cognitive abilities in cognitively intact older women . METHOD This prospect i ve observational study in nondemented postmenopausal women aged 50 - 89 from the Baltimore Longitudinal Study of Aging involved study groups consisting of 103 women who were receiving oral or transdermal estrogen-replacement therapy ( 44 of whom were receiving adjuvant progesterone ) and 81 women who had never received such therapy . Groups were naturally matched on education , health status , depressive symptoms , annual income , and general verbal ability . To restrict the study group to cognitively healthy women , prospect i ve clinical data were used to exclude women who developed dementia up to 5 years after assessment . Data were cross-sectional . Multivariate analysis of variance and follow-up univariate analyses of variance were performed to compare those women who were receiving and those who had never received hormone-replacement therapy on measures of verbal memory , figural memory , mental rotations , attention , and working memory . RESULTS The women receiving hormone-replacement therapy performed significantly better on measures of verbal learning and memory than did those who had never received hormones , but there were no significant differences in scores on other cognitive tests . Specific aspects of memory performance , including encoding and retrieval , were superior among the women receiving hormone therapy . CONCLUSIONS These findings , based on groups of women who were receiving and had never received hormone-replacement therapy and who were naturally matched on health and cognitive status , suggest that hormone-replacement therapy may have a selective beneficial effect on verbal memory in older nondemented women |
13,728 | 25,227,551 | Conclusions Mind – body practice s have encouraging results for patients with cardiac disease . | Background Due to new treatment modalities in the last decades , a decline in cardiovascular deaths has been observed .
There is an emerging field of secondary prevention and behavioural programmes with increased interest in the use of mind – body practice s. Until now , these have not been established in cardiovascular disease treatment programmes .
Design We performed a systematic review and meta- analysis of the available evidence on the effectiveness of mind – body practice s for patients with diagnosed cardiac disease . | Objective : The underlying changes in biological processes that are associated with reported changes in mental and physical health in response to meditation have not been systematic ally explored . We performed a r and omized , controlled study on the effects on brain and immune function of a well‐known and widely used 8‐week clinical training program in mindfulness meditation applied in a work environment with healthy employees . Methods : We measured brain electrical activity before and immediately after , and then 4 months after an 8‐week training program in mindfulness meditation . Twenty‐five subjects were tested in the meditation group . A wait‐list control group ( N = 16 ) was tested at the same points in time as the meditators . At the end of the 8‐week period , subjects in both groups were vaccinated with influenza vaccine . Results : We report for the first time significant increases in left‐sided anterior activation , a pattern previously associated with positive affect , in the meditators compared with the nonmeditators . We also found significant increases in antibody titers to influenza vaccine among subjects in the meditation compared with those in the wait‐list control group . Finally , the magnitude of increase in left‐sided activation predicted the magnitude of antibody titer rise to the vaccine . Conclusions : These findings demonstrate that a short program in mindfulness meditation produces demonstrable effects on brain and immune function . These findings suggest that meditation may change brain and immune function in positive ways and underscore the need for additional research Background — Although numerous studies have reported that cardiac rehabilitation ( CR ) is associated with reduced mortality after myocardial infa rct ion , less is known about its association with mortality after percutaneous coronary intervention . Methods and Results — We performed a retrospective analysis of data from a prospect ively collected registry of 2395 consecutive patients who underwent percutaneous coronary intervention in Olmsted County , Minnesota , from 1994 to 2008 . The association of CR with all-cause mortality , cardiac mortality , myocardial infa rct ion , or revascularization was assessed with 3 statistical techniques : propensity score – matched analysis ( n=1438 ) , propensity score stratification ( n=2351 ) , and regression adjustment with propensity score in a 3-month l and mark analysis ( n=2009 ) . During a median follow-up of 6.3 years , 503 deaths ( 199 cardiac ) , 394 myocardial infa rct ions , and 755 revascularization procedures occurred in the study subjects . Participation in CR , noted in 40 % ( 964 of 2395 ) of the cohort , was associated with a significant decrease in all-cause mortality by all 3 statistical techniques ( hazard ratio , 0.53 to 0.55 ; P<0.001 ) . A trend toward decreased cardiac mortality was also observed in CR participants ; however , no effect was observed for subsequent myocardial infa rct ion or revascularization . The association between CR participation and reduced mortality rates was similar for men and women , for older and younger patients , and for patients undergoing elective or nonelective percutaneous coronary intervention . Conclusions — We found that CR participation after percutaneous coronary intervention was associated with a significant reduction in mortality rates . These findings add support to published clinical practice guidelines , performance measures , and insurance coverage policies that recommend CR for patients after percutaneous coronary intervention CONTEXT Observational studies have shown that psychosocial factors are associated with increased risk for cardiovascular morbidity and mortality , but the effects of behavioral interventions on psychosocial and medical end points remain uncertain . OBJECTIVE To determine the effect of 2 behavioral programs , aerobic exercise training and stress management training , with routine medical care on psychosocial functioning and markers of cardiovascular risk . DESIGN , SETTING , AND PATIENTS R and omized controlled trial of 134 patients ( 92 male and 42 female ; aged 40 - 84 years ) with stable ischemic heart disease ( IHD ) and exercise-induced myocardial ischemia . Conducted from January 1999 to February 2003 . INTERVENTIONS Routine medical care ( usual care ) ; usual care plus supervised aerobic exercise training for 35 minutes 3 times per week for 16 weeks ; usual care plus weekly 1.5-hour stress management training for 16 weeks . MAIN OUTCOME MEASURES Self-reported measures of general distress ( General Health Question naire [ GHQ ] ) and depression ( Beck Depression Inventory [ BDI ] ) ; left ventricular ejection fraction ( LVEF ) and wall motion abnormalities ( WMA ) ; flow-mediated dilation ; and cardiac autonomic control ( heart rate variability during deep breathing and baroreflex sensitivity ) . RESULTS Patients in the exercise and stress management groups had lower mean ( SE ) BDI scores ( exercise : 8.2 [ 0.6 ] ; stress management : 8.2 [ 0.6 ] ) vs usual care ( 10.1 [ 0.6 ] ; P = .02 ) ; reduced distress by GHQ scores ( exercise : 56.3 [ 0.9 ] ; stress management : 56.8 [ 0.9 ] ) vs usual care ( 53.6 [ 0.9 ] ; P = .02 ) ; and smaller reductions in LVEF during mental stress testing ( exercise : -0.54 % [ 0.44 % ] ; stress management : -0.34 % [ 0.45 % ] ) vs usual care ( -1.69 % [ 0.46 % ] ; P = .03 ) . Exercise and stress management were associated with lower mean ( SE ) WMA rating scores ( exercise : 0.20 [ 0.07 ] ; stress management : 0.10 [ 0.07 ] ) in a subset of patients with significant stress-induced WMA at baseline vs usual care ( 0.36 [ 0.07 ] ; P = .02 ) . Patients in the exercise and stress management groups had greater mean ( SE ) improvements in flow-mediated dilation ( exercise : mean [ SD ] , 5.6 % [ 0.45 % ] ; stress management : 5.2 % [ 0.47 % ] ) vs usual care patients ( 4.1 % [ 0.48 % ] ; P = .03 ) . In a subgroup , those receiving stress management showed improved mean ( SE ) baroreflex sensitivity ( 8.2 [ 0.8 ] ms/mm Hg ) vs usual care ( 5.1 [ 0.9 ] ms/mm Hg ; P = .02 ) and significant increases in heart rate variability ( 193.7 [ 19.6 ] ms ) vs usual care ( 132.1 [ 21.5 ] ms ; P = .04 ) . CONCLUSION For patients with stable IHD , exercise and stress management training reduced emotional distress and improved markers of cardiovascular risk more than usual medical care alone PURPOSE Patients with various medical conditions benefit from eliciting the relaxation response ( RR ) , using a variety of techniques , but few studies have focused on chronic heart failure ( CHF ) . We evaluated the efficacy of an RR intervention program on the quality of life ( QOL ) and exercise capacity of CHF patients by conducting a single-blind , 3-arm , r and omized , controlled trial . METHODS Between April 2000 and June 2002 , we enrolled 95 patients with moderate severity CHF from the Veterans Affairs Boston Healthcare System . Patients in the study intervention group attended a weekly RR group for 15 weeks and were requested to practice the techniques at home twice a day . A 15-week cardiac education ( EDU ) program was used as an alternative intervention , and usual care ( UC ) was the control group . The QOL question naires and a bicycle test were administered at baseline and after intervention or 15 to 19 weeks . RESULTS Eighty-three ( 87 % ) of the 95 enrolled patients completed both baseline and post-intervention QOL measures ( 31 RR , 24 EDU , and 28 UC ) . No dropout bias was observed . The RR group had significantly better QOL change scores in peace-spiritual scales than did the UC group ( P = .02 ) , adjusting for baseline scores , time between assessment s , age , education , diet , and medication , whereas no significant difference was observed between the EDU and UC groups . A similar trend was observed in emotional QOL ( RR and UC group comparison , P = .07 ) . No statistically significant intervention effect on physical QOL or exercise capacity was observed . CONCLUSIONS A short RR intervention can improve some aspects of QOL in CHF patients OBJECTIVES This study sought to estimate the extent to which behavioral and pathophysiological risk factors account for the association between psychological distress and incident cardiovascular events . BACKGROUND The intermediate processes through which psychological distress increases the risk of cardiovascular disease ( CVD ) are incompletely understood . An underst and ing of these processes is important for treating psychological distress in an attempt to reduce CVD risk . METHODS In a prospect i ve study of 6,576 healthy men and women ( ages 50.9 + /- 13.1 years ) , we measured psychological distress ( using the 12-item version of the General Health Question naire > or=4 ) and behavioral ( smoking , alcohol , physical activity ) and pathophysiological ( C-reactive protein , fibrinogen , total and high-density lipoprotein cholesterol , obesity , hypertension ) risk factors at baseline . The main outcome was CVD events ( hospitalization for nonfatal myocardial infa rct ion , coronary artery bypass , angioplasty , stroke , heart failure , and CVD-related mortality ) . RESULTS Cigarette smoking , physical activity , alcohol intake , C-reactive protein , and hypertension were independently associated with psychological distress . There were 223 incident CVD events ( 63 fatal ) over an average follow-up of 7.2 years . The risk of CVD increased in relation to presence of psychological distress in age- and sex-adjusted models ( hazard ratio : 1.54 , 95 % confidence interval : 1.09 to 2.18 , p = 0.013 ) . In models that were adjusted for potential mediators , behavioral factors explained the largest proportion of variance ( approximately 65 % ) , whereas pathophysiological factors accounted for a modest amount ( C-reactive protein approximately 5.5 % , hypertension , approximately 13 % ) . CONCLUSIONS The association between psychological distress and CVD risk is largely explained by behavioral processes . Therefore , treatment of psychological distress that aims to reduce CVD risk should primarily focus on health behavior change BACKGROUND Previous studies demonstrated the effects of progressive muscle relaxation training ( PMRT ) on improvements in the health outcomes of cardiac patients . This study examined the effects of PMRT on the psychologic status and symptoms of older Chinese patients with heart failure . METHODS In a longitudinal , r and omized , and controlled study , 59 patients were allocated to receive a PMRT program and 62 were provided with the attention placebo . The PMRT program included two PMRT sessions , one revision workshop , twice-daily PMRT home practice s , and a biweekly telephone follow-up call . The attention placebo included a regular telephone call at a schedule similar to that made by the interventionist of the PMRT program with the intervention group . Main outcome measures , including psychologic distress , dyspnea , and fatigue , were taken at baseline , the 8th week , and the 14th week . RESULTS A medium effect on psychologic distress in favor of the PMRT program was detected . Patients practicing PMRT however only demonstrated a nonsignificant trend of greater improvement in symptom status . CONCLUSION Progressive muscle relaxation training seems to be useful as an adjunctive nonpharmacologic treatment modality in the management of heart failure Background Mental stress has been linked to increased morbidity and mortality in coronary artery disease and to atherosclerosis progression . Experimental studies have suggested that damage to the endothelium may be an important mechanism . Methods and Results Endothelial function was studied in 10 healthy men ( aged 50.4±9.6 years ) and in 8 non – insulin-dependent diabetic men ( aged 52.0±7.2 years ) . Brachial artery flow-mediated dilation ( FMD , endothelium dependent ) and response to 50 & mgr;g of sublingual glyceryl trinitrate ( GTN , endothelium independent ) were measured noninvasively by use of high-resolution ultrasound before and after ( 30 , 90 , and 240 minutes ) a st and ardized mental stress test . The same protocol without mental stress was repeated on a separate occasion in the healthy men . In healthy subjects , FMD ( 5.0±2.1 % ) was significantly ( P < 0.01 ) reduced at 30 and 90 minutes after mental stress ( 2.8±2.3 % and 2.3±2.4 % , respectively ) and returned toward normal after 4 hours ( 4.1±2.0 % ) . Mental stress had no effect on the response to GTN . In the repeated studies without mental stress , FMD did not change . The diabetic subjects had lower FMD than did the control subjects ( 3.0±1.5 % versus 5.0±2.1 % , respectively;P = 0.02 ) but showed no changes in FMD ( 2.7±1.1 % after 30 minutes , 2.8±1.9 % after 90 minutes , and 3.1±2.3 % after 240 minutes ) or GTN responses after mental stress . Conclusions These findings suggest that brief episodes of mental stress , similar to those encountered in everyday life , may cause transient ( up to 4 hours ) endothelial dysfunction in healthy young individuals . This might represent a mechanistic link between mental stress and atherogenesis Background —Blacks have disproportionately high rates of cardiovascular disease . Psychosocial stress may contribute to this disparity . Previous trials on stress reduction with the Transcendental Meditation ( TM ) program have reported improvements in cardiovascular disease risk factors , surrogate end points , and mortality in blacks and other population s. Methods and Results —This was a r and omized , controlled trial of 201 black men and women with coronary heart disease who were r and omized to the TM program or health education . The primary end point was the composite of all-cause mortality , myocardial infa rct ion , or stroke . Secondary end points included the composite of cardiovascular mortality , revascularizations , and cardiovascular hospitalizations ; blood pressure ; psychosocial stress factors ; and lifestyle behaviors . During an average follow-up of 5.4 years , there was a 48 % risk reduction in the primary end point in the TM group ( hazard ratio , 0.52 ; 95 % confidence interval , 0.29–0.92 ; P=0.025 ) . The TM group also showed a 24 % risk reduction in the secondary end point ( hazard ratio , 0.76 ; 95 % confidence interval , 0.51–0.1.13 ; P=0.17 ) . There were reductions of 4.9 mmHg in systolic blood pressure ( 95 % confidence interval −8.3 to –1.5 mmHg ; P=0.01 ) and anger expression ( P<0.05 for all scales ) . Adherence was associated with survival . Conclusions —A selected mind – body intervention , the TM program , significantly reduced risk for mortality , myocardial infa rct ion , and stroke in coronary heart disease patients . These changes were associated with lower blood pressure and psychosocial stress factors . Therefore , this practice may be clinical ly useful in the secondary prevention of cardiovascular disease . Clinical Trial Registration —URL : www . clinical trials.gov Unique identifier : NCT01299935 The objective of this study was to assess the impact of group-based stress management training on emotional well-being , functional status , social activity and chest pain in cardiac patients , within a r and omized controlled trial . Fifty acute myocardial infa rct ion and 50 coronary artery bypass patients were r and omized to experimental ( 27 myocardial infa rct ion and 23 coronary artery bypass ) and control ( 23 myocardial infa rct ion and 27 coronary artery bypass ) groups 3 months after infa rct ion or surgery . Experimental patients underwent a 10-week relaxation-based stress management programme , while the controls received normal care . Following assessment at the end of the treatment period , controls were offered the stress management programme . Follow-up data were collected 6 months post-treatment from both groups . Significantly greater improvements in emotional well-being as assessed on the Hospital Anxiety and Depression scale ( P < 0.005 ) and the Psychological General Well-being Index ( P < 0.001 ) were found in the experimental than control groups , and improvements were maintained at 6 month follow-up . Greater improvements were also recorded in experimental than control groups in activities of daily living ( P < 0.005 ) , satisfaction with health ( P < 0.025 ) , reports from spouses or relatives of patients ' emotional state ( P < 0.001 ) , and in disruption due to chest pain ( P < 0.001 ) . Similar responses to stress management were observed in myocardial infa rct ion and coronary artery bypass patients . When controls underwent treatment , they too showed significant reductions in anxiety and depression , but no changes in social or functional status . We conclude that stress management training may lead to improvements in the quality of life of myocardial infa rct ion and coronary artery bypass patients . Such programmes might usefully be made available even to patients who have participated in formal rehabilitation OBJECTIVE To evaluate the effectiveness of a Transcendental Meditation ( TM ) stress reduction program for African Americans with congestive heart failure ( CHF ) . DESIGN R and omized , controlled study PARTICIPANTS AND INTERVENTION We recruited 23 African American patients > or = 55 years of age who were recently hospitalized with New York Heart Association class II or III CHF and with an ejection fraction of < .40 . Participants were r and omized to either TM or health education ( HE ) group . MAIN OUTCOME MEASURES Primary outcome measure was six-minute walk test ; secondary outcomes were generic and disease-specific health-related quality of life , quality of well being , perceived stress , Center for Epidemiologic Studies Depression Scale ( CES-D ) , rehospitalizations , brain natriuretic peptide , and cortisol . Changes in outcomes from baseline to three and six months after treatment were analyzed by using repeated measures analysis of variance , covarying for baseline score . RESULTS For the primary outcome of functional capacity , the TM group significantly improved on the six-minute walk test from baseline to six months after treatment compared to the HE group ( P = .034 ) . On the secondary outcome measures , the TM group showed improvements in SF-36 subscales and total score on the Minnesota Living with Heart Failure scale . On the CES-D , the TM group showed significant decrease from baseline to six months compared to the HE group ( P = .03 ) . Also , the TM group had fewer rehospitalizations during the six months of followup . CONCLUSIONS Results indicate that TM can be effective in improving the quality of life and functional capacity of African American CHF patients . Further validation of outcomes is planned via a large , multicenter trial with long-term follow-up AIM This paper is a report of a study conducted to examine the effects of a relaxation training programme on the health-related quality of life of Chinese patients with chronic heart failure . BACKGROUND Despite the substantial evidence indicating the beneficial effects of relaxation therapy on the health-related quality of life of various cardiac population s , the value of this intervention in patients with chronic heart failure remains uncertain . Even less is known about its therapeutic effects in Chinese culture . METHOD A total of 121 Chinese patients with chronic heart failure and over 60 years of age were recruited in 2002 - 2003 and r and omly allocated to a relaxation training programme ( n = 59 ) or an attention-control intervention ( n = 62 ) . The training included two relaxation training sessions , one skill revision workshop , twice daily relaxation self- practice and biweekly telephone follow-up . The World Health Organization Quality of Life question naire was completed at hospital discharge and at the 8th and 14th weeks after discharge . RESULTS Repeated measures analysis of covariance indicated that those who attended the relaxation training programme reported statistically significantly greater improvement in psychological ( P = 0.007 , eta(2 ) = 0.043 ) and social ( P = 0.016 , eta(2 ) = 0.035 ) health-related quality of life than those who received the attention-control intervention over the evaluative period . Comparing outcomes at timepoints showed that the statistically significant group differences in the improvement of psychological and social health-related quality of life occurred mainly during the first evaluative endpoints . CONCLUSION Relaxation techniques are beneficial to the emotional and social health-related quality of life of Chinese patients with chronic heart failure . Combining this intervention with other treatment modalities may produce a more substantial improvement in their health-related quality of life OBJECTIVE We tested whether meditation can reduce sympathetic activation , evaluated by norepinephrine blood levels ( NE ) , and improve quality of life in elderly persons with congestive heart failure ( CHF ) . DESIGN AND SETTING This was a prospect i ve , r and omized study conducted from April 2000 to October 2001 in an ambulatory care teaching hospital in São Paulo , Brazil . SUBJECTS We studied 19 patients with CHF , 74.8 + /- 6.7 years old , receiving diuretics , optimal doses of an angiotensin-converting enzyme inhibitor or angiotensin II inhibitor , maximum tolerated carvedilol dose ( 23.1 + /- 13.6 mg ) and spironolactone 25 mg ( 10 patients ) . INTERVENTIONS After 2 months of optimal treatment with carvedilol , patients were r and omized into two groups . The meditation group ( M ) was provided an audiotape , 30 minutes long , to listen to at home , twice a day , for 12 weeks , plus a weekly meeting . The control group ( C ) just had weekly meetings . MAIN OUTCOME MEASURES We determined before and after 14 + /- k1 weeks , NE ( in pg/mL ) ; quality of life with the Minnesota Living with Heart Failure Question naire ( MLWHFQ ) ; VO2 and VE/VCO2 slope by cardiopulmonary exercise testing ; left ventricular ejection fraction ( LVEF ) , and left ventricular end-diastolic volume index ( LVDDi ) measured by echocardiography . RESULTS Meditation reduced NE ( mean + /- SEM ) from 677.7 + /- 96.6 to 387.1 + /- 39.1 pg/mL ( p = 0.008 ) in M versus 491.4 + /- 35.9 to 470.6 + /- 31.2 ( p = 0.34 ) in C ; improved MLWHFQ total score ( mean + /- SEM ) from 33.2 + /- 6.6 to 21.6 + /- 6.8 points ( p = 0.02 ) in M versus 18.4 + /- 8.0 to 25.1 + /- 8.9 ( p = 0.41 ) in C ; and reduced the VE/VCO2 slope ( mean + /- SEM ) from 31.2 + /- 3.0 to 28.2 + /- 2.6 ( p = 0.04 ) in M versus 28.4 + /- 2.7 to 28.8 + /- 2.6 ( p = 0.24 ) in C. No changes occurred in LVEF , LVDDi , and VO(2 ) . CONCLUSIONS In elderly patients with optimally treated CHF , meditation reduced NE , improved quality of life , and reduced the VE/VCO(2 ) slope . Our results support the possible role of meditation as a new hope in the treatment of CHF Summary : Heart disease is the leading cause of death among Americans each year , yet the misperception still exists that cardiovascular disease is not a serious health problem for women . Evidence indicates that anxiety contributes to the development of heart disease . The primary purpose of this study was to assess the effectiveness of Kabat-Zinn 's mindfulness-based stress reduction program to reduce anxiety in women with heart disease . Anxiety , emotional control , coping styles , and health locus of control were compared in a treatment and control group of women with heart disease . Post-intervention analyses provide initial support for beneficial effects of this program This study examined the effects of exercise and stress management training on clinical outcomes and medical expenditures over a 5-year follow-up period in 94 male patients with established coronary artery disease ( CAD ) and evidence of ambulatory or mental stress-induced myocardial ischemia . Patients were r and omly assigned to 4 months of aerobic exercise 3 times per week or to a 1.5-hour weekly class on stress management ; patients who lived too far from Duke to participate in the weekly treatments formed the usual care control group . Follow-up was performed at the end of treatment and annually thereafter for 5 years . Stress management was associated with a significant reduction in clinical CAD events relative to usual care over each of the first 2 years of follow-up and after 5 years . Economic analyses revealed that stress management was associated with lower medical costs than usual care and exercise in the first 2 years , and that the cumulative cost over 5 years was also lower for stress management relative to usual care . These results suggest that there may be clinical and economic benefit to offering the type of preventive stress management and exercise interventions provided to patients with myocardial ischemia . Moreover , these findings suggest that the financial benefits that accrue from an appropriately targeted intervention may be substantial and immediate OBJECTIVE Stress has been cited as a causal factor in heart disease . The objective of this study was to examine the effects of an 8-week mindfulness-based stress-reduction program on the resting levels of stress hormones , physical functioning , and submaximal exercise responses in women with heart disease . SUBJECTS R and om selection with the numbers 1 and 2 were used to assign 18 women ( 60 + /-6.3 years old ) with documented histories of heart disease to a treatment group ( n = 9 ) or a control group ( n = 9 ) . Speilberger 's state anxiety scores for the treatment ( M = 37.88 ; st and ard deviation ( SD ) = 10.91 ) and control group ( M = 43.22 ; SD = 12.26 ) were not significantly different prior to the start of the study . However , their scores fell in the upper percentile rank for normal adults in their age category . INTERVENTION The intervention was provided one night each week for 2 hours over a period of 8 weeks . The intervention included didactic , inductive , and experiential modes of learning regarding stress responses and mindfulness skill-development training . DESIGN Pre-post test hormonal measurements and physical function were analyzed using a 2 ( group ) by 2 ( time ) analysis of variance ( ANOVA ) with repeated measures following the 8-week program . Submaximal exercise responses were also compared between the treatment group and the control group following the 8-week program . A 2 ( group ) by 3 ( time ) ANOVA with repeated measures was used to analyze the data . SETTING S/LOCATION Weekly meetings were held on a university medical school campus . Submaximal exercise responses were recorded while participants cycled on a stationary bike in an applied physiology laboratory following the 8-week program . RESULTS There were no significant main effects or interaction for the resting levels of stress hormones or physical functioning . There were no significant interactions for the submaximal exercise responses , however , there were significant main effects between groups for ventilation [ F(2,32 ) = 7.65 , p < .01 , f = 0.8 ] , and between group [ F(1,16 ) = 8.84 , p < .01 , f = 0.8 ] and time [ F(2,32 ) = 10.42 , p < .01 , f = 0.9 ] , for breathing frequency . CONCLUSION While the 8-week stress reduction program for women with heart disease did not show significant interactions between groups for resting levels of stress hormones , physical functioning , or submaximal exercise responses , there was a significant difference in breathing patterns between the 2 groups during exercise following the mindfulness-based stress-reduction program . There was also a trend for change in the intervention group in the resting levels of cortisol and physical function scores that was not seen in the control group . Future studies could use the effect size generated from this pilot study to calculate the number of subjects needed for adequate power to detect significant differences between groups The aim of the present study was to assess the use of complementary and alternative medicine ( CAM ) treatments in out patients with cardiovascular disease and their interest in future use . The increasing popularity of CAM therapies highlights the need to explore their use among patients with cardiovascular disease . Data were collected with a prospect i ve , point-of-care , anonymous , 17- question survey about basic medical information and previous use and interest in the future use of dietary supplements and other CAM interventions among patients undergoing outpatient cardiology evaluation at a Midwestern tertiary care center . The survey was completed by 1,055 patients ( 655 men , 351 women ; mean age 63.5 years ) of whom 98.1 % were white . Of these , 36.8 % had cardiac symptoms for > 10 years , 48.2 % had coronary artery disease , and 82.5 % reported use of CAM therapies . Of these patients , 75.4 % reported using dietary supplements , 31.5 % chiropractic therapy , 23.9 % mind-body therapies , and 19.2 % massage . Only 14.4 % had discussed the use of CAM treatments with their physicians . The top 4 treatments used for cardiac symptoms were relaxation techniques , stress management , meditation , and guided imagery . Also , 48.6 % were interested in participating in a future clinical trial of an alternative treatment . The great majority of patients seen in current practice use CAM therapies , and a large proportion expressed an interest in participating in research with CAM therapies . In conclusion , research directed with an integrative approach to cardiovascular care might prove beneficial when design ing future studies ABCD : Appropriate Blood pressure Control in Diabetes ABI : ankle – brachial index ABPM : ambulatory blood pressure monitoring ACCESS : Acute C and esartan Cilexetil Therapy in Stroke Survival ACCOMPLISH : Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension ACCORD : Action to Control Cardiovascular Risk in Diabetes ACE : angiotensin-converting enzyme ACTIVE I : Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events ADVANCE : Action in Diabetes and Vascular Disease : Preterax and Diamicron-MR Controlled Evaluation AHEAD : Action for HEAlth in Diabetes ALLHAT : Antihypertensive and Lipid-Lowering Treatment to Prevent Heart ATtack ALTITUDE : ALiskiren Trial In Type 2 Diabetes Using Cardio-renal Endpoints ANTIPAF : ANgioTensin II Antagonist In Paroxysmal Atrial Fibrillation APOLLO : A R and omized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People ARB : angiotensin receptor blocker ARIC : Atherosclerosis Risk In Communities ARR : aldosterone renin ratio ASCOT : Anglo-Sc and inavian Cardiac Outcomes Trial ASCOT-LLA : Anglo-Sc and inavian Cardiac Outcomes Trial — Lipid Lowering Arm ASTRAL : Angioplasty and STenting for Renal Artery Lesions A-V : atrioventricular BB : beta-blocker BMI : body mass index BP : blood pressure BSA : body surface area CA : calcium antagonist CABG : coronary artery bypass graft CAPPP : CAPtopril Prevention Project CAPRAF : C And esartan in the Prevention of Relapsing Atrial Fibrillation CHD : coronary heart disease CHHIPS : Controlling Hypertension and Hypertension Immediately Post-Stroke CKD : chronic kidney disease CKD-EPI : Chronic Kidney Disease — EPIdemiology collaboration CONVINCE : Controlled ONset Verapamil INvestigation of CV Endpoints CT : computed tomography CV : cardiovascular CVD : cardiovascular disease D : diuretic DASH : Dietary Approaches to Stop Hypertension DBP : diastolic blood pressure DCCT : Diabetes Control and Complications Study DIRECT : DIabetic REtinopathy C and esartan Trials DM : diabetes mellitus DPP-4 : dipeptidyl peptidase 4 EAS : European Atherosclerosis Society EASD : European Association for the Study of Diabetes ECG : electrocardiogram EF : ejection fraction eGFR : estimated glomerular filtration rate ELSA : European Lacidipine Study on Atherosclerosis ESC : European Society of Cardiology ESH : European Society of Hypertension ESRD : end-stage renal disease EXPLOR : Amlodipine – Valsartan Combination Decreases Central Systolic Blood Pressure more Effectively than the Amlodipine – Atenolol Combination FDA : U.S. Food and Drug Administration FEVER : Felodipine EVent Reduction study GISSI-AF : Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Atrial Fibrillation HbA1c : glycated haemoglobin HBPM : home blood pressure monitoring HOPE : Heart Outcomes Prevention Evaluation HOT : Hypertension Optimal Treatment HRT : hormone replacement therapy HT : hypertension HYVET : HYpertension in the Very Elderly Trial IMT : intima-media thickness I-PRESERVE : Irbesartan in Heart Failure with Preserved Systolic Function INTERHEART : Effect of Potentially Modifiable Risk Factors associated with Myocardial Infa rct ion in 52 Countries INVEST : INternational VErapamil SR/T Tr and olapril ISH : Isolated systolic hypertension JNC : Joint National Committee JUPITER : Justification for the Use of Statins in Primary Prevention : an Intervention Trial Evaluating Rosuvastatin LAVi : left atrial volume index LIFE : Losartan Intervention For Endpoint Reduction in Hypertensives LV : left ventricle/left ventricular LVH : left ventricular hypertrophy LVM : left ventricular mass MDRD : Modification of Diet in Renal Disease MRFIT : Multiple Risk Factor Intervention Trial MRI : magnetic resonance imaging NORDIL : The Nordic Diltiazem Intervention study OC : oral contraceptive OD : organ damage ONTARGET : ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial PAD : peripheral artery disease PATHS : Prevention And Treatment of Hypertension Study PCI : percutaneous coronary intervention PPAR : peroxisome proliferator-activated receptor PREVEND : Prevention of REnal and Vascular ENdstage Disease PROFESS : Prevention Regimen for Effectively Avoiding Secondary Strokes PROGRESS : Perindopril Protection Against Recurrent Stroke Study PWV : pulse wave velocity QALY : Quality adjusted life years RAA : renin-angiotensin-aldosterone RAS : renin-angiotensin system RCT : r and omized controlled trials RF : risk factor ROADMAP : R and omized Olmesartan And Diabetes MicroAlbuminuria Prevention SBP : systolic blood pressure SCAST : Angiotensin-Receptor Blocker C and esartan for Treatment of Acute STroke SCOPE : Study on COgnition and Prognosis in the Elderly SCORE : Systematic COronary Risk Evaluation SHEP : Systolic Hypertension in the Elderly Program STOP : Swedish Trials in Old Patients with Hypertension STOP-2 : The second Swedish Trial in Old Patients with Hypertension SYSTCHINA : SYSTolic Hypertension in the Elderly : Chinese trial SYSTEUR : SYSTolic Hypertension in Europe TIA : transient ischaemic attack TOHP : Trials Of Hypertension Prevention TRANSCEND : Telmisartan R and omised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease UKPDS : United Kingdom Prospect i ve Diabetes Study VADT : Veterans ' Affairs Diabetes Trial VALUE : Valsartan Antihypertensive Long-term Use Evaluation WHO : World Health Organization # # # 1.1 Principles The 2013 guidelines on hypertension of the European Society of Hypertension ( ESH ) and the European Society of Cardiology BACKGROUND The Support , Education , and Research in Chronic Heart Failure ( SEARCH ) study was design ed to assess the impact of a mindfulness-based psychoeducational intervention on clinical outcomes , depression , and quality of life in patients with chronic heart failure ( CHF ) . Although research has shown that psychosocial factors including depression are important risk factors for adverse events in patients with CHF , no large clinical trials have investigated the efficacy of psychosocial interventions to reduce these factors in this population . METHODS This was a prospect i ve cohort study of 208 adults with left ventricular ejection fraction < or = 40 % and CHF geographically assigned to treatment or control groups with follow-up at 3 , 6 , and 12 months . Treatment groups met weekly for 8 consecutive weeks for training in mindfulness meditation , coping skills , and support group discussion . RESULTS Subjects had a mean age of 61 years , left ventricular ejection fraction 26 % , and median New York Heart Association class II . The majority were treated with angiotensin-converting enzyme inhibitors ( 80 % ) and beta-blockers ( 86 % ) . At baseline , patients in the treatment group had more severe CHF with higher New York Heart Association class ( P = .0209 ) and more severe psychological distress ( Center of Epidemiology - Depression , Profile of Mood States ; P < .05 ) . When compared with controls , treatment result ed in lower anxiety ( Profile of Mood States , P = .003 ) , depression ( Center of Epidemiology - Depression , P = .05 ) , improved symptoms ( Kansas City Cardiomyopathy Question naire symptom scale , P = .033 ) and clinical scores ( Kansas City Cardiomyopathy Question naire clinical score , P = .024 ) over time . There were no treatment effects on death/rehospitalization at 1 year . CONCLUSIONS An 8-week mindfulness-based psychoeducational intervention reduced anxiety and depression ; this effect was attenuated at 1 year . Importantly , the intervention led to significantly better symptoms of CHF at 12 months compared to control subjects . Our results suggest that interventions of this type might have a role in optimal therapy for CHF PURPOSE To examine the effect of a cardiac rehabilitation program with relaxation therapy ( CPRT ) in comparison with cardiac rehabilitation alone on psychological stress , hemodynamic variables , cardiac risk factors , and cardiac-related hospital admissions in patients with coronary artery disease . METHODS Patients ( N = 81 ) were r and omly assigned to either a 12-week cardiac rehabilitation program alone ( CPA ) or a CPRT . Perceived stress , blood pressure , heart rate , rate-pressure product value , total cholesterol level , body mass index , smoking status , and physical activity were recorded at baseline and following the 12-week intervention . Cardiac-related hospital admissions were analyzed in a 2-year follow-up . RESULTS Perceived stress declined in both groups , although this improvement was significantly superior in the CPRT ( 31.5 ± 4.9 vs 23.4 ± 4.1 ; P ≤ .0001 ) . CPRT , but not CPA , had significantly lower heart rate , blood pressure , and rate-pressure product values after the program ( P ≤ .0001 ) . Both groups improved smoking status , physical activity , body mass index , and total cholesterol level . During follow-up , the odds of being admitted to the hospital with cardiac-related problems , after adjusting for heart rate , blood pressure , smoking status , physical activity status , and total cholesterol ( OR , 0.37 ; 95 % CI , 0.045–2.98 ) , was not significantly different between groups . CONCLUSIONS Relaxation therapy was associated with a positive effect on psychological stress and hemodynamic variables beyond that promoted by cardiac rehabilitation alone |
13,729 | 21,150,584 | Plasma concentrations of plasma L-arginine are substantially decreased in patients with sepsis in the absence of trauma or surgery . | INTRODUCTION L-arginine is a conditionally essential amino acid that plays an important role in immune and vascular function in sepsis .
Plasma concentrations of L-arginine are decreased after trauma or surgery but have been variably reported to be normal or decreased in patients with sepsis . | Although reports of decreased plasma taurine in trauma , sepsis and critical illness are available , very little is known about the relationships among changes in plasma taurine , other amino acid levels and metabolic variables . We analyzed a large series of plasma amino acid profiles obtained in trauma patients with sepsis who were undergoing total parenteral nutrition . The correlations between plasma taurine , other amino acid levels , parenteral substrate doses and metabolic and cardiorespiratory variables were assessed by regression analysis . Post-traumatic hypotaurinemia was followed by partial recovery toward less abnormal values when sepsis developed . Levels of taurine were directly and significantly related to levels of glutamate , aspartate , beta-alanine and phosphoethanolamine ( and unrelated to other amino acids ) . Levels of these amino acids increased simultaneously with increasing doses of leucine , isoleucine and valine in total parenteral nutrition . Decreasing taurine was associated with increasing lactate , arteriovenous O(2 ) concentration difference and respiratory index , and with decreasing cholesterol and cardiac index . These results characterize the relationships between plasma taurine and other amino acid levels in sepsis , provide evidence of amino acid interactions that may support taurine availability and show more severe decreases in plasma taurine with the worsening of metabolic and cardiorespiratory patterns Objective : l-arginine supplementation in sepsis is controversial . Septic shock has been alternatively viewed as an l-arginine-deficient state or as a syndrome caused by excess nitric oxide , an end-product of l-arginine metabolism . Design : R and omized , placebo-controlled , and double-blinded ( investigators , veterinarians , and pharmacists ) . Setting : Laboratory . Subjects : Purpose -bred , 1- to 2-yr-old , 10- to 12-kg beagles . Interventions : The effects of parenteral l-arginine alone or in combination with N-acetylcysteine were compared with vehicle alone in a well-characterized canine model of Escherichia coli peritonitis . Two doses were studied that delivered approximately 1.5-fold ( 10 mg·kg−1·hr−1 ) and 15-fold ( 100 mg·kg−1·hr−1 ) the l-arginine dose typically administered with st and ard total parenteral nutrition . Animals in the low- and high-dose l-arginine arms were further r and omized to receive vehicle alone or N-acetylcysteine ( 20 mg·kg−1·hr−1 ) as an antioxidant to prevent peroxynitrite formation . Measurements and Main Results : The main measurements were hemodynamics , plasma arginine and ornithine , serum nitrate/nitrite , laboratory studies for organ injury , and survival . Both doses of l-arginine similarly increased mortality ( p = .02 ) , and worsened shock ( p = .001 for reduced mean arterial pressure ) . These effects were associated with significant increases in plasma arginine ( p = .0013 ) and ornithine ( p = .0021 ) . In addition , serum nitrate/nitrite ( p = .02 ) , liver enzymes ( p = .08 ) , and blood urea nitrogen/creatinine ratios ( p = .001 ) rose , whereas arterial pH ( p = .001 ) and bicarbonate levels ( p = .001 ) fell . N-acetylcysteine did not significantly decrease any of the harmful effects of l-arginine . Thus , parenteral l-arginine monotherapy was markedly harmful in animals with septic shock . Conclusions : These findings suggest that supplemental parenteral l-arginine , at doses above st and ard dietary practice s , should be avoided in critically ill patients with septic shock Asymmetric dimethylarginine ( ADMA ) is an endogenous inhibitor of endothelial nitric oxide ( NO ) synthase . Its concentration is elevated in patients with end-stage renal disease ( ESRD ) , in part because it is excreted via the kidneys . In this study , the plasma concentrations of ADMA , symmetric dimethylarginine , and L-arginine were determined in relation to plasma nitrate levels ( as an index of NO formation ) for a group of 80 patients with ESRD . The effects of two treatment methods , i.e. , hemodialysis ( HD ) and peritoneal dialysis ( PD ) , and the role of the presence of atherosclerotic disease were evaluated . Forty-three patients receiving HD and 37 patients receiving PD were compared with healthy control subjects . Plasma L-arginine and dimethylarginine levels were determined by HPLC , using precolumn derivatization with o-phthaldialdehyde . Plasma nitrate levels were determined by gas chromatography-mass spectrometry . Predialysis ADMA concentrations in HD-treated patients were approximately sixfold higher than those in the control group ( 6.0+/-0.5 versus 1.0+/-0.1 micromol/L ; P < 0.05 ) . Plasma nitrate concentrations were significantly lower in HD-treated patients , which suggests that ADMA may inhibit NO synthase . In contrast , plasma ADMA levels and nitrate concentrations in PD-treated patients were similar to those in control subjects . Plasma L-arginine concentrations were not significantly decreased in patients with ESRD . ADMA concentrations were significantly decreased 5 h after HD , compared with baseline values . ADMA levels were significantly higher in HD-treated patients with manifest atherosclerotic disease than in HD-treated patients without atherosclerotic disease ( 7.31+/-0.70 versus 3.95+/-0.52 micromol/L ; P < 0.05 ) . This study confirms that ADMA is accumulated in ESRD . PD-treated patients exhibit significantly lower ADMA levels than do HD-treated patients . Accumulation of ADMA may be a risk factor for the development of endothelial dysfunction and cardiovascular disease in patients with ESRD Objective To investigate the role of nitric oxide in the regulation of vascular tone in patients with the sepsis syndrome . Design Prospect i ve , intervention study . Setting Tertiary care hospital . Patients Fifteen patients admitted to our medical intensive care unit with the diagnosis of sepsis syndrome by defined criteria . Interventions Eight patients received Nω-nitro-L-arginine was followed by hypertension ( mean blood pressure increased from 89 ± 8 to a maximum of 140 ± 12 mm Hg ) accompanied by a decrease in cardiac index ( from 3.51 ± 0.39 to a minimum of 2.65 ± 0.21 L/min/m2 ) and an increase in right atrial and pulmonary artery occlusion pressure . Systemic vascular resistance index increased from 1871.1 ± 302.3 to 3825.6 ± 244.4 dyne·sec/cm5·m2 , and pulmonary vascular resistance increased from 533.2 ± 125.8 to 816.0 ± 117.3 dyne·sec/cm5·m2 . These changes induced by Nω-nitro-L-arginine were reversed by the administration of L-arginine . The administration of L-arginine to another group of patients caused transient hypotension ( from 103 ± 6 to 81 ± 10 mm Hg ) and an increase in cardic index ( from 3.57 ± 0.15 to 4.74 ± 0.54 L/min/m2 ) . Both systemic and pulmonary vascular resistance indices decreased ( from 1987.6 ± 163.9 to 1251.4 ± 231.5 dyne·sec/cm5·m2 , and from 486.1 ± 65.2 to 380.5 ± 70.3 dyne·sec/cm5·m2 ) . Parallel to the increase in oxygen transport due to the increase in cardiac output , oxygen consumption index increased significantly 1 min after L-arginine ( from 127.0 ± 19.0 to 182.5 ± 37.3 mL/min/m2 ) . All mentioned changes were statistically significant ( p<.05 ) . Conclusions A continuous basal release of nitric oxide plays a role in the regulation of systemic and pulmonary vascular tone in patients with sepsis syndrome . L-arginine has systemic and pulmonary vasodilatory actions . ( Crit Care Med 1993 ; 21:1287–1295 Vascular risk factors increase the risk of developing Alzheimer 's disease . Increased concentrations of circulating homocysteine are associated with an increased risk of both vascular disease and Alzheimer 's disease . Asymmetric dimethylarginine ( ADMA ) is an endogenous inhibitor of nitric oxide synthase . There is an increase in the concentration of ADMA in the circulation in vascular disease . We measured the concentrations of homocysteine , ADMA and nitric oxide ( as nitrate and nitrite ) in the plasma of 25 patients with Alzheimer 's disease and 25 control subjects . There was a highly significant increase in the plasma concentration of homocysteine ( P<0.001 ) and ADMA ( P<0.0001 ) and a highly significant decrease in the plasma concentration of nitric oxide ( P<0.0001 ) among the Alzheimer 's patients . In the combined patient and control groups a highly significant positive correlation was found between the plasma concentrations of homocysteine and ADMA ( r=0.782 , P<0.0001 ) . In addition , significant negative correlations were detected between the plasma concentration of nitric oxide and the plasma concentration of homocysteine ( r=-0.592 , P<0.0001 ) and ADMA ( r=-0.789 , P<0.0001 ) . These significant correlations were found to persist , even when they were restricted to the Alzheimer 's patients . The inhibition of endothelial nitric oxide synthesis by ADMA impairs cerebral blood flow , which may contribute to the development of Alzheimer 's disease . Endothelial dysfunction is also associated with atherosclerosis and stroke , which are important risk factors for Alzheimer 's disease . Inflammation plays an important role in Alzheimer 's disease and the inhibition of endothelial nitric oxide by ADMA may increase the concentration of inflammatory mediators in the brain . The inhibition of neuronal nitric oxide synthesis by ADMA may cause cognitive dysfunction in Alzheimer 's disease Sepsis has been associated with specific plasma amino acid patterns . Sixty-five patients were prospect ively investigated as to whether these patterns are indeed sepsis specific , or specific for metabolic stress without concomitant sepsis , or associated with the presence of organ failure . Virtually all aminoacid levels were decreased by 10–30 % ( p < 0.05 ) , whereas cystine and phenyl-alanine were significantly elevated . These changes were more pronounced in severe sepsis . Organ failure was not associated with significantly altered amino acid profiles . No differences were found between sepsis and stress without signs of sepsis . In addition , imminent death was not associated with aberrant amino acid profiles . We conclude that sepsis and metabolic stress are associated with changes in plasma amino acid profiles , but that such changes are aspeciflc and therefore poor indicators of disease severity Acute inflammation impairs vascular function . Based on the association between endothelial dysfunction and plasma concentrations of L-arginine and the endogenous nitric oxide synthase inhibitor ADMA ( asymmetrical dimethylarginine ) , we hypothesized that the ratio between L-arginine and ADMA could be affected by experimental inflammation . Plasma concentrations of L-arginine , ADMA and SDMA ( symmetrical dimethylarginine ) were studied at baseline and 3.5 h after intravenous administration of Escherichia coli endotoxin [ LPS ( lipopolysaccharide ) , 20 units/kg of body mass ; n = 8 ] or placebo ( n = 9 ) in healthy males . L-Arginine and dimethylarginines were quantified after solid-phase extraction by reversed-phase HPLC . Body temperature , heart rate and leucocyte count increased after LPS administration ( P < 0.01 for all ) . LPS administration decreased plasma concentrations of L-arginine from 66 micromol/l [ 95 % CI ( confidence interval ) : 56 , 88 ] at baseline to 48 micromol/l ( CI : 40 , 60 ) after 3.5 h ( P < 0.02 ) , but did not affect ADMA and SDMA concentrations . Consequently , the L-arginine/ADMA ratio declined significantly from a median of 159 ( CI : 137 , 193 ) to 135 ( CI : 103 , 146 ) ; a decrease of 25 ( CI : -68 , -13 ; P < 0.02 ) . L-Arginine , ADMA , SDMA and the L-arginine/ADMA ratio remained constant over time in controls . Acute inflammation reduces the L-arginine/ADMA ratio which could contribute to impaired vascular function Objective To determine the effect of trauma on arginase , an arginine-metabolizing enzyme , in cells of the immune system in humans . Summary Background Data Arginase , classically considered an enzyme exclusive to the liver , is now known to exist in cells of the immune system . Arginase expression is induced in these cells by cytokines interleukin ( IL ) 4 , IL-10 , and transforming growth factor beta , corresponding to a T-helper 2 cytokine profile . In contrast , nitric oxide synthase expression is induced by IL-1 , tumor necrosis factor , and gamma interferon , a T-helper 1 cytokine profile . Trauma is associated with a decrease in the production of nitric oxide metabolites and a state of immunosuppression characterized by an increase in the production of IL-4 , IL-10 , and transforming growth factor beta . This study tests the hypothesis that trauma increases arginase activity and expression in cells of the immune system . Methods Seventeen severely traumatized patients were prospect ively followed up in the intensive care unit for 7 days . Twenty volunteers served as controls . Peripheral mononuclear cells were isolated and assayed for arginase activity and expression , and plasma was collected for evaluation of levels of arginine , citrulline , ornithine , nitrogen oxides , and IL-10 . Results Markedly increased mononuclear cell arginase activity was observed early after trauma and persisted throughout the intensive care unit stay . Increased arginase activity corresponded with increased arginase I expression . Increased arginase activity coincided with decreased plasma arginine concentration . Plasma arginine and citrulline levels were decreased throughout the study period . Ornithine levels decreased early after injury but recovered by postinjury day 3 . Increased arginase activity correlated with the severity of trauma , early alterations in lactate level , and increased levels of circulating IL-10 . Increased arginase activity was associated with an increase in length of stay . Plasma nitric oxide metabolites were decreased during this same period . Conclusions Markedly altered arginase expression and activity in cells of the human immune system after trauma have not been reported previously . Increased mononuclear cell arginase may partially explain the benefit of arginine supplementation for trauma patients . Arginase , rather than nitric oxide synthase , appears to be the dominant route for arginine metabolism in immune cells after trauma |
13,730 | 30,397,006 | Cupping was found to reduce neck pain in patients compared with no intervention or active control groups , or as an add-on treatment . | OBJECTIVES Neck pain is a significant condition that is second only to depression as a cause of years lived with disability worldwide .
Thus , identifying and underst and ing effective treatment modalities for neck pain is of heightened importance .
This systematic review aim ed to investigate the effects of cupping on neck pain from the current literature . | OBJECTIVES This was a r and omized controlled pilot trial to evaluate the effectiveness of cupping therapy for neck pain in video display terminal ( VDT ) workers . METHODS Forty VDT workers with moderate to severe neck pain were recruited from May , 2011 to February , 2012 . Participants were r and omly allocated into one of the two interventions : 6 sessions of wet and dry cupping or heating pad application . The participants were offered an exercise program to perform during the participation period . A 0 to 100 numeric rating scale ( NRS ) for neck pain , measure yourself medical outcome profile 2 score ( MYMOP2 score ) , cervical spine range of motion ( C-spine ROM ) , neck disability index ( NDI ) , the EuroQol health index ( EQ-5D ) , short form stress response inventory ( SRI-SF ) and fatigue severity scale ( FSS ) were assessed at several points during a 7-week period . RESULTS Compared with a heating pad , cupping was more effective in improving pain ( adjusted NRS difference : -1.29 [ 95 % CI -1.61 , -0.97 ] at 3 weeks ( p=0.025 ) and -1.16 [ -1.48 , -0.84 ] at 7 weeks ( p=0.005 ) ) , neck function ( adjusted NDI difference : -0.79 [ -1.11 , -0.47 ] at 3 ( p=0.0039 ) and 7 weeks ( p<0.0001 ) ) and discomfort ( adjusted MYMOP2 difference score : -0.72 [ -1.04 to -0.40 ] at 3 weeks and -0.92 [ -1.24 , -0.60 ] at 7 weeks ) . Significant improvement in EQ-5D was observed at 7 weeks ( 1.0 [ 0.88 , 1.0 ] with cupping and 0.91 [ 0.86 , 0.91 ] with heating pad treatment , p=0.0054 ) . Four participants reported mild adverse events of cupping . CONCLUSION Two weeks of cupping therapy and an exercise program may be effective in reducing pain and improving neck function in VDT workers Introduction . Cupping has been used since antiquity in the treatment of pain conditions . In this pilot study , we investigated the effect of traditional cupping therapy on chronic nonspecific neck pain ( CNP ) and mechanical sensory thresholds . Methods . Fifty CNP patients were r and omly assigned to treatment ( TG , n = 25 ) or waiting list control group ( WL , n = 25 ) . TG received a single cupping treatment . Pain at rest ( PR ) , pain related to movement ( PM ) , quality of life ( SF-36 ) , Neck Disability Index ( NDI ) , mechanical detection ( MDT ) , vibration detection ( MDT ) , and pressure pain thresholds ( PPT ) were measured before and three days after a single cupping treatment . Patients also kept a pain and medication diary ( PaDi , MeDi ) during the study . Results . Baseline characteristics were similar in the two groups . After cupping TG reported significantly less pain ( PR : −17.9 mm VAS , 95%CI −29.2 to −6.6 ; PM : −19.7 , 95%CI −32.2 to −7.2 ; PaDi : −1.5 points on NRS , 95%CI −2.5 to −0.4 ; all P < 0.05 ) and higher quality of life than WL ( SF-36 , Physical Functioning : 7.5 , 95%CI 1.4 to 13.5 ; Bodily Pain : 14.9 , 95%CI 4.4 to 25.4 ; Physical Component Score : 5.0 , 95%CI 1.4 to 8.5 ; all P < 0.05 ) . No significant effect was found for NDI , MDT , or VDT , but TG showed significantly higher PPT at pain- areas than WL ( in lg(kPa ) ; pain-maximum : 0.088 , 95%CI 0.029 to 0.148 , pain-adjacent : 0.118 , 95%CI 0.038 to 0.199 ; both P < 0.01 ) . Conclusion . A single application of traditional cupping might be an effective treatment for improving pain , quality of life , and hyperalgesia in CNP Background : Chronic neck pain is a major public health burden with only limited evidence for the effectiveness of complementary therapies . This study aim ed to test the efficacy of cupping massage in patients with neck pain . Patients and Methods : Patients with chronic non-specific neck pain were r and omly assigned to cupping massage or a wait list control . The intervention group received 5 cupping massages on a twice-weekly basis while the control patients continued their usual treatments . The primary outcome measure was neck pain intensity ( 0 - 100 mm visual analogue scale ( VAS ) ) after 3 weeks . Secondary outcomes included pain on movement , functional disability , health-related quality of life , mechanical detection and pain thresholds and adverse events . Results : 50 patients ( 52.6 ± 10.3 years , 92 % female ) were r and omised to either cupping massage or a wait list ( N = 25 each ) . Patients in the cupping group reported significantly less neck pain post intervention ( difference per protocol -14.3 mm , 95 % confidence interval ( CI ) -27.7 to -1.0 , p = 0.037 ; difference intention-to-treat -10.8 mm , 95 % CI -21.5 to -0.1 , p = 0.047 ) . Significant group differences in favour of the intervention were further found for pain on movement ( p = 0.019 ) and functional disability ( p < 0.001 ) , the quality -of-life subscales pain ( p = 0.002 ) and mental health ( p = 0.003 ) and the mental component summary ( p = 0.036 ) . Changes were also found for pressure pain sensitivity at the site of maximal pain ( p = 0.022 ) . Five adverse events were reported . Conclusions : Cupping massage appears to be effective in reducing pain and increasing function and quality of life in patients with chronic non-specific neck pain . More rigorous studies are needed to confirm and extend these results Chronic neck pain is a major public health problem with very few evidence -based complementary treatment options . This study aim ed to test the efficacy of 12 weeks of a partner-delivered home-based cupping massage , compared to the same period of progressive muscle relaxation in patients with chronic non-specific neck pain . Patients were r and omly assigned to self-directed cupping massage or progressive muscle relaxation . They were trained and asked to undertake the assigned treatment twice weekly for 12 weeks . Primary outcome measure was the current neck pain intensity ( 0–100 mm visual analog scale ; VAS ) after 12 weeks . Secondary outcome measures included pain on motion , affective pain perception , functional disability , psychological distress , wellbeing , health-related quality of life , pressure pain thresholds and adverse events . Sixty one patients ( 54.1±12.7 years ; 73.8%female ) were r and omized to cupping massage ( n = 30 ) or progressive muscle relaxation ( n = 31 ) . After treatment , both groups showed significantly less pain compared to baseline however without significant group differences . Significant effects in favor of cupping massage were only found for wellbeing and pressure pain thresholds . In conclusion , cupping massage is no more effective than progressive muscle relaxation in reducing chronic non-specific neck pain . Both therapies can be easily used at home and can reduce pain to a minimal clinical ly relevant extent . Cupping massage may however be better than PMR in improving well-being and decreasing pressure pain sensitivity but more studies with larger sample s and longer follow-up periods are needed to confirm these results . Trial Registration Clinical Trials.gov OBJECTIVES To determine the efficacy of wet-cupping for treating persistent nonspecific low back pain . BACKGROUND Wet-cupping therapy is one of the oldest known medical techniques . It is still used in several contemporary societies . Very minimal empirical study has been conducted on its efficacy . DESIGN R and omized controlled trial with two parallel groups . Patients in the experimental group were offered the option of referral to the wet-cupping service ; all accepted that option . The control group received usual care . SETTING Medical clinic in Kermanshah , Iran . PARTICIPANTS In total , 98 patients aged 17 - 68 years with nonspecific low back pain ; 48 were r and omly assigned to experimental group and 50 to the control group . INTERVENTION Patients in the experimental group were prescribed a series of three staged wet-cupping treatments , placed at 3 days intervals ( i.e. , 0 , 3 , and 6 days ) . Patients in the control group received usual care from their general practitioner . MAIN OUTCOME MEASURES Three outcomes assessed at baseline and again 3 months following intervention : the McGill Present Pain Index , Oswestry Pain Disability Index , and the Medication Quantification Scale . RESULTS Wet-cupping care was associated with clinical ly significant improvement at 3-month follow-up . The experimental group who received wet-cupping care had significantly lower levels of pain intensity ( [ 95 % confidence interval ( CI ) 1.72 - 2.60 ] mean difference=2.17 , p<0.01 ) , pain-related disability ( 95 % CI=11.18 - 18.82 , means difference=14.99 , p<0.01 ) , and medication use ( 95 % CI=3.60 - 9.50 , mean difference=6.55 , p<0.01 ) than the control group . The differences in all three measures were maintained after controlling for age , gender , and duration of lower back pain in regression models ( p<0.01 ) . CONCLUSIONS Traditional wet-cupping care delivered in a primary care setting was safe and acceptable to patients with nonspecific low back pain . Wet-cupping care was significantly more effective in reducing bodily pain than usual care at 3-month follow-up Background In this preliminary trial we investigated the effects of dry cupping , an ancient method for treating pain syndromes , on patients with chronic non-specific neck pain . Sensory mechanical thresholds and the participants ' self-reported outcome measures of pain and quality of life were evaluated . Methods Fifty patients ( 50.5 ± 11.9 years ) were r and omised to a treatment group ( TG ) or a waiting-list control group ( WL ) . Patients in the TG received a series of 5 cupping treatments over a period of 2 weeks ; the control group did not . Self-reported outcome measures before and after the cupping series included the following : Pain at rest ( PR ) and maximal pain related to movement ( PM ) on a 100-mm visual analogue scale ( VAS ) , pain diary ( PD ) data on a 0 - 10 numeric rating scale ( NRS ) , Neck Disability Index ( NDI ) , and health-related quality of life ( SF-36 ) . In addition , the mechanical-detection thresholds ( MDT ) , vibration-detection thresholds ( VDT ) , and pressure-pain thresholds ( PPT ) were determined at pain-related and control areas . Results Patients of the TG had significantly less pain after cupping therapy than patients of the WL group ( PR : Δ-22.5 mm , p = 0.00002 ; PM : Δ-17.8 mm , p = 0.01 ) . Pain diaries ( PD ) revealed that neck pain decreased gradually in the TG patients and that pain reported by the two groups differed significantly after the fifth cupping session ( Δ-1.1 , p = 0.001 ) . There were also significant differences in the SF-36 subscales for bodily pain ( Δ13.8 , p = 0.006 ) and vitality ( Δ10.2 , p = 0.006 ) . Group differences in PPT were significant at pain-related and control areas ( all p < 0.05 ) , but were not significant for MDT or VDT . Conclusions A series of five dry cupping treatments appeared to be effective in relieving chronic non-specific neck pain . Not only subjective measures improved , but also mechanical pain sensitivity differed significantly between the two groups , suggesting that cupping has an influence on functional pain processing . Trial registration The trial was registered at clinical trials.gov ( NCT01289964 ) The research aim ed to investigate the effectiveness of cupping therapy ( CT ) in changes on skin surface temperature ( SST ) for relieving chronic neck and shoulder pain ( NSP ) among community residents . A single-blind experimental design constituted of sixty subjects with self-perceived NSP . The subjects were r and omly allocated to two groups . The cupping group received CT at SI 15 , GB 21 , and LI 15 acupuncture points , and the control group received no intervention . Pain was assessed using the SST , visual analog scale ( VAS ) , and blood pressure ( BP ) . The main results were SST of GB 21 acupuncture point raised from 30.6 ° C to 32.7 ° C and from 30.7 ° C to 30.6 ° C in the control group . Neck pain intensity ( NPI ) severity scores were reduced from 9.7 to 3.6 in the cupping group and from 9.7 to 9.5 in the control group . The SST and NPI differences between the groups were statistically significant ( P < 0.001 ) . One treatment of CT is shown to increase SST . In conjunction with the physiological effect the subjective experience of NSP is reduced in intensity . Further studies are required to improve the underst and ing and potential long-term effects of CT Background : Pneumatic pulsation therapy may combine the effects of cupping therapy and massage . This study investigated the effect of pneumatic pulsation therapy on chronic neck pain compared to st and ard medical care . Methods : 50 patients ( 79.15 % female ; 46.17 ± 12.21 years ) with chronic nonspecific neck pain were r and omized to treatment group ( TG ; n = 25 ) or control group ( CG ; n = 25 ) . The TG received 5 pneumatic pulsation treatments over a period of 2 weeks utilizing a mechanical device . Treatment was applied as a combination of moving and stationary pulsating cupping . Main outcome measure was pain intensity in pain diaries ( numerical rating scale ) . Secondary outcome measures included functional disability ( NDI ) , quality of life ( SF-36 ) , and pain at motion . Sensory thresholds , including pressure pain threshold , were measured at pain-related sites . Results : After the intervention , significant group differences occurred regarding pain intensity ( baseline : 4.12 ± 1.45 in TG and 4.20 ± 1.57 in CG ; post-intervention : 2.72 ± 1.62 in TG and 4.44 ± 1.96 in CG ; analysis of covariance : p = 0.001 ) , NDI ( baseline : 25.92 ± 8.23 and 29.83 ; post-intervention : 20.44 ± 10.17 and 28.83 ; p = 0.025 ) , and physical quality of life ( baseline : 43.85 ± 7.65 and 41.66 ± 7.09 ; post-intervention : 47.60 ± 7.93 and 40.49 ± 8.03 ; p = 0.002 ) . Further significant group differences were found for pain at motion ( p = 0.004 ) and pressure pain threshold ( p = 0.002 ) . No serious adverse events were reported . Conclusion : Pneumatic pulsation therapy appears to be a safe and effective method to relieve pain and to improve function and quality of life in patients with chronic neck pain |
13,731 | 30,914,471 | Limited evidence hindered recommendations on alpha-2-agonists .
Inconsistent evidence was found in the studies investigating pregabalin and transversus abdominis plane block , and no evidence was found for intraperitoneal local anesthetics , port site infiltration , or single-port laparoscopy .
Measures to lower peritoneal insufflation pressure or humidify or heat insufflated gas seem to reduce the incidence of shoulder pain , but not abdominal pain . | Background and objectives Laparoscopic hysterectomy is increasingly performed because it is associated with less postoperative pain and earlier recovery as compared with open abdominal hysterectomy .
The aim of this systematic review was to evaluate the available literature regarding the management of pain after laparoscopic hysterectomy . | STUDY OBJECTIVE To compare operative outcomes and postoperative pain of laparoscopic hysterectomy ( LH ) versus minilaparoscopic hysterectomy ( MLH ) . DESIGN R and omized controlled trial ( Canadian Task Force Classification I ) . SETTING Tertiary care center . PATIENTS Seventy-six women scheduled to undergo a hysterectomy for a supposed benign gynecologic condition . INTERVENTIONS Participants were r and omly assigned to LH ( n = 38 ) or MLH ( n = 38 ) . MLH was performed with use of 3-mm ports . Both patients and assessors of the postoperative outcomes were blinded to the size of port used , and patients ' wounds were concealed by st and ard-size nontransparent dressings . MEASUREMENTS Primary outcome was postoperative pain ( both rest and incident on coughing and abdominal pain , as well as shoulder pain ) by use of a 100-mm visual analogue scale . MAIN RESULTS The two groups were similar in terms of operative outcomes . No intraoperative conversion from MLH to both LH and open surgery occurred . No significant difference in pain scores at 1 , 3 , 8 , and 24 hours after surgery between groups was found . Rescue analgesic requirement was similar in the MLH and LH groups ( 21.1 % vs 13.2 % , p = .54 ) . CONCLUSIONS Ports can safely be reduced in size without a negative impact on the surgeon 's ability to perform LH . MLH appears to have no advantage over LH in terms of postoperative pain Objective The aim of this study was to investigate the optimum dosage of dexmedetomidine for prevention of postanesthetic shivering . Methods One-hundred thirty two ASA physical status I-II patients scheduled for elective laparoscopic total hysterectomy were enrolled in this r and omised , placebo-controlled study . Patients were r and omly allocated to receive dexmedetomidine in four groups : group S ( 0.9 % normal saline ) , group D0.5 ( dexmedetomidine 0.5 µg/kg ) , group D0.75 ( dexmedetomidine 0.75 µg/kg ) , group D1.0 ( dexmedetomidine 1.0 µg/kg ) . Time to extubation and tympanic temperature during and after operation were measured . Shivering was grade d ( 0 - 3 scale ) upon patients arrival to the PACU and every ten minutes thereafter up to forty minutes . Sedation and first rescue analgesic time at the PACU were evaluated . Results The incidence of shivering was significantly lower in group D0.75 and D1.0 than in group S ( P < 0.05 ) . There were significantly fewer patients with a shivering score of 2 or 3 in groups D0.75 and D1.0 than in group S ( P < 0.05 , P < 0.001 ) . Extubation time was shorter in group S than in groups D0.75 and D1.0 ( P < 0.05 ) . Tympanic temperature at 40 minutes postoperatively in the recovery room was higher in group S than in the other dexmedetomidine groups ( P < 0.05 ) Fewer patients required rescue analgesia in groups D0.75 and D1.0 than in group S ( P < 0.001 ) , and the time to rescue analgesia was longer in group D1.0 than in group S ( P < 0.001 ) . Modified Observer 's Assessment of Alertness/Sedation ( MOAA/S ) at arrival in the PACU was lower in all dexmedetomidine groups than in group S ( P < 0.05 ) . Conclusions Our results suggest that dexmedetomidine 0.75 or 1.0 µg/kg provides effective prophylaxis against postoperative shivering as well as an analgesic effect . Though potential for intraoperative requirement for atropine , sedation in the immediate recovery period and delayed extubation time with dexmedetomidine was noted , there were no major clinical impacts on the overall recovery from anesthesia BACKGROUND : In this r and omized , controlled , observer-blinded study , we evaluated analgesia provided by transversus abdominis plane ( TAP ) block after elective total laparoscopic hysterectomy in terms of reduced postoperative morphine consumption as the primary end point . METHODS : Fifty-two patients were r and omly divided into 2 groups : patients in group T ( TAP , n = 26 ) received an ultrasound-guided bilateral TAP block with 40 mL of 0.375 % levobupivacaine and morphine patient-controlled analgesia , whereas patients in group C ( control , n = 26 ) received morphine patient-controlled analgesia . Secondary outcomes included pain measurements ( Numeric Rating Scale from 0 to 10 ) during the first 24 hours postoperatively , times to postanesthesia care unit discharge , times to surgical ward discharge , incidence of postoperative nausea and vomiting , functional capacity measurements in terms of 2-minute walking test , and first oral solid intake . RESULTS : Demographic and anthropometric variables were similar in the 2 groups . The total dose of morphine consumed by patients during postanesthesia care unit stay was 6 ( 0–8 ) mg in group T vs 8 ( 5.5–8.5 ) mg in group C ( P = 0.154 ) . Postoperative morphine consumption during the first 24 hours was 10.55 ± 10.24 mg in group C vs 10.73 ± 13.45 mg in group T ( P = 0.950 ) . The 95 % confidence interval of the difference between means of 24-hour morphine consumption was −7.45 to + 7.09 . The 2 groups were comparable . There were no significant differences in secondary outcome variables between groups . CONCLUSIONS : TAP block did not reduce morphine consumption during the first postoperative 24 hours after elective total laparoscopic hysterectomy STUDY OBJECTIVE To compare the use of low pneumoperitoneum pressure ( LPP ; 8 mm Hg ) vs st and ard pneumoperitoneum pressure ( SPP ; 12 mm Hg ) during mini-laparoscopic hysterectomy ( MLH ) . DESIGN R and omized controlled trial ( Canadian Task Force classification I ) . SETTING Tertiary care center . PATIENTS Forty-two consecutive women scheduled to undergo MLH to treat benign uterine disease . INTERVENTIONS Women were r and omly selected to undergo MLH using LPP ( n = 20 ) or SPP ( n = 22 ) . MLH was performed via 3-mm ancillary ports . MEASUREMENTS AND MAIN RESULTS The primary outcome was to evaluate changes in abdominal and shoulder-tip pain via a 100-mm visual analog scale at 1 , 3 , and 24 hours postoperatively . All procedures were completed via mini-laparoscopy without the need to increase intra-abdominal pressure or convert to conventional laparoscopy or open surgery . Intraoperatively , 1 episode of severe bradycardia occurred in the LPP group , whereas no intraoperative complications were recorded in the SPP group ( p = .47 ) . No postoperative complications were recorded ( p > .99 ) . Abdominal pain was similar between groups at each time point . Incidence and intensity of shoulder-tip pain at 1 and 3 hours postoperatively was lower in the LPP group than in the SPP group ( p < .05 ) , whereas no between-group differences were observed at 24 hours ( p > .05 ) . Rescue analgesic requirement did not differ statistically between the LPP and SPP groups ( 20 % vs 41 % , respectively ; p = .19 ; odds ratio , 2.7 ; 95 % confidence interval , 0.69 - 11.08 ) . CONCLUSION In experienced h and s , use of LPP is safe and feasible . During performance of MLH , compared with SPP , LPP is a simple method that offers advantages of less shoulder-tip pain OBJECTIVE The objective of the study was to determine whether transversus abdominis plane ( TAP ) block reduces postoperative pain when compared with trocar site infiltration of bupivacaine in gynecological laparoscopy . STUDY DESIGN This was a prospect i ve , r and omized , double-blinded clinical trial using patients as their own controls . Women undergoing gynecologic laparoscopy using a 4-port symmetrical technique were r and omly assigned to right- or left-sided TAP block using 30 mL of 0.25 % bupivacaine with epinephrine . Two cohorts of patients were studied . Cohort 1 consisted of anesthesiologist-administered ultrasound-guided TAP block . Cohort 2 consisted of surgeon-administered laparoscopic-guided TAP block . In both cohorts , contralateral port sites were infiltrated with an equal amount of bupivacaine in divided doses . All patients received intraoperative acetaminophen and ketorolac . Postoperative abdominal pain was assessed at 1 , 2 , 4 , 6 , 8 , 12 , 18 , 24 , and 48 hours on the block and contralateral sides , before and after palpation , using the 10 point visual analog scale . A 2 point difference in the reported pain scores was considered clinical ly meaningful . RESULTS Eighty-eight patients were eligible for statistical analysis : 45 and 43 patients in cohorts 1 and 2 , respectively . In both cohorts , most patients reported equal pain on the block side and local side . In cohort 1 , there was a statistically significant difference in mean reported pain scores at 2 hours and across time favoring the ultrasound-guided block ; however , this did not reach clinical significance . There was no statistically significant difference found at all other time points or when pain scores were objective ly assessed after palpation of the incisions . When comparing laparoscopic-guided block with local infiltration , there was no statistically significant difference in reported mean pain scores at all time points or after palpation . CONCLUSION As part of this multimodal analgesic regimen , neither block method provided a significant clinical benefit compared with trocar site bupivacaine infiltration BACKGROUND : Apart from being antiemetic , glucocorticoids have an analgesic property . The optimal dose of dexamethasone in the management of pain after surgery has not been established . In this placebo-controlled , dose-finding study , we evaluated the analgesic effect of three doses of dexamethasone after laparoscopic hysterectomy . METHODS : We r and omized 129 women scheduled for laparoscopic hysterectomy to receive placebo , dexamethasone 5 mg ( D5 ) , 10 mg ( D10 ) , or 15 mg ( D15 ) IV before the induction of anesthesia . The patients were anesthetized with propofol and remifentanil in a st and ardized manner . Until the first postoperative morning , postoperative pain was managed with IV oxycodone using patient-controlled analgesia . The visual analog scale scores for pain and side effects , and the amounts of the analgesics were recorded for 3 days after surgery . RESULTS : The total dose of oxycodone ( 0–24 h after surgery ) was smaller in the D15 ( 0.34 mg/kg [ 0.11–0.87 ] ) group than in the placebo group ( 0.55 mg/kg [ 0.19–1.13 ] ) ( P = 0.003 ) . The doses of oxycodone during Hours 0–2 after surgery were smaller in the D10 ( 0.17 mg/kg [ 0.03–0.36 ] ) and D15 ( 0.17 mg/kg [ 0.03–0.35 ] ) groups than in the placebo ( 0.26 mg/kg [ 0.10–0.48 ] ) ( P = 0.001 , D10 versus placebo ; P < 0.001 , D15 versus placebo ) group . During Hours 2–24 after surgery , however , the doses of oxycodone were equal in the placebo , D5 , D10 , and D15 groups ( 0.31 mg/kg [ 0.03–0.78 ] , 0.22 mg/kg [ 0.03–0.92 ] , 0.24 mg/kg [ 0.05–0.87 ] , and 0.20 mg/kg [ 0–0.65 ] , respectively ) . The visual analog scale scores for pain at rest , in motion , or at cough did not differ in the study groups . The incidence of dizziness was lower in the D15 group than in the placebo group ( P = 0.001 ) , the D5 group ( P = 0.006 ) , and the D10 group ( P = 0.030 ) during the first 24 h after surgery . During the later course of recovery , the incidence of dizziness did not differ among the four study groups . CONCLUSIONS : IV dexamethasone 15 mg before induction of anesthesia decreases the oxycodone consumption during the first 24 h after laparoscopic hysterectomy . During first 2 h after surgery , dexamethasone 10 mg reduces the oxycodone consumption as effectively as the 15 mg dose PURPOSE The purpose of this study was to compare the effects of ondansetron combined with dexamethasone on Post-Operative Nausea and Vomiting ( PONV ) and pain with ondansetron alone in patients with laparoscopy assisted vaginal hysterectomy under general anesthesia . METHODS Data were collected from April 1 through September 30 , 2005 using a double blind method . Ondansetron 4 mg and dexamethasone 10 mg were administered to the experimental group ( 25 patients ) , and ondansetron 4 mg only to the control group ( 25 patients ) . The medications were administered through an intravenous line at the beginning peritoneum suture . PONV by Index of Nausea Vomiting and Retching ( INVR ) , nausea by Visual Analogue Scale ( VAS ) , and pain ( VAS ) were assessed at postoperative 1 hr , 3 hr , 6 hr , 24 hr , and 48 hr . Data were analyzed using repeated measures ANOVA , and Bonferroni methods . RESULTS The experimental group that received ondansetron combined with dexamethasone had less PONV ( p=.048 ) , and nausea ( p=.012 ) than control group that received ondansetron alone . However , there was no difference in pain ( p=.557 ) between the patients in the two groups . CONCLUSION We conclude that the administration of ondansetron combined with dexamethasone is more effective than the administration of ondansetron alone to reduce PONV in patients with laparoscopic hysterectomy Background This r and omized , double-blinded clinical study was design ed to evaluate the efficiency and safety of remifentanil with ketorolac for IV PCA after laparoscopic-assisted vaginal hysterectomy . Methods Eighty patients were r and omly allocated into four groups . Group R received IV PCA using only remifentanil at a basal rate of 0.025 µg/kg/min and a bolus of 0.375 µg/kg . Group RK1 received IV PCA using remifentanil at a basal rate of 0.015 µg/kg/min and a bolus of 0.225 µg/kg . Group RK2 received IV PCA using remifentanil at a basal rate of 0.0075 µg/kg/min and a bolus of 0.1125 µg/kg . Group F received IV PCA using fentanyl at a basal rate of 0.3 µg/kg/h and a bolus of 0.075 µg/kg . In addition , ketorolac at a basal rate of 0.04 mg/kg/h and a bolus of 0.01 mg/kg was added to Group RK1 , RK2 , and F. All PCA conditions had a lock out period of 15 minutes . Pulse rate , systolic and diastolic BP , sedation score , visual analogue scale ( VAS ) , and PONV score were recorded at 1 , 3 , 6 , 12 , and 24 hours after the operation . Total opioid use and the patients ' number for rescue analgesic drug were also collected . Results The groups did not differ in PONV score and hemodynamic changes . The VAS in Group RK2 was high compared with the other groups . In addition , the sedation score was high in Group R. Conclusions The additional ketorolac administration in remifentanil IV PCA had remifentanil sparing effects and reduced sedation among the side effects . Further studies will be needed to evaluate the precise and adequate dosage of ketorolac Background Nefopam is a non-opioid , non-steroidal , central ly acting analgesic drug . The concomitant use of opioids and nefopam is believed to have many advantages over the administration of opioids alone for postoperative pain management . We conducted a r and omized , double-blind study to determine the fentanyl-sparing effect of co-administration of nefopam with fentanyl for postoperative pain management via patient controlled analgesia ( PCA ) . Methods Ninety female patients who underwent laparoscopic total hysterectomy under general anesthesia were r and omized into 3 groups , Group A , fentanyl 1,000 µg ; Group B , fentanyl 500 µg + nefopam 200 mg ; and Group C , fentanyl 500 µg + nefopam 400 mg , in a total volume of 100 ml PCA to be administered over the first 48 h postoperatively without basal infusion . The primary outcome was total fentanyl consumption during 48 h ; secondary outcomes included pain scores and incidence of side effects . Results Eighty-one patients were included in the analysis . The overall fentanyl-sparing effects of PCA with concomitant administration of nefopam during the first 48 h postoperatively were 54.5 % in Group B and 48.9 % group C. Fentanyl use was not significantly different between Groups B and C despite the difference in the nefopam dose . There were no differences among the three groups in terms of PCA-related side effects , although the overall sedation score of Group B was significantly lower than that of Group A. Conclusions The concomitant administration of nefopam with fentanyl for postoperative pain management may allow reduction of fentanyl dose , thereby reducing the risk of opioid-related adverse effects STUDY OBJECTIVE To evaluate if preincision infiltration with extended-release liposomal bupivacaine provides improved overall pain relief compared with 0.25 % bupivacaine after laparoscopic or robotic-assisted hysterectomy . DESIGN A single-center double-masked r and omized controlled trial ( Canadian Task Force Classification I ) . SETTING A tertiary-care community hospital . PATIENTS Patients recruited from July 2015 through January 2016 . Sixty-four patients were r and omized , and 59 were analyzed for the primary outcome . INTERVENTIONS Women scheduled to undergo multiport laparoscopic or robotic-assisted total hysterectomy for benign indications were r and omized to receive preincision infiltration with undiluted liposomal bupivacaine or 0.25 % bupivacaine . MEASUREMENTS AND MAIN RESULTS The primary outcome was overall average pain intensity by numeric rating scale ( 0 - 10 ) using the Brief Pain Inventory ( BPI ) via telephone survey on postoperative day ( POD ) 3 . A sample size of 28 per group ( N = 56 ) was planned to detect a 30 % change in pain scores . Secondary outcomes were overall average and worst numeric pain scores on PODs 1 , 2 , and 14 ; pain scores in hospital ; BPI pain interference scores ; and total opioid use . There were no demographic differences between the 2 groups . For the primary outcome , we found a decrease in the average ( p = .02 ) pain scores on POD 3 in the liposomal bupivacaine group . We also found a decrease in worst pain scores on POD 2 ( p = .03 ) and POD 3 ( p = .01 ) . There were no differences in pain scores while in the hospital or on POD 1 or POD 14 . There were no differences in BPI pain interference scores , opioid use , or reported adverse effects . CONCLUSION For laparoscopic and robotic-assisted multiport hysterectomies , there is evidence of decreased average postoperative pain with liposomal bupivacaine compared with 0.25 % bupivacaine for port-site analgesia on POD 3 , but no difference in opioid use or measures of functioning Background We planned to compare the effect of intravenous oxycodone and fentanyl on post-operative pain after laparoscopic hysterectomy . Methods We examined 60 patients were r and omized to postoperative pain treatment with either oxycodone ( n = 30 , Group O ) or fentanyl ( n = 30 , Group F ) . The patients received 10 mg oxycodone/100 µg fentanyl with ketorolac 30 mg before the end of anesthesia and then continued with patient-controlled analgesia for 48 h postoperatively . Results The accumulated oxycodone consumption was less than fentanyl during 8 , 24 and 48 h postoperatively . Numeric rating score of Group O showed significantly lower than that of Group F during 30 min , 2 , 4 , 8 and 24 h postoperatively . The incidences of adverse reactions were similar in the two groups , though the incidence of nausea was higher in the Group O during the 24 and 48 h postoperative period . Conclusions Oxycodone IV-PCA was more advantageous than fentanyl IV-PCA for laparoscopic hysterectomy in view of accumulated oxycodone consumption , pain control and cost beneficial effect . However , patient satisfaction was not good in the group O compared to group OBJECTIVE : To compare transumbilical single-port laparoscopic hysterectomy ( TSPLH ) with traditional four-port total laparoscopic hysterectomy ( TLH ) . METHODS : Patients with benign uterine disease were assigned to receive either TSPLH ( n = 52 ) or TLH ( n = 56 ) . Duration of surgery , intraoperative blood loss , conversion rate , time to first flatus , duration of immobilization , post-operative analgesia requirement , port site infection , port hernia , duration of hospital stay , postoperative fever rate and percentage patient satisfaction were recorded . RESULTS : TSPLH and TLH were both performed successfully . TSPLH was associated with significantly longer duration of surgery , shorter duration of immobilization , lower rate of port site infection and higher patient satisfaction than TLH . There were no other significant differences between the two groups . All subjects recovered fully and no postoperative complications occurred during a 6-month ( minimum ) follow-up period . CONCLUSIONS : TSPLH was found to be a feasible and safe approach for laparoscopic hysterectomy STUDY OBJECTIVE To compare perioperative outcomes and postoperative pain of minilaparoscopic ( M-LPS ) and laparoendoscopic single-site total hysterectomy ( LESS ) . DESIGN Prospect ively r and omized study ( Canadian Task Force classification II-2 ) . SETTING Department of Obstetrics and Gynecology , Division of Gynecologic Oncology , Catholic University of the Sacred Heart , Rome . PATIENTS A total of 86 patients underwent total hysterectomy . Seventy-one met the inclusion criteria and were included in this study . Three of them refused r and omization , 34 were r and omly assigned to undergo to single-port hysterectomy and 34 to undergo to minilaparoscopy . INTERVENTIONS The operative technique is the same in the 2 groups with the exception of videolaparoscopy , port type , and some specific instruments . All surgical procedures were performed with an intrauterine manipulator . Single-port hysterectomy was performed through a multichannel single trocar inserted in the umbilicus . Minilaparoscopic hysterectomy was performed through one optical transumbilical 5-mm trocar and three 3-mm suprapubic ancillary ports . MEASUREMENTS AND MAIN RESULTS Sixty-eight patients met the inclusion criteria and were enrolled in the study . The baseline characteristics of the 2 groups were comparable . Median operative time was longer in LESS with respect to M-LPS ( 120 minutes vs 90 minutes ; p = .038 ) . There were no differences between the 2 groups for median estimated blood loss , ileus , and postoperative stay . Additional 5-mm port insertion was needed in 1 case ( 2.9 % ) in the M-LPS group and in 2 cases ( 5.9 % ) in the LESS group , respectively ( p = .311 ) . No patient had development of intraoperative or early postoperative complications . Patients in the M-LPS group experienced a minor pain at each evaluation , compared with patients who underwent LESS . The rescue analgesic requirement was similar in the 2 groups . CONCLUSIONS Laparoscopic hysterectomy can be safely performed by M-LPS and LESS . M-LPS is associated with significantly lower operative time and less postoperative pain than LESS . Advantages of M-LPS hysterectomy than LESS have no noteworthy impact on the patients ' early postoperative management . The decision on the best access to the hysterectomy might take into account the surgeon 's skill and feeling with the different possible approaches STUDY OBJECTIVE To determine if the use of a 5-mm umbilical incision and laparoscope would result in a higher likelihood of earlier discharge from hospital after total laparoscopic hysterectomy ( TLH ) compared with a 10-mm umbilical incision and laparoscope . Secondary objectives of the study were to determine if the use of a 5-mm laparoscope would lead to a reduction in postoperative pain scores and a shorter operating time without an increase in complication rates . DESIGN Prospect i ve , r and omized , double-blinded , clinical trial ( Canadian Task Force classification I ) . SETTING A tertiary care setting . PATIENTS Seventy-eight patients scheduled for TLH were prospect ively recruited . INTERVENTIONS Women undergoing TLH were assigned to either a 5-mm umbilical port and laparoscope ( 5LH ) or a 10-mm umbilical port and laparoscope ( 10LH ) . All patients underwent a st and ardized operative technique and anesthetic protocol . Patients and research assistants responsible for postoperative pain assessment were blinded to group . Analysis was by intention-to-treat . MEASUREMENTS AND MAIN RESULTS The primary outcome measure was length of hospital stay . Secondary outcome measures were operating time , pain scores on postoperative days 1 and 7 , and complication rates . There was no difference in length of hospital stay between the 2 arms . Compared with the 10LH group , the 5LH group had shorter operative times ( 32.6 vs 40 minutes ; p = .01 ) and less postoperative pain on day 1 ( 2.5 vs 3.3 ; p = .03 for " pain with movement " ) and on day 7 ( .92 vs 1.8 ; p = .002 ) . Complication rates were similar between the 2 groups . CONCLUSION TLH with a 5-mm laparoscope result ed in shorter operative times and less pain on postoperative days 1 and 7 , compared with a 10-mm laparoscope , with similar length of stay and complications STUDY OBJECTIVE To compare operative time with use of THUNDERBEAT ( TB ) vs st and ard electrosurgery ( SES ) during laparoscopic radical hysterectomy and pelvic lymphadenectomy to treat gynecologic tumors . DESIGN Evidence obtained from a properly design ed , r and omized , controlled trial ( Canadian Task Force classification I ) . SETTING Gynecologic Oncology Unit of the Catholic University of the Sacred Heart in Rome , Italy . PATIENTS Fifty patients with early cervical cancer ( FIGO stages IA2 , IB1 , IIA < 2 cm ) or locally advanced cervical cancer ( FIGO stages IB2 , IIA > 2 cm , IIB ) who received neoadjuvant treatment ( chemotherapy or radiochemotherapy ) and demonstrated a complete or partial clinical response and early stage endometrioid endometrial cancer ( FIGO stages IB , II ) were r and omly assigned to undergo TB ( arm A ) or SES ( arm B ) . INTERVENTION Laparoscopic radical hysterectomy with bilateral pelvic lymphadenectomy , using an easily reproducible technique was performed . MEASUREMENTS AND MAIN RESULTS Fifty patients were available for analysis , with 25 women r and omly assigned to TB ( arm A ) and 25 to SES ( arm B ) . The median operative time was 85 minutes for TB vs 115 minutes for SES ( p = .001 ) . At multivariate analysis , endometrial cancer ( p = .001 ) and TB ( p = .001 ) were independently associated with shorter operating time . No differences in perioperative outcomes and postoperative complications were observed between the 2 arms . Patients who underwent TB reported less postoperative pain , both at rest ( p = .005 ) and after the Valsalva maneuver ( p = .008 ) , with less additional analgesic therapy other than st and ard therapy required in patients who underwent SES ( p = .02 ) . CONCLUSION TB is associated with shorter operative time and less postoperative pain than is the st and ard technique ( SES ) in patients with uterine cancer OBJECTIVE : To examine the effect of a preoperative transversus abdominis plane infiltration on postoperative quality of recovery and analgesia in patients undergoing laparoscopic hysterectomy . METHODS : The study was a r and omized , double-blinded , placebo-controlled trial . Seventy-five healthy women were r and omized to receive a preoperative infiltration with 0.5 % ropivacaine , 0.25 % ropivacaine , or saline . Postoperative quality of recovery score ( QoR-40 ) , pain , and opioid consumption were assessed up to 24 hours after the surgical procedure . Data were analyzed using Kruskal-Wallis test . Post hoc pair-wise comparisons were made using Dunn test . P<.05 was required to reject the null hypothesis . RESULTS : Sixty-six patients completed the study . Patients ' baseline characteristics and surgical factors were not different between groups . The ropivacaine group experienced a better quality recovery and less postoperative pain than the saline group . The median difference ( 99.2 % confidence interval ) in global recovery scores at 24 hours after surgery was 28 ( QoR score 4–39 , P=.001 ) for ropivacaine 0.5 % and 28 ( QoR score 10–43 , P<.001 ) for ropivacaine 0.25 % compared with saline , respectively . The 0.5 % ropivacaine group also had less pain , lower opioid consumption , and faster postanesthesia care unit discharge than the saline group . Linear regression demonstrated an inverse relationship between opioid consumption and global quality of recovery at 24 hours ( P<.001 ) . CONCLUSION : The transversus abdominis plane infiltration improves quality of recovery . There was an inverse linear relationship between postoperative opioid consumption and quality of recovery . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT01074229 . LEVEL OF EVIDENCE : This prospect i ve , r and omized , double-blind study compared the effects of dexmedetomidine and remifentanil on haemodynamic stability , sedation and postoperative pain control in the postanaesthetic care unit ( PACU ) . Fifty consecutive patients scheduled for total laparoscopic hysterectomy were r and omly assigned to receive infusions of either dexmedetomidine ( 1 μg/kg ) i.v . over 10 min followed by 0.2 - 0.7 μg/kg per h continuous i.v . infusion or remifentanil ( 0.8 - 1.2 μg/kg ) i.v . over 1 min followed by 0.05 - 0.1 μg/kg i.v . per min , starting at the end of surgery to the time in the PACU . Modified observer 's assessment of alertness scores were significantly lower in the dexmedetomidine group than in the remifentanil group at 0 , 5 and 10 min after arrival in the PACU . Blood pressure and heart rate in the dexmedetomidine group were significantly lower than that recorded in the remifentanil group in the PACU . Dexmedetomidine , at the doses used in this study , had a significant advantage over remifentanil in terms of postoperative haemodynamic stability Aims and objectives To compare the three techniques of hysterectomy — total laparoscopic hysterectomy ( TLH ) , laparoscopic assisted vaginal hysterectomy ( LAVH ) and non-descent vaginal hysterectomy ( NDVH ) . Material s and methods Ninety women with benign disease of uterus with failed medical management or not amenable to medical management were r and omised into three groups for either technique of hysterectomy , thirty in each group , by the same surgeon . For each patient , intra-operative parameters including total duration of surgery , blood loss , surgical difficulty and intra-operative complications were recorded . Total hospital stay , adverse events , satisfaction rate and recuperation time was analysed and compared . Statistical analysis was done using SPSS15 software . Results Non-descent vaginal hysterectomy ( NDVH ) took least operative time and significantly lesser blood loss ( p = 0.02 ) compared to TLH and LAVH . There was no significant difference between adverse events , recuperation time and postoperative pain between the three techniques . Conclusions Non-descent vaginal hysterectomy may be a preferred technique over laparoscopic hysterectomy for benign diseases of uterus where extensive pelvic dissection is not required Background Postoperative nausea and vomiting ( PONV ) commonly occur after general anesthesia , especially in women . In this study , we evaluated the antiemetic efficacy of propofol administered at the end of surgery in highly susceptible patients undergoing a laparoscopy-assisted vaginal hysterectomy . Methods A total of 107 women undergoing a laparoscopy-assisted vaginal hysterectomy under general anesthesia were enrolled for this prospect i ve , double-blind , r and omized study . Fifteen minutes before the end of surgery , all patients received 50 µg fentanyl and 1 of following 3 doses ; 0.5 mg/kg of propofol ( propofol 0.5 group ) , 1 mg/kg of propofol ( propofol 1.0 group ) , and normal saline ( control group ) . All patients received intravenous patient-controlled analgesia ( PCA ) . Emergence time , a visual analog scale for pain and nausea , duration of postanesthesia care unit ( PACU ) stay , and frequency of antiemetic use were recorded at 0 - 2 , 2 - 24 , and 24 - 48 hours postoperatively . Results The incidence of nausea significantly lower in the propofol 0.5 and propofol 1.0 groups than in the control group ( 12.1 vs 14.7 vs 40 % ) . During the first postoperative 2 hours , antiemetics were less frequently administered in the propofol 0.5 and propofol 1.0 groups than in the control group ( 3.0 vs 5.9 vs 22.5 % ) . Emergence time was slightly longer in the propofol 0.5 and propofol 1.0 groups than in the control group , but there was no significant difference in PACU stay time was observed between the 3 groups . Conclusions The results of this study suggest that low-dose propofol administration at the end of surgery may effectively reduce the incidence of PONV within 2 hours postoperatively in highly susceptible women undergoing a laparoscopiy-assisted vaginal hysterectomy and receiving opioid-based PCA Background Coughing , hypertension , tachycardia , and even laryngospasm can occur due to airway irritation during emergence from anesthesia . We investigated the effect of maintaining a sufentanil infusion during emergence from anesthesia by evaluating the incidence of cough and recovery profiles at extubation . Methods In total , eighty-four patients undergoing an elective laparoscopic hysterectomy were r and omly divided into two sufentanil groups and a control group . During emergence , sufentanil was administered in the sufentanil groups at a rate of 0.2 µg/kg/hr ( Group S1 ) or 0.3 µg/kg/hr ( Group S2 ) , and saline was administered to the control group . Cough score , hemodynamic changes , and recovery profiles , such as duration from skin closure to a bispectral index of 80 , to eye opening at verbal comm and , to tracheal extubation and the total duration of study solution infusion , were recorded . The pain score , the total volume of administered patient-controlled analgesia ( PCA ) , and the postoperative nausea and vomiting ( PONV ) score were evaluated 1 , 6 , and 24 hours after surgery . Results Groups S1 and S2 showed significantly lower cough scores and smaller hemodynamic changes on extubation compared to Group C. Recovery profiles showed no significant differences among the three groups . Pain score , PONV at 1 hour postoperatively , and the total volume of PCA administered at all evaluation times were significantly lower in Groups S1 and S2 than in the control group . However , pain score , and PONV at 6 hours and 24 hours postoperatively showed no significant differences . Conclusions A sufentanil infusion ( 0.2 - 0.3 µg/kg/hr ) during emergence from desflurane anesthesia may suppress coughing on extubation in patients with body mass indexes ( BMI ) of 21 - 26 without delaying extubation time . It may also reduce the postoperative analgesic requirement without increasing PONV Background . We tested the hypothesis that warm-humidified carbon dioxide ( CO2 ) insufflation would reduce postoperative pain and morphine requirement compared to cold-dry CO2 insufflation . Methods . A double-blinded , r and omized , controlled trial was conducted to compare warm , humidified CO2 and cold-dry CO2 . Patients with benign uterine diseases were r and omized to either treatment ( n = 48 ) or control ( n = 49 ) group during laparoscopically assisted vaginal hysterectomy . Primary endpoints of the study were rest pain , movement pain , shoulder-tip pain , and cough pain at 2 , 4 , 6 , 24 , and 48 hours postoperatively , measured by visual analogue scale . Secondary outcomes were morphine consumption , rejected boli , temperature change , recovery room stay , and length of hospital stay . Results . There were no significant differences in all baseline characteristics . Shoulder-tip pain at 6 h postoperatively was significantly reduced in the intervention group . Pain at rest , movement pain , and cough pain did not differ . Total morphine consumption and rejected boli at 24 h postoperatively were significantly higher in the control group . Temperature change , recovery room stay , and length of hospital were similar . Conclusions . Warm , humidified insufflation gas significantly reduces postoperative shoulder-tip pain as well as morphine dem and . This trial is registered with Clinical Trial Registration Number DRKS00003853 ( German Clinical Trials Register ( DRKS ) ) Background Opioids are widely used in boluses and patient-controlled analgesia ( PCA ) for postoperative pain control . In this study , we compared the effects of oxycodone and fentanyl on postoperative pain in patients with intravenous patient-controlled analgesia ( IV-PCA ) after laparoscopic gynecological surgery . Methods Seventy-four patients undergoing elective total laparoscopic hysterectomy or laparoscopic myomectomy were r and omly assigned to the administration of either fentanyl or oxycodone using IV-PCA ( potency ratio 1 : 60 ) . The cumulative dose administered in the patient-controlled mode during the initial 48 hours after the operation was measured . Patients were also assessed for postoperative pain severity , adverse effects , and patient satisfaction . Results No significant differences were observed in patient satisfaction with the analgesia during the postoperative period . Patients in the oxycodone group experienced significantly more dizziness compared to the fentanyl group . Patients in the oxycodone group showed significantly lower consumption of opioid in the patient-controlled mode ( 10.1 ± 8.5 ml vs. 16.6 ± 12.0 ml , P = 0.013 ) . Conclusions Our data suggest that oxycodone and fentanyl demonstrated similar effects , and therefore oxycodone may be a good alternative to fentanyl in postoperative pain management . Further studies in various clinical setting s will be needed to determine the adequate potency ratio Background . Total laparoscopic hysterectomy ( TLH ) causes various types of postoperative pain , and the pain pattern has not been evaluated in detail to date . This prospect i ve observational study investigated the types of postoperative pain , intensity in the course of time , and pain characteristics during the first postoperative 72 hr after TLH . Methods . Sixty four female patients undergoing TLH were enrolled , which finally 50 patients were included for the data analyses . The locations of pain included overall pain , abdominal visceral and incisional pains , shoulder pain , and perineal pain . Assessment s were made at rest and in motion , and pain level was scored with the use of the 100 mm visual analog scale . The pain was assessed at baseline , and at postoperative 30 min , 1 hr , 3 hr , 6 hr , 24 hr , 48 hr , and 72 hr . Results . Overall , visceral , and incisional pains were most intense on the day of operation and then decreased following surgery . In contrast , shoulder pain gradually increased , peaking at postoperative 24 hr . Shoulder pain developed in 90 % of all patients ( 44/50 ) . It was not more aggravated in motion than at rest , in comparison with other pains , and right shoulder pain was more severe than left shoulder pain ( p=0.006 ) . In addition , the preoperative exercise habit of patients increased the threshold of shoulder pain . Most patients ( 46/50 ) had perineal pain , which was more severe than abdominal pain in approximately 30 % of patients ( 17/50 ) . Conclusion . Pain after TLH showed considerably different duration , severity , and characteristics , compared with other laparoscopic procedures . Shoulder pain was most intense at postoperative 24 hr , and the intensity was associated with the prior exercise habit of patients and the high level of analgesic request Background : Oxycodone , a semisynthetic thebaine derivative opioid , is widely used for the relief of moderate to severe pain . The aim of this study was to compare the efficacy and side effects of oxycodone and fentanyl in the management of postoperative pain by intravenous patient-controlled analgesia ( IV-PCA ) in patients who underwent laparoscopic supracervical hysterectomy ( LSH ) . Methods : The 127 patients were r and omized to postoperative pain treatment with either oxycodone ( n = 64 , group O ) or fentanyl group ( n = 63 , group F ) . Patients received 7.5 mg oxycodone or 100 & mgr;g fentanyl with 30-mg ketorolac at the end of anesthesia followed by IV-PCA ( potency ratio 75:1 ) for 48 hours postoperatively . A blinded observer assessed postoperative pain based on the numerical rating scale ( NRS ) , infused PCA dose , patient satisfaction , sedation level , and side effects . Results : Accumulated IV-PCA consumption in group O was less ( 63.5 ± 23.9 mL ) than in group F ( 85.3 ± 2.41 mL ) during the first 48 hours postoperatively ( P = 0.012 ) . The NRS score of group O was significantly lower than that of group F at 4 and 8 hours postoperatively ( P < .001 ) ; however , the incidence of postoperative nausea and vomiting ( PONV ) , dizziness , and drowsiness was significantly higher in group O than in group F. Patient satisfaction was lower in group O than in group F during the 48 hours after surgery ( P < 0.001 ) . Conclusions : Oxycodone IV-PCA ( potency ratio 1:75 ) provided superior analgesia to fentanyl IV-PCA after LSH ; however , the higher incidence of side effects , including PONV , dizziness , and drowsiness , suggests that the doses used in this study were not equipotent We aim ed to compare fentanyl , remifentanil and dexmedetomidine with respect to hemodynamic stability , postoperative pain control and achievement of sedation at the postanesthetic care unit ( PACU ) . In this r and omized double-blind study , 90 consecutive total laparoscopic hysterectomy patients scheduled for elective surgery were r and omly assigned to receive fentanyl ( 1.0 µg/kg ) over 1 minute followed by a 0.4 µg/kg/hr infusion ( FK group , n = 30 ) , or remifentanil ( 1.0 µg/kg ) over 1 minute followed by a 0.08 µg/kg/min infusion ( RK group , n = 30 ) , or dexmedetomidine ( 1 µg/kg ) over 10 minutes followed by a 0.5 µg/kg/hr infusion ( DK group , n = 30 ) initiating at the end of main procedures of the operation to the time in the PACU . A single dose of intravenous ketorolac ( 30 mg ) was given to all patients at the end of surgery . We respectively evaluated the pain VAS scores , the modified OAA/S scores , the BIS , the vital signs and the perioperative side effects to compare the efficacy of fentanyl , remifentanil and dexmedetomidine . Compared with other groups , the modified OAA/S scores were significantly lower in DK group at 0 , 5 and 10 minutes after arrival at the PACU ( P < 0.05 ) , whereas the pain VAS and BIS were not significantly different from other groups . The blood pressure and heart rate in the DK group were significantly lower than those of other groups at the PACU ( P < 0.05 ) . DK group , at sedative doses , had the better postoperative hemodynamic stability than RK group or FK group and demonstrated a similar effect of pain control as RK group and FK group with patient awareness during sedation in the PACU . ( World Health Organization registry , KCT0001524 ) STUDY OBJECTIVE To present a descriptive study on same-day discharge after total laparoscopic hysterectomy ( TLH ) , documenting the effectiveness of our preoperative and postoperative protocol , and surgical technique for minimizing postoperative pain scores in case of uterine volume equivalent to < 14 weeks of gestation . DESIGN Prospect i ve observational study ( Canadian Task Force classification II-2 ) . SETTING University hospital . PATIENTS One hundred and five patients undergoing TLH , with same-day discharge . INTERVENTIONS Anesthesia and surgery were performed using the same protocol in all patients . MEASUREMENTS AND MAIN RESULTS Primary endpoints evaluated pain scores using a visual analog scale ( VAS ) . Secondary endpoints included duration of surgery , operating room occupancy , time to discharge , overnight hospitalization , complication rate , readmission rate and patient satisfaction . All ( 100 % ) patients were able to return home within 4.9 ± 1.4 hours of surgery . At 1 hour after surgery , the mean VAS score was < 4 ( 3.5 ± 2.6 ) ; the mean score dropped to < 2 ( 1.9 ± 1.2 ) by 4 hours after surgery and remained so throughout day 1 ( 1.8 ± 1.4 ) . Thus , VAS scores were significantly lower at 4 hours and day 1 postsurgery than at 1 hour postsurgery . CONCLUSION Our results clearly confirm that outpatient TLH is a feasible procedure , allowing same-day discharge and generating low levels of pain . Patients can leave the hospital in less than 5 hours after surgery . St and ardized techniques , as well as coordination with the anesthesiologist , adequate postoperative nursing care , and preoperative patient counseling , are required OBJECTIVE Residual carbon dioxide contributes substantially to pain following laparoscopic surgery . We evaluated the effects of extended assisted ventilation ( EAV ) with an open umbilical trocar valve for five additional minutes following laparoscopic hysterectomy on postoperative abdominal and shoulder pain levels . We also examined whether a combination of EAV and trocar site infiltration ( TSI ) with lidocaine could further reduce postoperative pain levels . STUDY DESIGN In this prospect i ve r and omized trial , the effectiveness of EAV and EAV/TSI in reducing postoperative abdominal and shoulder pain were compared with that of a st and ard treatment regime in 283 patients undergoing laparoscopic hysterectomy ( total or supracervical ) . Pain levels were evaluated by self- assessment question naire using a numeric rating scale ( NRS ) and by postoperative piritramid requirement , a surrogate parameter for postoperative analgesic drug requirement . The incidence of nausea and vomiting was also assessed . RESULTS Compared with the st and ard treatment regime , EAV reduced abdominal pain levels significantly at 3h ( NRS score , 3.21 ± 1.56 vs. 4.73 ± 1.71 ) and 24h ( 3.82 ± 1.49 vs. 4.95 ± 1.68 ) postoperatively ( both p < 0.01 ) . EAV also significantly reduced shoulder pain at 24h ( EAV vs. control , 4.28 ± 1.51 vs. 5.14 ± 1.49 ) and 48 h ( 3.64 ± 1.66 vs. 4.22 ± 1.43 ) postoperatively ( both p < 0.01 ) . Patients in the EAV group had significantly lower piritramid requirements compared with st and ard treatment at 3h post-operatively ( 4.28 ± 2.09 mg vs. 6.31 ± 2.21 mg ; p<0.01 ) . EAV/TSI showed no additional benefit in terms of pain reduction compared with EAV alone . Incidences of postoperative nausea and vomiting were not reduced by EAV or EAV/TSI . CONCLUSION EAV was found to be an effective and safe method to reduce postoperative pain levels in patients undergoing laparoscopic hysterectomy STUDY OBJECTIVE To estimate whether closed suction drainage of the pelvis after laparoscopic-assisted vaginal hysterectomy ( LAVH ) reduces the frequency and intensity of shoulder-tip , abdominal , and back pain . DESIGN Prospect i ve , r and omized study ( Canadian Task Force classification 1 ) . SETTING Teaching medical center . PATIENTS One hundred sixty-four women . INTERVENTION LAVH . MEASUREMENTS AND MAIN RESULTS For group 1 ( 80 women ) , closed suction ( Jackson-Pratt ) drains were inserted into the peritoneal cavity and cul-de-sac , whereas for group 2 ( 84 ) , no drains were placed . Shoulder-tip , abdominal , and back pain were evaluated by visual analog scores ( VAS ) 3 , 24 , and 48 hours after surgery . The frequency of shoulder-tip pain was significantly lower in group 1 at 24 hours ( 23 % vs 40 % , p = 0.013 ) and 48 hours ( 9 % vs 21 % , p = 0.024 ; VAS scores at 24 hrs 2.2 + /- 1.1 vs 3.8 + /- 1.3 , p = 0.010 ; VAS scores at 48 hours 1.5 + /- 1.0 vs 2.5 + /- 1.2 , p = 0.018 ) . At 48 hours fewer women in group 1 experienced abdominal pain ( 31 % vs 50 % , p = 0.039 ; VAS scores 2.0 + /- 1.1 vs 4.0 + /- 1.3 , p = 0.007 ) . No statistically significant differences in frequency and VAS scores for back pain were found at any time . The quantity of oral analgesics was greater for group 2 than for group 1 ( 12.4 + /- 1.6 vs 9.0 + /- 1.4 , p < 0.001 ) . Economic evaluation of analgesic requirements and material costs for the two groups showed that simple analgesics were more cost-effective than closed suction drainage in the treatment of pain . CONCLUSION Closed suction drains may reduce the frequency and intensity of shoulder-tip and abdominal pain and postoperative analgesia requirements after LAVH , but simple oral analgesics are more cost effective Background This study aim ed to compare single-port transumbilical total laparoscopic hysterectomy ( SPLS-TLH ) and four-port total laparoscopic hysterectomy ( TLH ) in terms of postoperative pain . Methods The study enrolled 68 patients who underwent TLH from October 2009 to March 2010 and r and omly assigned them to one of two groups . Patient demographics , operative outcomes , and postoperative pain were prospect ively examined . Results Four cases in the SPLS-TLH group were converted to other laparoscopic approaches . The two study groups did not differ in terms of patient demographics and surgical outcomes . Postoperative pain scores , measured using a visual analog scale , did not differ between the two groups . However , significantly higher total requests for analgesics were observed in the SPLS-TLH group ( 11.3 ± 4.1 vs. 7.7 ± 2.7 ; p < 0.001 ) . Conclusion Compared with four-port TLH , SPLS-TLH is a feasible approach with comparable operative outcomes . However , reduction of postoperative pain is not evident with SPLS-TLH The efficacy of local anaesthetic infiltration and /or non-steroidal anti-inflammatory drugs for post-operative analgesia following laparoscopic-assisted vaginal hysterectomy ( LAVH ) was investigated in 83 patients , r and omized into four groups in this double-blind , placebo-controlled study : group BK , local infiltration with bupivacaine and pre-incisional intramuscular ( IM ) ketorolac ; group NN , saline local infiltration IM ; group BN , local infiltration with bupivacaine and saline IM ; group NK , local infiltration with saline and ketorolac IM . Post-operative pain scores were assessed at 1 h , 3 h , 6 h , 12 h and 24 h using a visual analogue scale ( VAS ) . The major pain site , first analgesic request time and incidence of analgesic requests were also recorded . At 1 h , 3 h and 6 h after surgery , group BK patients had significantly lower VAS pain scores than group NN patients . The first analgesic request time was significantly longer in group BK than in groups NN , BN and NK . Pre-incisional treatment with ketorolac IM and local infiltration with bupivacaine reduced post-operative pain after LAVH Summary A range of clinical ly important difference values is provided according to the patients ’ baseline pain severity and duration of pain . Abstract The aim of this study was to estimate a range of clinical ly important difference ( CID ) values of the visual analog scale for pain intensity ( VAS‐PI ) , and to assess the effect of patient baseline characteristics on VAS change scores . Data from a prospect i ve cohort study with 678 patients with subacute and chronic temporom and ibular disorder pain were analyzed . Patients were divided into 9 cohorts on the basis of the baseline VAS score and the duration of pain . The CID was estimated over a 12‐week period , and 2 different methods were used : ( 1 ) mean change scores , and ( 2 ) optimal cutoff point in receiver operator characteristic curves . The patient 's global impression of change was used as an external criterion . The general linear model univariate analysis was applied to assess the effect of baseline pain level and duration of pain on the raw VAS change scores , while adjusting for age and sex . The CID mean change ranged from 20.9 to 57.5 mm ( 64.1–76.3 % ) , and the CID optimal cutoff point from 11.5 to 28.5 mm ( 29.9–47.7 % ) . For the VAS change scores , the main effect of the variable baseline pain level was significant ( F = 107.09 , P < .001 ) . However , there was no significant baseline pain level by duration of pain interaction effect ( F = 1.13 , P = .340 ) . On the basis of the results , we advocate the choice of a single CID value according to the context of the patient 's baseline level of pain OBJECTIVE The purpose of this study was to compare operative time and intra- and postoperative complications between total laparoscopic hysterectomy and robotic-assisted total laparoscopic hysterectomy . STUDY DESIGN This study was a blinded , prospect i ve r and omized controlled trial conducted at 2 institutions . Subjects consisted of women who planned laparoscopic hysterectomy for benign indications . Preoperative r and omization to total laparoscopic hysterectomy or robotic-assisted total laparoscopic hysterectomy was stratified by surgeon and uterine size ( > or ≤12 weeks ) . Vali date d question naires , activity assessment scales , and visual analogue scales were administered at baseline and during follow-up evaluation . RESULTS Sixty-two women gave consent and were enrolled and r and omly assigned ; 53 women underwent surgery ( laparoscopic , 27 women ; robot-assisted , 26 women ) . There were no demographic differences between groups . Compared with laparoscopic hysterectomy , total case time ( skin incision to skin closure ) was significantly longer in the robot-assisted group ( mean difference , + 77 minutes ; 95 % confidence interval , 33 - 121 ; P < .001 ] as was total operating room time ( entry into operating room to exit ; mean difference , + 72 minutes ; 95 % confidence interval , 14 - 130 ; P = .016 ) . Mean docking time was 6 ± 4 minutes . There were no significant differences between groups in estimated blood loss , pre- and postoperative hematocrit change , and length of stay . There were very few complications , with no difference in individual complication types or total complications between groups . Postoperative pain and return to daily activities were no different between groups . CONCLUSION Although laparoscopic and robotic-assisted hysterectomies are safe approaches to hysterectomy , robotic-assisted hysterectomy requires a significantly longer operative time Objective To compare the impact of peritoneal closure on postoperative pain after vaginal ( VH ) and laparoscopic-assisted vaginal hysterectomy ( LAVH ) . Study design A prospect i ve , r and omized , double-blind study was design ed to investigate as primary outcome the postoperative pain after VH and LAVH with and without peritoneal closure . The postoperative pain was measured using visual analogue scale ( VAS ) . Results The patients were recruited between August , 2007 and July , 2014 . A total of 192 patients with benign uterine diseases were eligible for analysis and were divided in four groups : LAVH and VH with and without peritoneal closure ( PC ) , respectively . The patients ’ characteristics including parity , BMI , previous abdominal operations , and uterus weight were well balanced between the groups . The patients who received LAVH were significantly younger ( p = 0.0443 ) . LAVH was associated with increased postoperative pain and reduced patients ’ mobility in the first 72 and 24 h , respectively , after surgery . The use of analgesics remained similar in all four groups . The operating time was significantly shorter after VH ( VH + PC 59 ± 17 ; VH − PC 56 ± 19 ) than after LAVH ( LAVH + PC 106 ± 29 min ; LAVH − PC 99 ± 30 ) ( p < 0.0001 ) . The PC did not affect the patients ’ outcome . The blood loss , the hemoglobin drop , the hospital stay , and the rate of intra- and postoperative complications rate were similar in all four groups . No conversation to laparotomy occurred in whole study population . Conclusion VH is associated with shorter operating time and reduced postoperative pain compared to LAVH BACKGROUND The st and ard surgery for early-stage endometrial cancer is total abdominal hysterectomy ( TAH ) and bilateral salpingo-oophorectomy , which is associated with substantial morbidity . Total laparoscopic hysterectomy ( TLH ) and bilateral salpingo-oophorectomy is less invasive and is assumed to be associated with lower morbidity , particularly in obese women . This study investigated the complication rate of TLH versus TAH in women with early-stage endometrial cancer . METHODS This r and omised trial was done in 21 hospitals in The Netherl and s , and 26 gynaecologists with proven sufficient skills in TLH participated . 283 patients with stage I endometrioid adenocarcinoma or complex atypical hyperplasia were r and omly allocated ( 2:1 ) to the intervention group ( TLH , n=187 ) or control group ( TAH , n=96 ) . R and omisation by sequential number generation was done central ly in alternate blocks of six and three participants , with stratification by trial centre . After assignment , the study coordinators , patients , gynaecologists , and members of the panel were not masked to intervention . The primary outcome was major complication rate , assessed by an independent panel . Data were analysed by a modified intention-to-treat analysis , since two patients in both groups were excluded from the main analysis . This trial is registered with the Dutch trial registry , number NTR821 . FINDINGS The proportion of major complications was 14.6 % ( 27 of 185 ) in the TLH group versus 14.9 % ( 14 of 94 ) in the TAH group , with a difference of -0.3 % ( 95 % CI -9.1 to 8.5 ; p=0.95 ) . The proportion of patients with an intraoperative major complication ( nine of 279 [ 3.2 % ] ) was lower than the proportion with a postoperative major complication ( 32 of 279 [ 11.5 % ] ) and did not differ between TLH ( five of 185 [ 2.7 % ] ) and TAH ( four of 94 [ 4.3 % ] ; p=0.49 ) . The proportion of patients with a minor complication was 13.0 % ( 24 of 185 ) in the TLH group and 11.7 % ( 11 of 94 ) in the TAH group ( p=0.76 ) . Conversion to laparotomy occurred in 10.8 % ( 20 of 185 ) of the laparoscopic procedures . TLH was associated with significantly less blood loss ( p<0.0001 ) , less use of pain medication ( p<0.0001 ) , a shorter hospital stay ( p<0.0001 ) , and a faster recovery ( p=0.002 ) , but the procedure took longer than TAH ( p<0.0001 ) . INTERPRETATION Our results showed no evidence of a benefit for TLH over TAH in terms of major complications , but TLH ( done by skilled surgeons ) was beneficial in terms of a shorter hospital stay , less pain , and quicker resumption of daily activities . FUNDING The Dutch Organization for Health Research and Development ( ZonMw ) , programme efficacy STUDY OBJECTIVE The aim of this study was to compare operative and early postoperative outcomes of laparoscopic-assisted vaginal hysterectomy ( LAVH ) and minilaparotomy in a r and omized clinical trial including patients undergoing total hysterectomy for benign gynecologic disease and having 1 or more of the generally considered contraindications to vaginal route . DESIGN Prospect i ve , r and omized , multicenter trial ( Canadian Task Force classification I ) . SETTING Departments of Gynecology from 3 major university hospitals in Rome . PATIENTS Eighty-one patients who were c and i date s for abdominal hysterectomy . INTERVENTIONS Laparoscopic-assisted vaginal hysterectomy and minilaparotomy hysterectomy . MEASUREMENTS AND MAIN RESULTS Forty patients were r and omized to LAVH and 41 to minilaparotomy . Characteristics of patients and indications for surgery in the 2 arms were comparable . In the minilaparotomy group , complications were as follows : 1 case ( 2.4 % ) of delayed laparotomy with 2 units of red blood cell transfusion , 2 cases ( 4.8 % ) of wound infection , and 3 cases ( 7.3 % ) of fever of unknown origin . No minor or major complications were observed in the LAVH group . Postoperative visual analog scale pain scores at days 1 and 2 were significantly lower in the LAVH group ( p < .05 ) . The complication rate between the 2 groups was significantly lower for LAVH ( p = .026 ) . CONCLUSION Because LAVH was associated with significantly lower early postoperative pain scores and complication rates , in general LAVH should be preferred to minilaparotomy hysterectomy when the vaginal approach can not be used Background and Objective : Surgical stress and general anesthesia suppress immune function . Preemptive epidural analgesia can affect the perioperative immune responses , and influence cancer management . Methods : Forty women undergoing elective laparoscopic radical hysterectomy for cervical cancer were allocated to this prospect i ve , r and omized , double‐blind trial . Before inducing anesthesia , 2 mg morphine dissolved in 15 mL of 1 % lidocaine ( preemptive group ) or the same volume of normal saline ( control group ) was administered into the epidural space through a prepared catheter in a double‐blind manner , using sealed syringes . After peritoneal closure , the other drugs in the remaining sealed syringe were administered in the reverse manner . All patients were then administered lidocaine plus morphine over a 72‐hour period , using a patient‐controlled epidural analgesia pump . Results : The interleukin‐6 levels in both groups increased significantly after surgery . These elevations were significantly less pronounced in the preemptive group than in the control group . The interleukin‐2 level in both groups decreased significantly after surgery . Seventy‐two hours after surgery , the interleukin‐2 level returned to its baseline value in the preemptive group but not in the control group . The number of lymphocytes in both groups decreased significantly after surgery . The pain scores at 6 and 12 hours after surgery in the preemptive group were significantly lower than in the control group . Conclusions : Preemptive epidural analgesia is a reasonable approach for potentially controlling perioperative immune function and preventing postoperative pain in patients undergoing cancer surgery We evaluated the timing effect of a 10-mg IV administration of dexamethasone on its efficacy as a prophylactic antiemetic on postoperative nausea and vomiting ( PONV ) . One hundred twenty women ( n = 40 in each of three groups ) undergoing abdominal total hysterectomy under general anesthesia were enrolled in this r and omized , double-blinded , placebo-controlled study . Group 1 received dexamethasone before the induction of anesthesia , Group 2 received dexamethasone at the end of anesthesia , and Group 3 received placebo ( saline ) . The incidence of PONV was evaluated . During the postoperative period of 0–2 h , patients in Group 1 reported a less frequent incidence of PONV ( 15 % ) than those in Groups 2 and 3 ( 45 % and 53 % , respectively ) . Patients in Group 1 also requested less rescue antiemetic ( 8 % ) than those in Groups 2 and 3 ( 30 % and 35 % , respectively ) . During the postoperative period of 2–24 h , patients in both Groups 1 and 2 reported less frequent incidences of PONV ( 25 % and 28 % ) and requested fewer rescue antiemetics ( 13 % and 15 % ) than those in Group 3 ( 55 % and 38 % , respectively ) . In conclusion , the prophylactic IV administration of dexamethasone immediately before the induction , rather than at the end of anesthesia , was more effective in preventing PONV . Implication s We evaluated the effect of timing of dexamethasone administration on its efficacy as a prophylactic antiemetic on postoperative nausea and vomiting . We found that dexamethasone , when given immediately before the induction of anesthesia , was more effective than when given at the end of anesthesia OBJECTIVE The objective of the study was to determine whether transversus abdominis plane ( TAP ) block improves the early postoperative quality of recovery ( QoR-40 ) . The secondary objectives measured postoperative pain , length of stay , and narcotic use . STUDY DESIGN This was a r and omized , single-blinded trial of TAP block versus no block on women undergoing laparoscopic hysterectomy . TAP block patients received 20 mL of 0.5 % ropivacaine with epinephrine 1:200,000 placed under ultrasound guidance on each side . The outcomes were measured using vali date d quality of recovery question naires ( QoR-40 ) , visual analog scales ( VAS ) for pain , and documented narcotic use in the electronic medical record . RESULTS In 58 women , no differences in demographics were noted between groups . Comparisons of pain and recovery between the 2 groups showed no differences . There was no decrease in narcotic use or length of stay among those who received the TAP block . CONCLUSIONS TAP block does not improve postoperative QoR-40 scores or VAS pain scores following laparoscopic hysterectomy , nor does it decrease narcotic pain medication use Background : Laparoscopic hysterectomy ( LH ) is expected to provide fast and comfortable recovery , plus an early return to normal daily activities . This study was carried out to compare the outcome after LH in patients anesthetized with isoflurane or propofol OBJECTIVE : To compare the immediate results of patients undergoing either two-channel single-port laparoscopic-assisted vaginal hysterectomy or conventional multiport laparoscopic-assisted vaginal hysterectomy . METHODS : Patients were r and omly assigned to undergo laparoscopic-assisted vaginal hysterectomy using the single-port ( n=50 ) or conventional ( n=50 ) approach . The outcome measures included blood loss , operative time , intraoperative and immediate postoperative complications , time to flatus passage after operation , and postoperative pain ( assessed by the visual analog scale score and postoperative analgesics use ) . RESULTS : The general characteristics of the patients were similar in both groups . There were no statistically significant differences in operative time , estimated blood loss , time to first flatus , intraoperative and immediate postoperative complications , shoulder tip pain , or length of hospital stay between the two groups . However , postoperative pain was significantly less in the single-port group compared with the conventional group , as evidence d by lower mean scores on the visual analog scale ( 3.64±2.75 compared with 5.08±2.76 at 24 hours , P=.011 and 1.94±2.31 compared with 2.84±2.07 at 48 hours , P=.043 ) and less mean accumulated dose of postoperative analgesics ( 74.40±24.25 mg compared with 104.80±57.08 mg of meperidine , P=.001 ; 16±13.40 mg compared with 33.6±28.7 mg of tenoxicam , P<.001 ) . CONCLUSION : Transumbilical two-channel single-port laparoscopic-assisted vaginal hysterectomy significantly decreases postoperative pain and analgesic use . Clinical Trial Registration : Clinical Trials.gov , www . clinical trials.gov , NCT01048931 . LEVEL OF EVIDENCE : & NA ; The purpose of this study was to determine the levels of change on st and ard pain scales that represent clinical ly important differences to patients . Data from analgesic studies are often difficult to interpret because the clinical importance of the results is not obvious . Differences between groups , as summarized by a change in mean values over time , can be difficult to apply to clinical care . Baseline scores vary widely and group mean differences could reflect large changes in a few patients , small changes in many patients , or any combination of these outcomes . Determination of the proportion of patients who have a clinical ly important improvement in their pain would provide a more interpretable result with direct clinical implication s. However , determining a clinical ly important outcome requires information about the degree of change over time that is clinical ly important . Data from the titration phase of a multiple cross‐over r and omized clinical trial of oral transmucosal fentanyl citrate ( OTFC ) for the treatment of cancer‐related breakthrough pain were re‐analyzed to examine the differences in pain scores between treatment episodes that did and did not yield adequate pain relief . The scales evaluated were absolute pain intensity difference ( PID , 0–10 scale ) , percentage pain intensity difference ( PID% , 0–100 % scale ) , pain relief ( PR , 0 ( none ) , 1 ( slight ) , 2 ( moderate ) , 3 ( lots ) , 4 ( complete ) ) , sum of the pain intensity difference ( SPID over 60 min ) , percentage of maximum total pain relief ( % Max TOTPAR over 60 min ) , and global medication performance ( 0 ( poor ) , 1 ( fair ) , 2 ( good ) , 3 ( very good ) , 4 ( excellent ) ) . Adequate relief was defined by the patient 's decision not to use another dose of opioid medication as a rescue , in addition to the study medication , to treat each painful episode . One hundred thirty OTFC naive patients contributed data on 1268 episodes of breakthrough pain . The scales that were converted to a percentage change yielded the best accuracy in predicting adequate relief , with balanced sensitivity and specificity . The best cut‐off point for both the % Max TOTPAR and the PID% was 33 % . The best cut‐off points for the absolute scales were absolute pain intensity difference of 2 , pain relief of 2 ( moderate ) , and SPID of 2 . The global medication performance of 2 ( good ) had excellent values as well . This study presents data ‐derived cut‐off points for the changes in several pain scales , each reflecting the clinical ly important improvement for patients treating breakthrough cancer pain episodes with OTFC . Confirmation in other patient population s and different pain syndromes will be needed . The use of consistent clinical ly important cut‐off points as the primary outcome in future pain therapy clinical trials will enhance their validity , comparability , and clinical applicability OBJECTIVES Transversus abdominis plane block is a regional anaesthesia technique that has proven to be effective for postoperative pain reduction in different abdominal surgical procedures . This study evaluated its efficacy on post laparoscopic hysterectomy pain intensity and analgesic consumption . MATERIAL S AND METHODS R and omized controlled trial which included 40 patients scheduled for laparoscopic hysterectomy , enrolled in 2 groups : transversus abdominis plane block+systemic analgesia ( Group 1 ; n=20 ) , versus systemic analgesia ( Group 2 ; n=20 ) . Opioid consumption within the first 24 postoperative hours , pain intensity scores at 60min , 2 , 8 and 24h after surgery , adverse events related to systemic analgesia and time to hospital discharge were evaluated and registered . RESULTS We found no differences between both groups in opioid consumption ( 10 mg vs. 7 mg ; P=.2 ) and pain scores ( NVS ) within the first 24 postoperative hours , at 60min ( 3 vs. 5 ; P=.65 ) , 120min ( 0 vs. 2 ; P=.15 ) , 8 and 24h ( 0 vs. 0 ; P>.50 ) for the last 2 points in time analysed . Adverse events related to medication and time to hospital discharge showed similar results . CONCLUSIONS Adding a transversus abdominis plane block technique to opioid PCA does not seem to improve postoperative pain management in laparoscopic hysterectomy . Patient preparation time and costs could be incremented and complications ( although rare ) related to the technique could appear BACKGROUND To compare surgical outcomes of two procedures for laparoendoscopic single-site ( LESS ) hysterectomy : total laparoscopic hysterectomy ( TLH ) and laparoscopically assisted vaginal hysterectomy ( LAVH ) . MATERIAL S AND METHODS Seventy-six patients who had an indication for hysterectomy for benign uterine disease were r and omized to LESS-TLH or LESS-LAVH . Surgical outcomes were assessed and compared between the two groups . RESULTS There were no differences in baseline demographics between the two groups . Surgical outcomes such as operative time , estimated blood loss , length of hospital stay , and complication rate were similar between the two groups . The failure rate in the LESS-TLH group was higher than that in the LESS-LAVH group ( 5/38 [ 11 % ] versus 0/38 [ 0 % ] ) , although this difference did not reach statistical significance ( P=.054 ) . Among the 5 cases that failed in the LESS-TLH group , 4 were related to a large lower uterine segment prohibiting visualization during colpotomy . The postoperative pain scores at 18 and 36 hours after surgery were significantly lower in the LESS-TLH group than in the LESS-LAVH group ( all P<.001 ) . Vaginal discharge at 1 and 4 weeks after surgery was significantly lower in the LESS-TLH group than in the LESS-LAVH group ( all P<.001 ) . CONCLUSIONS LESS-TLH and LESS-LAVH are both safe , feasible procedures with similar surgical outcomes . LESS-TLH was associated with less postoperative pain and less postoperative vaginal discharge , whereas LESS-LAVH may be preferred in patients with a uterus with a large lower uterine segment & NA ; Pregabalin has anticonvulsant , antihyperalgesic , and anxiolytic properties . In this study we evaluated the control of pain after perioperative administration of pregabalin 300 or 600 mg , compared with diazepam 10 mg . Altogether 91 women scheduled for laparoscopic hysterectomy were r and omized to receive diazepam 10 mg ( D10 ) , pregabalin 150 mg ( P300 ) or 300 mg ( P600 ) for premedication , and the dose was repeated after 12 h , except for the D10 group , in which the patients received placebo . Up until the 1st postoperative morning , analgesia was provided by oxycodone using patient controlled analgesia . The visual analogue scale scores for pain and side effects , and the amounts of the analgesics were recorded for three days after surgery . The doses of oxycodone during hours 0–12 after surgery were similar in the three groups , whereas the dose of oxycodone during hours 12–24 after surgery was smaller in the P600 group than in the P300 group ( 0.09 vs. 0.16 mg kg−1 ; P = 0.025 ) . The total dose of oxycodone ( 0–24 h after surgery ) was smaller in the P600 group than in the D10 group ( 0.34 vs. 0.45 mg kg−1 ; P = 0.046 ) . The incidence of dizziness ( 70 % vs. 35 % ; P = 0.012 ) , blurred vision ( 63 % vs. 14 % ; P = 0.002 ) and headache ( 31 % vs. 7 % ; P = 0.041 ) were higher in the P600 group than in the D10 group . In conclusion , perioperative administration of pregabalin 600 mg decreases oxycodone consumption compared with diazepam 10 mg , but is associated with an increased incidence of adverse effects STUDY OBJECTIVE To compare the operative outcomes of patients undergoing either single-port or multiport laparoscopic hysterectomy ( LH ) . METHODS Two hundred fifty-six women scheduled for LH for symptomatic myoma and /or adenomyosis from 8 tertiary teaching hospitals were r and omized to single-port or multiport groups . Primary outcome was conversion and /or complication proportion of the planned procedure to determine whether the success proportion of the single-port approach was not inferior to that of the multiport approach . Secondary outcomes were postoperative pain and operative scar . RESULTS Demographic parameters including age , body mass index , parity , and history of vaginal and cesarean delivery were comparable between the 2 groups . The primary outcome of a combined conversion and /or complication rate was similar between the single-port and multiport groups at 8 % and 10.3 % , respectively . Conversions were similar between the groups with 4 % of single-port cases and .8 % of multiport cases . Transfusions were the most frequent complication required in 4.0 % of single-port cases and 7.9 % of multiport cases , with no difference between the groups . Concerning secondary outcomes , postoperative pain score and patient and observer scar assessment were not different between the 2 groups . Although not a specific outcome measure , there was no difference between the groups in blood loss , operative time , and postoperative hospital stay . CONCLUSION Single-port LH is not inferior to multiport LH in terms of conversion and /or complications rates , including transfusion . However , the single-port approach did not have any advantage over multiport LH with regard to pain or cosmetic outcomes . These findings were demonstrated by multi-institutional surgeons in Korea STUDY OBJECTIVE To compare cosmetic satisfaction with laparoendoscopic single-site surgery ( LESS ) compared with multi-port surgery . DESIGN R and omized controlled trial ( Canadian Task Force classification I ) . SETTING University hospital . PATIENTS Twenty women who underwent laparoscopically-assisted vaginal hysterectomy ( LAVH ) via LESS or multi-port surgery . INTERVENTIONS Laparoendoscopic single-site surgery or multi-port surgery . MEASUREMENT AND MAIN RESULTS Cosmetic satisfaction was assessed using the Body Image Question naire at baseline and at 1 , 4 , and 24 weeks after surgery . Of the 20 LESS procedures , 1 was converted to multi-port surgery because of severe adhesions , and 1 woman assigned to undergo multi-port surgery was lost to follow-up . The 2 surgery groups did not differ in clinical demographic data and surgical results or postoperative pain scores at 12 , 24 , and 36 hours . Compared with the multi-port group , the LESS group reported significantly higher cosmetic satisfaction at 1 , 4 , and 24 weeks after surgery ( p < .01 ) . CONCLUSION Compared with multi-port surgery , LESS is not only a feasible approach with comparable operative outcomes but also has an advantage insofar as cosmetic outcome OBJECTIVE To compare the EnSeal device with st and ard bipolar coagulation forceps in laparoscopic supracervical hysterectomy ( LASH ) . DESIGN Prospect i ve , r and omized , controlled trial ( Canadian Task Force classification I ) . SETTING University hospital . PATIENTS One hundred sixty patients who underwent LASH . INTERVENTION Eighty patients underwent LASH using the EnSeal device ( experimental group ) , and 80 patients underwent LASH using st and ard bipolar coagulation forceps ( control group ) ( www . clinical trials.gov ; study identifier NCT01806012 ) . MEASUREMENTS AND MAIN RESULTS Mean ( SD ) total operative time was 78.18 ( 33.96 ) minutes in the experimental group and 86.30 ( 35.34 ) minutes in the control group ( p = .03 ) . Documented blood loss was < 50 mL in 72 patients in the experimental group and 62 patients in the control group ( p = .03 ) , and was 50 to 100 mL in 8 patients in the experimental group and 18 patients in the control group ( p < .001 ) . Postoperative hospital stay was significantly shorter for patients in the experimental group compared with the control group : 2.01 ( 0.44 ) days vs 2.17 ( 0.47 ) days , respectively ( p = .03 ) . There was no difference in postoperative pain scores and complications between the two treatment groups . CONCLUSION Total resection time was shorter in the experimental group , and the other investigated clinical parameters were not inferior in the experimental group compared with the control group . The results of the present study indicate that use of the EnSeal device is at least as reliable as the conventional electrocoagulation technique in LASH STUDY OBJECTIVE To evaluate the effect on postoperative pain of intraperitoneal instillation of dilute bupivacaine at the conclusion of laparoscopic hysterectomy . DESIGN Prospect i ve , r and omized , double-blind , placebo-controlled trial ( Canadian Task Force classification I ) . SETTING Tertiary care , urban , academic teaching hospital . PATIENTS Women aged 18 to 65 years undergoing total or supracervical laparoscopic hysterectomy with or without salpingo-oophorectomy . INTERVENTION R and omization to intraperitoneal instillation of bupivacaine vs normal saline solution at the conclusion of laparoscopic hysterectomy performed because of benign indications . MEASUREMENTS AND MAIN RESULTS A total of 160 patients consented to participate in the study and were r and omized to receive either intraperitoneal instillation of 100 mg bupivacaine in 100 mL normal saline solution or 100 mL normal saline solution alone , at the conclusion of laparoscopic hysterectomy . Sixty seven of 77 patients ( 87 % ) in the treatment group and 73 of 80 patients ( 91 % ) in the placebo group completed the study . There were no significant differences in demographic profile , indication for hysterectomy , or number of previous surgeries between the two groups . All patients were prescribed a st and ardized routine postoperative analgesic regimen . Pain was measured by patient self-report using a 10-cm visual analog scale ( VAS ) at 1 , 2 , 4 , 6 , 12 , and 24 hours postoperatively . Mean VAS scores at all time points were between 2.0 and 4.3 and were highest in the first postoperative hour . VAS scores were not significantly different between the two groups at any time point . None of the measured secondary outcomes were significantly different between the bupivacaine and placebo groups , including total postoperative opioid analgesic use in morphine equivalents ( 23.2 mg vs 27.5 mg ; p = .09 ) , length of hospital stay in hours ( 23.3 vs 23.0 ; p = .49 ) , patient satisfaction on a 10-cm VAS ( 9.0 vs 8.2 ; p = .12 ) , and complication rates ( 9 % vs 15 % ; p = .35 ) . CONCLUSION Intraperitoneal instillation of bupivacaine at the conclusion of laparoscopic hysterectomy does not reduce postoperative pain . Opioid analgesic use , length of hospital stay , overall patient satisfaction , and complication rates are also unchanged . Self-reported postoperative pain was low in both groups after this major gynecologic surgery performed laparoscopically OBJECTIVE The study aim ed to investigate the preemptive analgesia efficacy of different concentrations ( 75 , 150 and 300 mg ) of preemptive pregabalin for the postoperative pain management after laparoscopic hysterectomy . DESIGN Prospect i ve , r and omized , placebo-controlled , double-blind study . SETTING The Gynecology and Obstetrics Center of Arash Hospital , Tehran , Iran , from October 2013 to November 2014 . PATIENTS A total of 96 women with American Association of Anesthesiologist ( ASA ) physical status I and II underwent elective laparoscopic hysterectomy surgery . Patients were then r and omly assigned to four groups , of which groups 1 - 3 ( treatment groups ; n=20 ) received orally pregabalin concentrations of 75 mg , 150 mg , and 300 mg , respectively , for a night before surgery , 30min before surgery and 6h after surgery , whereas group 4 ( control group ; n=22 ) received a matching dosage of placebo at the same scheme . MEASUREMENTS Visual Analog Scale ( VAS ) scores for postoperative pain at rest and on movement at first 24h after surgery were evaluated as primary outcome . Drug-related side effects were also evaluated as a secondary outcome . Somnolence was evaluated using Ramsay Sedation Scale , while nausea and vomiting were assessed using numeric scores . The data were analyzed using SPSS . MAIN RESULTS Preemptive pregabalin in different concentrations provided better pain relief as compared with placebo . Post-hoc test indicated that there was a significant difference among four groups , indicating where the concentration was increased , the pain score decreased as an independent variable of time . The highest concentration of pregabalin ( 300 mg ) revealed higher sedation scores as compared with other groups . CONCLUSION Our data demonstrated preemptive administration of 75 , 150 , and 300 mg pregabalin play an important role in reducing postoperative pain after laparoscopic hysterectomy . Comparison of different concentrations and side effects indicates oral administration of 150 mg pregabalin is an effective and safe method for postoperative pain management after laparoscopic hysterectomy OBJECTIVE : To compare surgical outcome and quality of life of robot-assisted laparoscopic hysterectomy with conventional laparoscopic hysterectomy . METHODS : For this controlled clinical trial , patients with benign indications for hysterectomy were r and omized to receive either a robotic ( robotic group ) or conventional laparoscopic hysterectomy ( conventional group ) . The primary end point was total operating time ; secondary end points were perioperative outcome , blood loss , and the change in quality of life . RESULTS : Ninety-five patients out of 100 r and omized patients completed the study . Patient age , body mass index , and uterus weight showed no significant differences between both groups . All results are given as mean ( ±st and ard deviation ; median ) . Total operating time for the robotic group was significantly higher with 106 ( ±29 ; 103 ) compared with 75 ( ±21 ; 74 ) ( conventional group ) minutes . Blood loss , complications , analgesics use , and return to activity for both groups were comparable . The change in preoperative to postoperative quality -of-life index ( quality of life measured on a linear scale from 0 to 100 ) was significantly higher in the robotic group , with 13 ( ±10 ; 13 ) compared with 5 ( ±14 ; 5 ) ( conventional group ) . CONCLUSION : Robot-assisted laparoscopic hysterectomy and conventional laparoscopy compare well in most surgical aspects , but the robotic procedure is associated with longer operating times . Postoperative quality -of-life index was better ; however , long-term , there was no difference . However , subjective postoperative parameters such as analgesic use and return to activity showed no significant difference between both groups . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00683293 . LEVEL OF EVIDENCE : Purpose A prospect i ve , r and omized , double blind , placebo-controlled study was undertaken to evaluate the efficacy of a single preoperative dose of dexamethasone , in different dosages , in providing postoperative analgesia in patients undergoing total laparoscopic hysterectomy ( TLH ) . Method The study included 55 patients r and omly divided into three groups . Patients in Groups P , D4 , and D8 received saline , 4 , and 8 mg dexamethasone , respectively , intravenously , 2 h before induction . Results The time to first analgesic requirement was significantly delayed in patients in the D8 group compared with the D4 group ( P = 0.01 ) and placebo ( P = 0.01 ) . Total postoperative fentanyl consumption was significantly less in patients in the D8 group compared with the D4 group ( P = 0.01 ) and placebo ( P = 0.01 ) . Use of 8 mg dexamethasone result ed in a 99.3 mcg decrease in total 24-h fentanyl consumption . Postoperative nausea and vomiting ( PONV ) was significantly less in the D8 group with a complete response rate ( no emetic episodes and no rescue medication for 24 h ) of 36.8 % compared with the placebo group in which all the patients had PONV . No adverse effects were observed in any group . Conclusion Dexamethasone at a dose of 8 mg given intravenously 2 h before induction , delays patient request for analgesia and reduces total fentanyl consumption and PONV in patients undergoing TLH Background and Aims : This controlled trial with II-1 evidence compared the safety and efficacy of the new laparoscopic-assisted combined hysterectomy ( LACH ) with the st and ard surgical technique laparoscopic-assisted vaginal hysterectomy ( LAVH ) in general and in patients displaying risk factors ( large uterus , vaginal nulliparity , prior caesarean section ) . Methods : From June 2007 to September 2008 , 101 patients underwent a hysterectomy at the Clinic of Gynaecology , Obstetrics and Gynaecological Oncology at the Pius Hospital , University Hospital for Gynaecology in Oldenburg . The main outcome measures were feasibility , postoperative analgesia , postoperative inflammatory reaction , and duration of surgery . Statistical analyses were performed using SPSS for Windows ( p < 0.05 ) . Results : We observed no significant differences between LACH and LAVH regarding outcome parameters or when risk factors were considered . Within the LACH group , the duration of surgery was significantly shorter for patients with UW < 400 g. Still within the normal range , caesarean sections from both groups revealed significant differences in the number of leucocytes on the 2nd post-operative day . No urinary tract injuries , no unplanned conversion to laparotomy , no severe perioperative complications occurred in either group . Conclusion : In terms of technical feasibility , LACH represents a safe alternative for abdominal HE when LAVH is contraindicated Background We evaluated the effect and safety of the immediate postoperative continuous infusion of remifentanil at two doses in patients undergoing laparoscopic-assisted vaginal hysterectomy ( LAVH ) with alfentanil-based patient-controlled analgesia ( PCA ) . Methods The study enrolled 50 ASA physical status 1 or 2 patients scheduled to undergo LAVH . Anesthesia was maintained with sevoflurane-remifentanil-air . At the last skin suture , the sevoflurane was discontinued , and patients were r and omized to receive remifentanil 0.05 µg/kg/min ( group I ) or 0.1 µg/kg/min ( group II ) . PCA was started at the time of eye opening and response to a verbal comm and . In the recovery room , we monitored the mean arterial blood pressure ( MAP ) , heart rate ( HR ) , respiratory rate ( RR ) , SpO2 , and bispectral index ( BIS ) at 5-minute intervals . Thirty minutes after starting PCA , the remifentanil was discontinued . Pain was assessed using a visual analog scale ( 0 = no pain ; 100 = the worst possible pain ) at 0 , 5 , 10 , and 30 minutes after stopping the remifentanil infusion . Results The eye opening time , BIS , MAP , and HR did not differ significantly between the two groups , and pain scores were similar between the two groups . Respiratory depression ( SpO2 < 90 % or RR < 8/min ) did not occur in group I but did occur in three patients in group II . Conclusions Continuous remifentanil infusion ( 0.05 µg/kg/min ) immediately postoperatively with alfentanil-based PCA had a similar effect as a 0.1 µg/kg/min infusion with respect to pain control without side effects . However , special attention must be given to respiratory depression INTRODUCTION Optimal pain control after major surgery contributes to a patient 's recovery and satisfaction . The use of liposomal bupivacaine in subcostal transversus abdominis plane ( TAP ) blocks for postoperative pain control after robot assisted abdominal surgery has yet to be studied . METHODS We conducted a prospect i ve r and omized controlled observer-blinded study comparing bilateral subcostal TAP blocks with bupivacaine to bilateral subcostal TAP blocks with liposomal bupivacaine . These were performed prior to the patient undergoing robot assisted hysterectomy . The patients ' pain scores , opioid use , side effects , and satisfaction were followed for 72h after injection . RESULTS Total opioid use in the first 72h after injection was significantly decreased in the group that received liposomal bupivacaine compared to bupivacaine . Patients in the liposomal bupivacaine group had significantly lower maximal pain scores at all time periods studied as well as decreased incidence of nausea/vomiting . There was a trend toward decreased length of stay in the liposomal bupivacaine group . CONCLUSION Subcostal TAP blocks with liposomal bupivacaine decreased the total opioid requirement for the first 72h after robot assisted hysterectomy when compared to subcostal TAP blocks with bupivacaine The 5‐HT3 antagonists tropisetron and granisetron have been shown to block the analgesic effect of acetaminophen in healthy volunteers . To study the interaction between ondansetron and acetaminophen in women undergoing laparoscopic hysterectomy , we r and omized 134 patients into three groups to receive acetaminophen – placebo ( AP ) , acetaminophen – ondansetron ( AO ) , or placebo – placebo ( PP ) . One gram of intravenous acetaminophen or placebo was administered at the induction of anesthesia and every 6 h thereafter for 24 h , and 4 mg of ondansetron or placebo was administered at the end of surgery . Pain control was provided by patient‐controlled analgesia (PCA)‐oxycodone . Acetaminophen ( as compared to placebo ) in periodic doses starting at induction of anesthesia reduced the total dosage of oxycodone required over 0–24 h ( P = 0.031 ) , but ondansetron given at the end of the surgery had no impact on the analgesic effect of acetaminophen ( P = 0.723 ) . The Numeric Rating Scale ( NRS ) scores for pain were similar whether ondansetron or placebo was administered at the end of the surgery . Therefore , it may be concluded that in women undergoing laparoscopic hysterectomy , the administration of periodic doses of intravenous acetaminophen ( as compared to placebo ) starting at induction of anesthesia reduces the total dose requirement of oxycodone , and a concomitant dose of a 5‐HT3 antagonist such as ondansetron at the end of the surgery does not block the analgesic effect of acetaminophen OBJECTIVE To quantify physician prescribing patterns and patient opioid use in the 2 weeks after hysterectomy at an academic institution and to determine whether patient factors predict postsurgical opioid use and pain recovery . METHODS We conducted a prospect i ve quality initiative study by recruiting all English-speaking patients undergoing hysterectomy for benign , nonobstetric indications at a university hospital between August 2015 and December 2015 , excluding those with major medical morbidities or substance abuse . Before hysterectomy , patients completed the Fibromyalgia Survey , a vali date d measure of central ized pain . After hysterectomy , opioid use ( converted to oral morphine equivalents ) and pain scores ( 0 - 10 numeric rating scale ) were collected by a daily diary and a structured telephone interview 14 days after surgery . Primary outcomes were total opioid prescribed and consumed in the 2 weeks after hysterectomy . Secondary outcomes included daily opioid use and daily pain severity for 14 days after hysterectomy . RESULTS Of 103 eligible patients , 102 ( 99 % ) agreed to participate , including 44 ( 43.1 % ) laparoscopic , 42 ( 41.2 % ) vaginal , and 16 ( 15.7 % ) abdominal hysterectomies . Telephone surveys were completed on 89 ( 87 % ) participants ; diaries were returned from 60 ( 59 % ) participants . Diary nonresponders had different baseline characteristics than nonresponders . Median amount of opioid prescribed was 200 oral morphine equivalents ( interquartile range 150 - 250 ) . Patients reported using approximately half of the opioids prescribed with a median excess of 110 morphine equivalents ( interquartile range 40 - 150 ) . The best fit model of total opioid consumption identified preoperative Fibromyalgia Survey Score , overall body pain , preoperative opioid use , prior endometriosis , abdominal hysterectomy ( compared with laparoscopic ) , and uterine weight as significant predictors . Highest tertile of Fibromyalgia Survey Score was associated with greater daily opioid consumption ( 13.9 [ 95 % CI 3.0 - 24.8 ] greater oral morphine equivalents at baseline , P=.02 ) . CONCLUSION Gynecologists at a large academic medical center prescribe twice the amount of opioids than the average patient uses after hysterectomy . A personalized approach to prescribing opioids for postoperative pain should be considered Importance Patterns of preoperative opioid use are not well characterized across different surgical services , and studies in this patient population have lacked important self-reported data of pain and affect . Objectives To assess the prevalence of preoperative opioid use and the characteristics of these patients in a broadly representative surgical cohort . Design , Setting , and Participants Cross-sectional , observational study of patients undergoing surgery at a tertiary care academic medical center . Data were collected as a part of large prospect i ve institutional research registries from March 1 , 2010 , through April 30 , 2016 . Exposures Preoperative patient and procedural characteristics , including prospect ively assessed self-reported pain and functional measures . Main Outcomes and Measures Patient-reported opioid use before surgery . Results Of the total 34 186 patients recruited ( 54.2 % women ; mean [ SD ] age , 53.1 [ 16.1 ] years ) , preoperative opioid use was reported in 7894 ( 23.1 % ) . The most common opioids used were hydrocodone bitartrate ( 4685 [ 59.4 % ] ) , tramadol hydrochloride ( 1677 [ 21.2 % ] ) , and oxycodone hydrochloride ( 1442 [ 18.3 % ] ) . Age of 31 to 40 years ( adjusted odds ratio [ aOR ] , 1.26 ; 95 % CI , 1.10 - 1.45 ) , tobacco use ( former use aOR , 1.32 [ 95 % CI , 1.22 - 1.42 ] ; current use aOR , 1.62 [ 95 % CI , 1.48 - 1.78 ] ) , illicit drug use ( aOR , 1.74 ; 95 % CI , 1.16 - 2.60 ) , higher pain severity ( aOR , 1.33 ; 95 % CI , 1.31 - 1.35 ) , depression ( aOR , 1.22 ; 95 % CI , 1.12 - 1.33 ) , higher Fibromyalgia Survey scores ( aOR , 1.06 , 95 % CI , 1.05 - 1.07 ) , lower life satisfaction ( aOR , 0.95 , 95 % CI , 0.93 - 0.96 ) , and more medical comorbidities ( American Society of Anesthesiology score aOR , 1.47 [ 95 % CI , 1.37 - 1.58 ] ; Charlson Comorbidity Index aOR , 1.29 [ 95 % CI , 1.18 - 1.41 ] ) were all independently associated with preoperative opioid use . Preoperative opioid use was most commonly reported by patients undergoing orthopedic ( 226 [ 65.1 % ] ) and neurosurgical spinal ( 596 [ 55.1 % ] ) procedures and least common among patients undergoing thoracic procedures ( 244 [ 15.7 % ] ) . After adjusting for patient characteristics , the patients undergoing lower extremity procedures were most likely to report preoperative opioid use ( aOR , 3.61 ; 95 % CI , 2.81 - 4.64 ) , as well as those undergoing pelvic ( excluding hip ) ( aOR , 3.09 ; 95 % CI , 1.88 - 5.08 ) , upper extremity ( aOR , 3.07 ; 95 % CI , 2.12 - 4.45 ) , and spinal or spinal cord ( aOR , 2.68 ; 95 % CI , 2.15 - 3.32 ) procedures , with the group undergoing intrathoracic surgery as the reference group . Conclusions and Relevance In this large study of preoperative opioid use that includes patient-reported outcome measures , more than 1 in 4 patients presenting for surgery reported opioid use . These data provide important insights into this complicated patient population that would appear to help guide future preoperative optimization and perioperative opioid-weaning interventions Background : Significant pain can be experienced after laparoscopic cholecystectomy . This systematic review aims to formulate PROSPECT ( PROcedure SPECific Postoperative Pain ManagemenT ) recommendations to reduce postoperative pain after laparoscopic cholecystectomy . Methods : R and omised controlled trials published in the English language from January 2006 ( date of last PROSPECT review ) to December 2017 , assessing analgesic , anaesthetic , or operative interventions for laparoscopic cholecystectomy in adults , and reporting pain scores , were retrieved from MEDLINE and Cochrane data bases using PRISMA ( Preferred Reporting Items for Systematic Review s and Meta‐Analyses ) search protocol s. PROSPECT methodology was used , and recommendations were formulated after review and discussion by the PROSPECT group ( an international group of leading pain specialists and surgeons ) . Results : Of 1988 r and omised controlled trials identified , 258 met the inclusion criteria and were included in this review . The studies were of mixed method ological quality , and quantitative analysis was not performed because of heterogeneous study design and how outcomes were reported . Conclusions : We recommend basic analgesic techniques : paracetamol + NSAID or cyclooxygenase‐2 specific inhibitor + surgical site local anaesthetic infiltration . Paracetamol and NSAID should be started before or during operation with dexamethasone ( GRADE A ) . Opioid should be reserved for rescue analgesia only ( GRADE B ) . Gabapentanoids , intraperitoneal local anaesthetic , and transversus abdominis plane blocks are not recommended ( GRADE D ) unless basic analgesia is not possible . Surgically , we recommend low‐pressure pneumoperitoneum , postprocedure saline lavage , and aspiration of pneumoperitoneum ( GRADE A ) . Single‐port incision techniques are not recommended to reduce pain ( GRADE A ) |
13,732 | 28,656,659 | On average , people with subacute LBP who receive MBR will do better than if they receive usual care , but it is not clear whether they do better than people who receive some other type of treatment . | BACKGROUND Low back pain ( LBP ) is associated with enormous personal and societal burdens , especially when it reaches the chronic stage of the disorder ( pain for a duration of more than three months ) .
Indeed , individuals who reach the chronic stage tend to show a more persistent course , and they account for the majority of social and economic costs .
As a result , there is increasing emphasis on the importance of intervening at the early stages of LBP.According to the biopsychosocial model , LBP is a condition best understood with reference to an interaction of physical , psychological , and social influences .
This has led to the development of multidisciplinary biopsychosocial rehabilitation ( MBR ) programs that target factors from the different domains , administered by healthcare professionals from different background s .
This review is an up date of a Cochrane Review on MBR for subacute LBP , which was published in 2003 .
It is part of a series of review s on MBR for musculoskeletal pain published by the Cochrane Back and Neck Group and the Cochrane Musculoskeletal Group .
OBJECTIVES To examine the effectiveness of MBR for subacute LBP ( pain for a duration of six to 12 weeks ) among adults , with a focus on pain , back-specific disability , and work status . | OBJECTIVE For long-term treatment effects , patients with subacute back pain need to adhere to treatment recommendations beyond the prescribed exercise treatment . Adherence rates are as low as 30 % , so we developed a cognitive-behavioural training programme to enhance patients ' self-efficacy , maximise severity perceptions and reduce barrier perceptions . METHOD A 2 x 4 ( group x time ) repeated measurement design was applied . Forty-seven patients with non-specific , subacute back pain were r and omly assigned to a training group ( exercise treatment plus cognitive-behavioural training programme ) or a control group ( exercise treatment only ) . RESULTS Repeated measures ANOVA revealed significant main and interaction effects ; the training group reported enhanced self-efficacy and severity perceptions , reduced barrier perceptions , and self-reported that they exercised more often than the control group over time . However , no group differences regarding pain intensity emerged . CONCLUSION Our findings demonstrate that a short and inexpensive cognitive-behavioural training programme is an effective tool to enable back pain patients to follow treatment recommendations on a regular basis . PRACTICE IMPLICATION S The short and simple intervention can easily be conducted by personnel , other than psychologists , i.e. , physiotherapists Study Design . A r and omized controlled design superimposed on treatment as usual was used to compare the effects of a cognitive-behavior intervention aim ed at preventing chronicity with two different forms of information . Objective . To develop a coping-oriented preventive intervention applicable in primary care , and to compare its impact with educational information . Summary of Background Data . Preventing long-term disability result ing from spinal pain has proved difficult . The information provided by health care professions and early interventions aim ed at preventing long-term disability may be important , but little scientific evidence exists concerning their use . Methods . A protocol for a six-session cognitive-behavior group intervention was developed on the basis of earlier research . The main focus was to prevent long-term disability by changing patients ’ behaviors and beliefs so they can cope better with their problems . Comparison groups received either a pamphlet shown earlier to have an effect , or a more extensive information package consisting of six installments . All the groups continued to receive treatment as usual in primary care . There were 243 patients with acute or subacute spinal pain who perceived that they were at risk for developing a chronic problem . These patients were r and omized to the cognitive-behavioral intervention or one of the two information groups . Because the aim was to prevent long-term disability , the key outcome variables at the 1-year follow-up assessment were sick absenteeism and health care use . Other variables were pain , function , fear-avoidance beliefs , and cognitions . Results . The comparison groups reported benefits . However , the risk for a long-term sick absence developing was lowered ninefold for the cognitive-behavior intervention group as compared with the risk for the information groups ( relative risk , 9.3 ) . Participants in the cognitive-behavior group also reported a significant decrease in perceived risk . In addition , the cognitive-behavior group demonstrated a significant decrease in physician and physical therapy use as compared with two groups receiving information , in which such use increased . All three groups tended to improve on the variables of pain , fear-avoidance , and cognitions . Conclusions . This study demonstrates that a cognitive-behavior group intervention can lower the risk of a long-term disability developing . These findings underscore the significance of early interventions that specifically aim to prevent chronic problems . This approach might be applied to primary care setting Background To describe the design of a population based r and omized controlled trial ( RCT ) , including a cost-effectiveness analysis , comparing participative ergonomics interventions between 2–8 weeks of sick leave and Grade d Activity after 8 weeks of sick leave with usual care , in occupational back pain management . Methods Design : An RCT and cost-effectiveness evaluation in employees sick-listed for a period of 2 to 6 weeks due to low back pain . Interventions used are 1 . Communication between general practitioner and occupational physician plus Participative Ergonomics protocol performed by an ergonomist . 2 . Grade d Activity based on cognitive behavioural principles by a physiotherapist . 3 . Usual care , provided by an occupational physician according to the Dutch guidelines for the occupational health management of workers with low back pain . The primary outcome measure is return to work . Secondary outcome measures are pain intensity , functional status and general improvement . Intermediate variables are kinesiophobia and pain coping . The cost-effectiveness analysis includes the direct and indirect costs due to low back pain . The outcome measures are assessed before r and omization ( after 2–6 weeks on sick leave ) and 12 weeks , 26 weeks and 52 weeks after first day of sick leave . Discussion The combination of these interventions has been subject of earlier research in Canada . The results of the current RCT will : 1 . crossvali date the Canadian findings in an different sociocultural environment ; 2 . add to the cost-effectiveness on treatment options for workers in the sub acute phase of low back pain . Results might lead to alterations of existing (inter)national guidelines Abstract Objective : To evaluate effectiveness of an exercise programme in a community setting for patients with low back pain to encourage a return to normal activities . Design : R and omised controlled trial of progressive exercise programme compared with usual primary care management . Patients ' preferences for type of management were elicited independently of r and omisation . Participants : 187 patients aged 18 - 60 years with mechanical low back pain of 4 weeks to 6 months ' duration . Interventions : Exercise classes led by a physiotherapist that included strengthening exercises for all main muscle groups , stretching exercises , relaxation session , and brief education on back care . A cognitive-behavioural approach was used . Main outcome measures : Assessment s of debilitating effects of back pain before and after intervention and at 6 months and 1 year later . Measures included Rol and disability question naire , Aberdeen back pain scale , pain diaries , and use of healthcare services . Results : At 6 weeks after r and omisation , the intervention group improved marginally more than the control group on the disability question naire and reported less distressing pain . At 6 months and 1 year , the intervention group showed significantly greater improvement in the disability question naire score ( mean difference in changes 1.35 , 95 % confidence interval 0.13 to 2.57 ) . At 1 year , the intervention group also showed significantly greater improvement in the Aberdeen back pain scale ( 4.44 , 1.01 to 7.87 ) and reported only 378 days off work compared with 607 in the control group . The intervention group used fewer healthcare re sources . Outcome was not influenced by patients ' preferences . Conclusions : The exercise class was more clinical ly effective than traditional general practitioner management , regardless of patient preference , and was cost effective . Key messages Patients with back pain need to return to normal activities as soon as possible but are often afraid that movement or activity may be harmful An exercise programme led by a physiotherapist in the community and based on cognitive-behavioural principles helped patients to cope better with their pain and function better even one year later Patients ' preferences for type of management did not affect outcome Patients in the intervention group tended to use fewer healthcare re sources and took fewer days off work This type of exercise programme should be more widely Study Design . R and omized controlled trial . Objectives . To investigate the effectiveness and costs of a mini-intervention , provided in addition to the usual care , and the incremental effect of a work site visit for patients with subacute disabling low back pain . Summary of Background Data . There is lack of data on cost-effectiveness of brief interventions for patients with prolonged low back pain . Methods . A total of 164 patients with subacute low back pain were r and omized to a mini-intervention group ( A ) , a work site visit group ( B ) , or a usual care group ( C ) . Groups A ( n = 56 ) and B ( n = 51 ) underwent one assessment by a physician plus a physiotherapist . Group B received a work site visit in addition . Group C served as controls ( n = 57 ) and was treated in municipal primary health care . All patients received a leaflet on back pain . Pain , disability , specific and generic health-related quality of life , satisfaction with care , days on sick leave , and use and costs of health care consumption were measured at 3- , 6- , and 12-month follow-ups . Results . During follow-up , fewer subjects had daily pain in Groups A and B than in Group C ( Group A vs. Group C , P = 0.002 ; Group B vs. Group C , P = 0.030 ) . In Group A , pain was less bothersome ( Group A vs. Group C , P = 0.032 ) and interfered less with daily life ( Group A vs. Group C , P = 0.040 ) than among controls . Average days on sick leave were 19 in Group A , 28 in Group B , and 41 in Group C ( Group A vs. Group C , P = 0.019 ) . Treatment satisfaction was better in the intervention groups than among the controls , and costs were lowest in the mini-intervention group . Conclusions . Mini-intervention reduced daily back pain symptoms and sickness absence , improved adaptation to pain and patient satisfaction among patients with subacute low back pain , without increasing health care costs . A work site visit did not increase effectiveness Stopping r and omized trials early because of an apparent benefit is a growing phenomenon . A recent systematic review found that the number of r and omized trials stopped early for benefit has more than doubled since 1990 ( 1 ) . To protect and promote the interests of trial participants , investigators may feel ethically obligated to stop a trial early because of the unexpected harm or apparent benefit of a study treatment . If a study treatment 's benefit far outweighs its adverse effects , is it not unethical to continue enrolling patients in a trial in which , as is typically the case , patients have a 50 % chance of receiving a placebo or an inferior treatment ? In this article , we argue that stopping a r and omized trial early for apparent benefit is often unethical and can be justified only under restricted circumstances . If the scientific community were to accept our arguments , then the approach that investigators , institutional review boards , and data monitoring committees take to the practice of stopping trials early for apparent benefit would substantially change . Ethical Considerations Emanuel and colleagues ( 2 ) describe a framework of 7 requirements for determining whether clinical research is ethical . We use this framework to identify and assess the ethical issues raised by stopping trials early because of apparent benefit ( Table ) . Table . Ethical Violations Result ing from Stopping a Trial Early for Apparent Benefit Scientific Validity The purpose of a trial of alternative interventions is to generate an estimate of treatment effect that closely approximates the true effect and is not misleading . This requires application of scientific procedures that yield valid and reliable data and thus minimize both systematic and r and om error . A systematic review of r and omized trials stopped early for apparent benefit ( 1 ) found that many of the trials yielded implausibly large treatment effects ; the median relative risk was 0.53 . Apparent large treatment effects occurred much more frequently when trials accrued only a small number of events . The odds of a treatment effect larger than the overall median relative risk of 0.53 was 28 times greater ( 95 % CI , 11 to 73 ) among trials in which fewer than the median of 66 events accrued than among trials in which more events accrued . These results , which are consistent with predictions from statistical theory ( 3 ) , suggest that stopping trials early for apparent benefit will systematic ally overestimate treatment effects . The scientific validity of trials that are stopped early is further compromised when trials yield inconclusive data about outcomes that did not influence trial truncation but are nonetheless important to patients , such as disease-free survival , symptom control , quality of life , and adverse effects of treatment . For example , a trial of vitamin E supplementation in premature newborns that was stopped early because of an apparent reduction in intracranial hemorrhage ( 4 ) failed to detect the increase in sepsis associated with vitamin E supplementation that subsequent trials identified ( 5 ) . Social or Scientific Value and Favorable RiskBenefit Ratio It is underst and able that investigators focus their ethical obligations on research participants . Such focus , however , risks neglecting obligations to society . The tendency of truncated trials to overestimate the effect of a treatment on the end point that result ed in trial truncation and to yield insufficient data about other important outcomes endangers the wider community to whom the results will be applied ( 6 ) . On review ing the results of a truncated trial , astute clinicians might appropriately conclude that the benefits of the intervention remain uncertain . However , less skeptical clinicians might assume that the results are true and inappropriately expose patients to the intervention and its unknown harms . Consider the results of a trial in which the investigators continued to enroll patients even though prespecified criteria for early stopping were met . Two interim analyses of a r and omized trial of 5 versus 4 courses of chemotherapy in patients with acute myeloid leukemia ( 7 ) found apparent large benefits to the 5-course regimen ( relative odds reduction of 53 % [ CI , 23 % to 71 % ; P= 0.003 ] in the first analysis and 45 % [ CI , 20 % to 62 % ; P= 0.0002 ] in the second analysis ) . Finding these results too good to be true , the data monitoring committee recommended continuing the trial , which ultimately showed a trend in favor of the 4-course regimen . Had the investigators terminated the trial in accordance with their stopping rule , subsequent patients with leukemia may have experienced the toxicity of an additional course of chemotherapy without benefit . Harm result ing from the misleading findings of truncated trials can be compounded if the findings influence the recommendations of clinical practice guideline panels . Investigators conducting a trial that involved patients undergoing vascular surgery ( 8) stopped the trial early when 2 of 53 patients r and omly assigned to receive the -blocker bisoprolol and 18 of 59 control patients had major cardiovascular events ( relative risk reduction , 90 % [ CI , 59 % to 98 % ] ) . These results contributed to recommendations by the American Heart Association and the American College of Cardiology favoring administration of -blockers to patients with cardiac risk factors who were undergoing noncardiac surgery ( 9 ) . However , these results contradict those of 2 much larger subsequently published trials , neither of which suggested that -blockers reduce cardiac risk in patients undergoing noncardiac surgery ( 10 , 11 ) . Further social detriment may occur when clinicians compromise the ability of others to conduct more definitive studies by placing undue confidence in the results of a truncated trial . Investigators ( including 2 contributors to this article ) who obtained funding for a trial of -blockers in noncardiac surgery with an enrollment target of 10000 patients ( 12 ) faced challenges in persuading clinicians that the question remained unanswered . Participant Consent and Respect for Participants Key prerequisites for informed consent include the participant 's decision-making capacity and voluntariness and whether he or she had received adequate information to decide that participation in the research was in alignment with his or her values and goals . However , informed consent is not a single event , but it is an ongoing collaboration between participants and investigators . When important changes occur during a trial , investigators should inform participants of the changes . One justification for stopping a trial early for benefit is to inform study participants of the preliminary results and offer them the superior treatment . According to this argument , uncertainty about the relative merits of alternative interventions ( equipoise ) has been lost and informed clinicians and patients will overwhelmingly choose the superior treatment ( 13 ) . However , as we have pointed out , the astute clinician or patient may remain skeptical about a treatment 's apparent benefits if the findings come from a truncated trial . Unfortunately , many clinicians and even more patients probably will not have the knowledge and underst and ing to appropriately interpret the results . Disclosing interim results to study participants may therefore prove misleading . Furthermore , if investigators were to continue a trial after informing patients of the interim results , patients would be unblinded and may cross over or leave the trial . These behaviors create problems in interpreting trial results by further weakening inferences about the efficacy and safety of the intervention and compromising the ethical requirement of scientific validity . Finally , stopping a trial early does not guarantee that current and potential trial participants will receive the apparently beneficial treatment ( assuming that one believes they should ) . Studies of dissemination of new treatments reveal that long delays , such as those between reports of r and omized trials and recommendations of experts in review articles and textbooks , are common ( 14 ) . Continuing a 2-group trial gives participants at least a 50 % chance of receiving the experimental treatment , whereas if the trial is stopped early , the probability that participants will receive the treatment due to rapid dissemination is likely to be considerably less than 50 % . Independent Review Trials may have stopping rules that allow early termination because of genuine ( although misguided ) ethical concerns . However , investigators , trial sponsors , journals , and patients may all have additional motives for stopping trials early for apparent benefit . For example , truncated trials that report a large treatment effect tend to be published in the most prestigious medical journals ( 1 ) , which enhances the careers of the investigators and increases the likelihood that they will receive grants . Funding agencies have an interest in stopping trials early to minimize research costs . Pharmaceutical and for-profit sources that financially support trials are interested not only in controlling costs but also in the publicity and market share that result from reporting a trial stopped early for apparent benefit . Medical journals are interested in these trials because of publicity and citations , which result in increased journal impact factor , prestige , and advertising revenue . And patients and their advocates are motivated to stop a trial early when the experimental intervention is promising in order to hasten delivery of the intervention to clinical practice . All of these motives may affect investigators ' decisions and encourage an inappropriately early stop to a trial . These considerations m and ate that institutional review boards and data monitoring committees underst and the principles outlined in this article and insist on appropriate st and ards for stopping a trial early for apparent benefit to maintain the ethical integrity of clinical trials . Background Non-specific low back pain is a common cause for consultation with the general practitioner , generating increased health and social costs . This study will analyse the effectiveness of a multidisciplinary intervention to reduce disability , severity of pain , anxiety and depression , to improve quality of life and to reduce the incidence of chronic low back pain in the working population with non-specific low back pain , compared to usual clinical care . Methods / Design A Cluster r and omised clinical trial will be conducted in 38 Primary Health Care Centres located in Barcelona , Spain and its surrounding areas . The centres are r and omly allocated to the multidisciplinary intervention or to usual clinical care . Patients between 18 and 65 years old ( n = 932 ; 466 per arm ) and with a diagnostic of a non-specific sub-acute low back pain are included . Patients in the intervention group are receiving the recommendations of clinical practice guidelines , in addition to a biopsychosocial multidisciplinary intervention consisting of group educational sessions lasting a total of 10 hours . The main outcome is change in the score in the Rol and Morris disability question naire at three months after onset of pain . Other outcomes are severity of pain , quality of life , duration of current non-specific low back pain episode , work sick leave and duration , Fear Avoidance Beliefs and Goldberg Question naires . Outcomes will be assessed at baseline , 3 , 6 and 12 months . Analysis will be by intention to treat . The intervention effect will be assessed through the st and ard error of measurement and the effect-size . Responsiveness of each scale will be evaluated by st and ardised response mean and receiver-operating characteristic method . Recovery according to the patient will be used as an external criterion . A multilevel regression will be performed on repeated measures . The time until the current episode of low back pain takes to subside will be analysed by Cox regression . Discussion We hope to provide evidence of the effectiveness of the proposed biopsychosocial multidisciplinary intervention in avoiding the chronification of low back pain , and to reduce the duration of non-specific low back pain episodes . If the intervention is effective , it could be applied to Primary Health Care Centres . Trial Registration IS RCT Study Design . Population ‐based r and omized clinical trial . Objectives . To develop and test a model of management of subacute back pain , to prevent prolonged disability . Summary of Background Data . The present management of back pain seems inadequate , and development of innovative models has been urged . Methods . A model for the treatment of subacute work‐related back pain has been developed and evaluated in a population ‐based r and omized clinical trial . Workers ( n = 130 ) from eligible workplaces in the Sherbrooke area ( N = 31 ) , who had been absent from work for more than 4 weeks for back pain , were r and omized , based on their workplace , in one of four treatment groups : usual care , clinical intervention , occupational intervention , and full intervention ( a combination of the last two ) . The duration of absence from regular work and from any work was evaluated using survival analysis . Functional status and pain were compared at study entry and after 1 year of follow‐up . Results . The full intervention group returned to regular work 2.41 times faster than the usual care intervention group ( 95 % confidence interval 1.19‐4.89 ; P = 0.01 ) . The specific effect of the occupational intervention accounted for the most important part of this result , with a rate ratio of return to regular work of 1.91 ( 95 % confidence interval = 1.18‐3.10 ; P < 0.01 ) . Pain and disability scales demonstrated either a statistically significant reduction or a trend toward reduction in the three intervention groups , compared with the trend in the usual care intervention group . Conclusions . Close association of occupational intervention with clinical care is of primary importance in impeding progression toward chronicity of low back pain The aim of the pilot study was to evaluate a multidisciplinary program for nonspecific low back pain ( NSLBP ) at a major U.S. Navy base . In this single blinded r and omized clinical trial , subjects were drawn from a larger , prospect i ve cohort of active duty service members seeking care for NSLBP pain at a U.S. Navy Branch Medical Clinic . Outcome measures included return to work , self-reported pain , function , and psychological distress . Subjects were r and omly allocated to one of two study arms : a multidisciplinary reconditioning program or the current st and ard of care for low back pain . The intervention lasted 4 weeks with a 12-week follow-up . Thirty-three subjects were enrolled . Subjects allocated to multidisciplinary care reported significantly lower perceived disability ( p = 0.014 ) and less pain than those allocated to usual care at the end of the intervention period . All subjects returned to their usual duty following the conclusion of the intervention . The implementation of the intervention program was successful . Subjects in the multidisciplinary program showed a clinical ly significant improvement in the perception of disability compared to the usual care group . This is an important finding since perception of disability is associated with long-term functional outcome Back-pain patients with onset in the preceding 1–10 days and comparable on a back examination were r and omly assigned to traditional management ( A regimen ) and behavioral treatment methods ( B regimen ) . Patients were compared at 6 weeks and 9–12 months on a set of “ Sick/Well ” scores derived from patient reported vocational status ( V ) , health-care utilization ( HCU ) , cl aim ed impairment ( CI ) , and pain drawings ( D ) and on two measures of activity level . No differences were found at 6 weeks , but at 9–12 months , A-group S 's were more “ sick . ” No A/B differences were found on activity-level measures . Group A S 's showed significant increases in cl aim ed impairment from preonset to follow-up , whereas Group B S 's had returned at follow-up to preonset Study Design . R and omized controlled trial . Objectives . To compare high- and low-intensity back schools with usual care in occupational health care . Summary of Background Data . The content and intensity of back schools vary widely and the method ologic quality of r and omized controlled trials is generally weak . Until now , no back school has proven to be superior for workers sick-listed because of subacute nonspecific low back pain . Methods . Workers ( n = 299 ) sick-listed for a period of 3 to 6 weeks because of nonspecific low back pain were recruited by the occupational physician and r and omly assigned to a high-intensity back school , a low-intensity back school , or care as usual . Outcome measures were days until return to work , total days of sick-leave , pain , functional status , kinesiophobia , and perceived recovery and were assessed at baseline and at 3 and 6 months of follow-up . Principal analyses were performed according to the intention-to-treat principle . Results . We r and omly allocated 299 workers . Workers in the low-intensity back school returned to work faster compared with usual care and the high-intensity back school , with hazard ratios of 1.4 ( P = 0.06 ) and 1.3 ( P = 0.09 ) , respectively . The comparison between high-intensity back school and usual care result ed in a hazard ratio of 1.0 ( P = 0.83 ) . The median number of sick-leave days was 68 , 75 , and 85 in the low-intensity back school , usual care , and high-intensity back school , respectively . Beneficial effects on functional status and kinesiophobia were found at 3 months in favor of the low-intensity back school . No substantial differences on pain and perceived recovery were found between groups . Conclusions . The low-intensity back school was most effective in reducing work absence , functional disability , and kinesiophobia , and more workers in this group scored a higher perceived recovery during the 6-month follow-up Study Design . R and omized clinical trial comparing two interventions in employees sick-listed 3 to 16 weeks because of low back pain ( LBP ) . Objective . To compare 1-year return to work ( RTW ) , pain , disability and physical and mental health dimensions in subjects offered a hospital-based multidisciplinary intervention or a brief intervention . Summary of Background Data . Previous studies in sick-listed employees with LBP have indicated efficacy of both brief and more comprehensive multidisciplinary interventions . However , it remains unknown , which is the more effective , and which elements are instrumental in furthering RTW , and improving health . Methods . The brief intervention comprised clinical examination and advice offered by a rehabilitation physician and a physiotherapist . In the multidisciplinary intervention , this intervention was supplemented with the expertise of a team and the assignment of a case manager who drew up a rehabilitation plan in collaboration with the patient and the multidisciplinary team . One-year RTW was estimated by data from a comprehensive national data base of social transfer payments . Question naires were used to obtain baseline and 1-year data on Rol and Morris disability score , LBP Rating Scale , SF36 , and fear-avoidance . Results . A total of 351 patients were included and r and omized and 344 ( 98 % ) patients participated in all the consultations according to the study protocol . RTW was achieved by 125 ( 71.0 % ) participants in the multidisciplinary and 133 ( 76.0 % ) participants in the brief intervention group . The hazard ratio was 0.84 after adjustment for sex , age , smoking , compensation cl aims , disability score , and diagnosis ( 95 % confidence interval [ CI ] : 0.65–1.08,P = 0.18 ) . Multiple linear regression analysis displayed no differences in secondary outcomes , except for the mental health score ( SF36 ) , which was a little higher in the multidisciplinary intervention group than in the brief intervention group . Conclusion . Hospital-based multidisciplinary intervention may be no better than brief intervention to increase RTW and improve health in sick-listed employees with low back pain Background Multidisciplinary intervention is recommended for rehabilitation of employees sick-listed for 4 - 12 weeks due to low back pain ( LBP ) . However , comparison of a brief and a multidisciplinary intervention in a r and omised comparative trial of sick-listed employees showed similar return to work ( RTW ) rates in the two groups . The aim of the present study was to identify subgroups , primarily defined by work-related baseline factors that would benefit more from the multidisciplinary intervention than from the brief intervention . Methods A total of 351 employees sick-listed for 3 - 16 weeks due to LBP were recruited from their general practitioners . They received a brief or a multidisciplinary intervention . Both interventions comprised clinical examination and advice by a rehabilitation doctor and a physiotherapist . The multidisciplinary intervention also comprised assignment of a case manager , who made a rehabilitation plan in collaboration with the patient and a multidisciplinary team . Using data from a national data base , we defined RTW as no sickness compensation benefit disbursement for four consecutive weeks within the first year after the intervention . At the first interview in the clinic , it was ensured that sick leave was primarily due to low back problems . Question naires were used to obtain data on health , disability , demographic and workplace-related factors . Cox hazard regression analyses were used with RTW as outcome measure and hazard rate ratios ( HRR = HRmultidisciplinary/HRbrief ) were adjusted for demographic and health-related variables . An interaction term consisting of a baseline variable*intervention group was added to the multivariable regression model to analyse whether the effects of the interventions were moderated by the baseline factor . Subsequently , a new study was performed that included 120 patients who followed the same protocol . This group was analyzed in the same way to verify the findings from the original study group . Results The multidisciplinary intervention group ensured a quicker RTW than the brief intervention group in a subgroup with low job satisfaction , notably when cl aim ants were excluded . The opposite effect was seen in the subgroup with high job satisfaction . When cl aim ants were excluded , the effect was also in favour of the multidisciplinary intervention in subgroups characterised by no influence on work planning and groups at risk of losing their job . Inversely , the effect was in favour of the brief intervention in the subgroups who were able to influence the planning of their work and who had no risk of losing their job due to current sick leave . Interaction analysis of the data in the new study displayed similar or even more pronounced differences between subgroups in relation to intervention type . Conclusions Multidisciplinary intervention seemed more effective than brief intervention in subgroups of patients with low job satisfaction , no influence on work planning and feeling at risk of losing their jobs due to their sick leave as compared with subgroups not fulfilling these criteria The objective of this study is to compare the costs and benefits of a grade d activity ( GA ) intervention to usual care ( UC ) for sick-listed workers with non-specific low back pain ( LBP ) . The study is a single-blind , r and omized controlled trial with 3-year follow-up . A total of 134 ( 126 men and 8 women ) predominantly blue-collar workers , sick-listed due to LBP were recruited and r and omly assigned to either GA ( N = 67 ; mean age 39 ± 9 years ) or to UC ( N = 67 ; mean age 37 ± 8 years ) . The main outcome measures were the costs of health care utilization during the first follow-up year and the costs of productivity loss during the second and the third follow-up year . At the end of the first follow-up year an average investment for the GA intervention of € 475 per worker , only € 83 more than health care utilization costs in UC group , yielded an average savings of at least € 999 ( 95 % CI : −1,073 ; 3,115 ) due to a reduction in productivity loss . The potential cumulative savings were an average of € 1,661 ( 95 % CI : −4,154 ; 6,913 ) per worker over a 3-year follow-up period . It may be concluded that the GA intervention for non-specific LBP is a cost-beneficial return-to-work intervention The aim of this study was to determine whether grade d activity restored occupational function in industrial blue-collar workers who were sick-listed for 8 weeks because of subacute , nonspecific , mechanical low back pain ( LBP ) . Patients with LBP , who had been examined by an orthopedic surgeon and a social worker , were r and omly assigned to either an activity group ( n = 51 ) or a control group ( n = 52 ) . Patients with defined orthopedic , medical , or psychiatric diagnoses were excluded before r and omization . The grade d activity program consisted of four parts : ( 1 ) measurements of functional capacity ; ( 2 ) a work-place visit ; ( 3 ) back school education ; and ( 4 ) an individual , submaximal , gradually increased exercise program , with an operant-conditioning behavioral approach , based on the results of the tests and the dem and s of the patient 's work . Records of the amount of sick leave taken over a 3-year period ( ie , the 1-year periods before , during , and after intervention ) were obtained from each patient 's Social Insurance Office . The patients in the activity group returned to work significantly earlier than did the patients in the control group . The median number of physical therapist appointments before return to work was 5 , and the average number of appointments was 10.7 ( SD = 12.3 ) . The average duration of sick leave attributable to LBP during the second follow-up year was 12.1 weeks ( SD = 18.4 ) in the activity group and 19.6 weeks ( SD = 20.7 ) in the control group . Four patients in the control group and 1 patient in the activity group received permanent disability pensions . The grade d activity program made the patients occupationally functional again , as measured by return to work and significantly reduced long-term sick leave OBJECTIVES To assess the feasibility of patient recruitment , the ability of patients and clinicians to comply with study protocol s , and the use of data collection instruments to collect cost-effectiveness data , and to obtain variability estimates for sample -size calculations for a full-scale trial . STUDY DESIGN Prospect i ve , observer-blinded , pilot r and omized clinical trial . SETTING Primary contact chiropractic and medical clinics . PATIENTS Ages 20 to 65 years , with low back-related radiating leg pain ( sciatica ) . OUTCOME MEASURES Self-report question naires were administered at baseline and 3 and 12 weeks after r and omization . The measures included leg and back pain severity , frequency and bothersomeness of symptoms , leg/back disability , medication use , global improvement , satisfaction , and health care utilization . INTERVENTIONS Medical care , chiropractic care , and epidural steroid injections . RESULTS A total of 706 persons were screened by phone to determine initial eligibility . Of these , over 90 % of those persons contacted did not meet the entrance criteria . The most common reason for disqualification was that the duration of the complaint was longer than 3 months . Twenty patients were r and omized into the study . All 3 groups showed substantial improvements in the main patient-rated outcomes at the end of the 12-week intervention phase . For leg pain , back pain , frequency and bothersomeness of leg symptoms , and Rol and -Morris disability score , the percent improvement varied from 50 % to 84 % , and the corresponding effect sizes ranged from 0.8 to 2.2 . Bothersomeness of leg symptoms was the most responsive outcome associated with the largest magnitude of effect size . All within-group changes from baseline were statistically significant ( P < .01 ) . No between-group comparisons were planned or performed because of the insufficient sample size and high risk of committing type I and type II errors . CONCLUSIONS Pilot studies such as these are important for the determination of the feasibility of conducting costly , larger scale trials . Recruitment for a full-scale study of sciatica of 2 to 12 weeks duration is not feasible , given the methods used in this pilot study . Our results do indicate , however , that there are substantial numbers of patients with sciatica more chronic in nature who would be interested in participating in a similar study . In addition , collaboration with a local health maintenance organization would likely facilitate clinician referrals and optimize the recruitment process . Patient and provider compliance was high in the pilot study , which indicates that most study protocol s are feasible . Additionally , we were able to collect complete outcomes data , including those regarding health care use . A suggested modification by investigators and outside consultants has result ed in the replacement of the medication group with a minimal intervention control group ( ie , self-care advice ) . As a result , a second pilot study of patients with sciatica of more than 4 weeks duration has been planned before a full-scale trial is attempted OBJECTIVE The objective of this study was to examine whether a multimodal , secondary prevention program ( MP ) is superior to a general physical exercise program ( EP ) in influencing the process leading to chronic low back pain ( LBP ) in nurses with a history of back pain . DESIGN The study was conducted as a r and omized controlled parallel-group trial . SETTING The interventions were performed in a single center at the Department of Physical and Rehabilitation Medicine at the University of Munich in Germany . PARTICIPANTS A total of 235 nurses from 14 nearby hospitals and nursing homes who experienced at least one episode of back pain during the previous 2 years were invited into the study . Of these , 183 nurses were enrolled and 169 ( 83 in the MP and 86 in the EP ) qualified for the intent-to-treat analysis . INTERVENTIONS The EP consisted of 11 group sessions , each lasting 1 hour . After introductory sessions , subsequent sessions included general physical strengthening and stretching exercises as well as instructions for a home-training program . The MP consisted of 17 group sessions of 1.75 hours and one individual session of 45 minutes . In addition to the full EP , the MP included 5 psychological units , 7 segmental stabilization exercises units , and 8 ergonomic and workplace-specific units . MAIN OUTCOME MEASUREMENTS The primary study end-point variable was pain interference , and the secondary study end-point variables were pain intensity and functioning as measured with the West Haven-Yale Multidimensional Pain Inventory and the Short Form-36 , respectively . These study end-point variables were defined a priori . RESULTS There was no statistically significant difference between the 2 groups . Small-to-moderate effects were observed in both intervention programs across all study end-point variables . For pain interference , the effect size at 12 months after intervention was 0.58 in the MP and 0.47 in the EP . CONCLUSIONS A multimodal program is not superior to a general exercise program in influencing the process leading to chronic LBP in a population of nurses with a history of pain . The most likely explanation is a common psychological mechanism leading to improved pain interference that is irrespective of the program used . Considering the lower re sources of the general exercise program , the expense for a multimodal program is not justified for the secondary prevention of LBP and disability STUDY DESIGN An investigation of the efficacy of an individually scheduled , risk factor-based cognitive behavioral therapy and a st and ardized electromyographic biofeedback intervention in the prevention of chronicity in patients with acute sciatica and psychosocial risk factors for chronicity . OBJECTIVES To investigate the possibility of enhancing pain relief and preventing chronicity in patients with acute sciatica , based on a screening for psychosocial high-risk factors of chronification . SUMMARY OF BACKGROUND DATA Psychological interventions were evaluated mainly in patients with chronic low back pain . Numerous r and omized trials have demonstrated their efficacy , whereas the amount of pain relief was found to be marginal . METHODS Subjective and behavioral outcome parameters were compared with the respective parameters in age- , gender- , and diagnosis-matched high- and low-risk patients . No additional behavioral treatment for in-patient medical therapy was offered to the patients . Outcome of these patients also was compared with that of a group of refusers of behavioral therapy . Psychological , functional , and behavioral variables were measured before and after treatment and at 3- , 6- , 12- and 18-month follow-up visits . Changes over time , group differences , and possible group x time interactions were analyzed by analysis of variance and nonparameteric comparisons . RESULTS Data analysis showed a statistically and clinical ly significant , beneficial effect of both behavioral interventions . However , risk factor-based cognitive behavioral therapy was superior to electromyographic biofeedback intervention with respect to pain relief and application for early retirement . The cognitive behavioral therapy showed a similar good outcome ( e.g. , 90 % showed a clinical significant pain reduction ) as the low-risk patients ( 83 % pain reduction ) . High risk patients and refusers of therapy showed a poor outcome in pain ( 33 % and 20 % pain reduction , respectively ) , disability , and work performance . CONCLUSIONS Individually scheduled , risk factor-based cognitive behavior therapy could be a beneficial treatment modality , which can be offered , in addition to a medical treatment , to patients with acute sciatica and psychosocial high risk factors for chronicity . It may be an effective way to prevent chronification in these patients This r and omized controlled clinical trial compares the effectiveness of a biopsychosocial treatment with a solely conventional biomedical therapy in patients with subacute low back pain using parameters for pain intensity , functional status , depressive dysfunction and work performance . Sixty-four patients with a first-time sick leave between 3 and 12 weeks due to low back pain were r and omly assigned to either a conventional biomedical therapy ( MT ; n=33 ) group , or a biopsychosocial therapy ( BT ; n=31 ) group including a psychotherapeutic module ; both in accordance with a st and ardized 3 weeks inpatient treatment . Pain intensity , functional back capacity , clinical parameters and depressive dysfunction revealed significant improvement in both treatment groups at end of 3 weeks therapy ( T1 ) . However , at 6 months ( T2 ) , analysis revealed significant better results for nearly all parameters in the BT group that showed further improvement from T1 to T2 , whereas the values in the MT group deteriorated from T1 back to the baseline values . During the 2-year period after therapy , 10 % in MT and 59 % in BT required no further sick leave due to low back pain . The results of the study indicate that a psychotherapeutic element in the treatment of low back pain appears to positively influence pain , functional status and work performance when conducted at an early stage of chronification and helps in the achievement of a better outcome A new r and omised controlled trial of intervention in low back pain has been described recently . In this trial , a screening and targeted approach was found to be more effective and cost-effective than current best practice . Nested within the intervention arm were three different interventions targeting patients identified as ' low ' , ' medium ' or ' high ' risk dependent on the presence of ( mainly ) psychosocial risk factors . In this paper , the development and content of the STarT Back trial 's ' high-risk ' intervention is described . It offers a systematic approach , termed ' psychologically informed practice ' , to the integration of physical and psychological approaches to treatment for the management of people with low back pain by physiotherapists . The term ' disability ' is used to refer to self-reported pain-associated functional limitations , and ' psychological ' is used to refer to the beliefs/expectations , emotional responses and behavioural responses associated with low back pain Context Low back pain causes frequent disability and lost productive time . Contribution This r and omized trial compared a behavioral-oriented grade d activity program with usual care in 134 Dutch airline company workers who had missed work because of persistent low back pain . Grade d activity consisted of biweekly 1-hour exercise sessions with physiotherapists who emphasized operant-conditioning principles . Over 6 months of follow-up , participants in the grade d activity program missed 58 days of work , while participants receiving usual care missed 87 days . Implication s A behavioral-oriented grade d activity program returned participants with low back pain to work more often than did usual care . The Editors Nonspecific low back pain is an uncomfortable medical condition that causes frequent disability and absence from work . Most episodes of low back pain resolve fairly quickly and cause only short periods of absence from work . However , some workers with low back pain miss work for several days to weeks and are at risk for more permanent disability ( 1 ) . To reduce the individual and socioeconomic burden related to this absenteeism , we need effective intervention strategies in occupational health care setting s that promote safe and rapid return to work . One promising and often-advocated intervention strategy for workers with prolonged nonspecific low back pain is active rehabilitation that is directed toward return to normal activity and work ( 2 ) . Examples are grade d activity interventions that include physical exercise , application of operant-conditioning behavioral principals , and promotion of improved functioning and safe return to work even if pain persists ( 3 - 6 ) . In a r and omized , controlled trial , Lindstrm and colleagues ( 3 , 4 ) found that a grade d activity intervention reduced absence from work more than did traditional care in Swedish workers employed in the automobile industry . We investigate , in a second r and omized , controlled trial , whether absence from work because of low back pain is reduced more with grade d activity intervention than with traditional care in an occupational health care setting in the Netherl and s. Methods Study Design and Sample The study was a single-blind , r and omized , controlled trial in an occupational health services center ( KLM Health , Safety and Environment ) at Schiphol Airport , Amsterdam , the Netherl and s. The center provides occupational health services for all employees of a major Dutch airline ( KLM Royal Dutch Airlines ) . The source sample ( n = 20 000 ) consisted of workers who were employed in the following organizational units of the airline : baggage and aircraft turnaround services , passenger services , engineering and maintenance , cargo , and cabin and cockpit . Workers who were listed as absent from work because of low back pain were invited for a consultation with the occupational physician . Those who were thought to be eligible for inclusion were referred to the research assistant , who judged whether they met the inclusion criteria : full or partial absence from work because of nonspecific low back pain and low back pain symptoms with a minimum duration of 4 weeks in succession . The exclusion criteria were low back pain with radiation below the knee with signs of nerve-root compression ( 7 ) ; cardiovascular contraindications for physical activity , as checked according to the Physical Activities Readiness Question naire ( 8 , 9 ) ; any conflict between worker and employer with legal involvement ; or pregnancy . Workers who met the inclusion criteria were informed of the purpose and procedures of the study and were enrolled after giving informed consent . The Medical Ethical Committee of the VU University Medical Center , Amsterdam , the Netherl and s , approved the study . Treatment Allocation The participants were assigned to grade d activity or usual care on the basis of block r and omization , after prestratification for the organizational unit in the workplace from which they were recruited ( the 5 organizational units listed earlier ) and for the severity of pain symptoms ( scored on a scale of 0 to 10 ; severity scores were < 6 or 6 points ) . This result ed in a total of 10 strata . R and omized , permuted blocks of 4 allocations were generated for each stratum through a computer-generated r and om-sequence table . Opaque , sequentially numbered , sealed envelopes were prepared for each stratum by a research er who was not involved in enrolling the participants or assigning them to their groups . The envelopes contained a sheet of paper that indicated 1 of the 2 interventions . Participants learned their group assignments after a research assistant completed the baseline measurements and delivered the sealed envelopes . Blinding The research assistants who collected the data were blinded to the treatment allocation . All participants were repeatedly asked not to reveal any information about their treatment allocation . The participants and treatment providers were not blinded to treatment allocation . Interventions In the Dutch occupational health care system , occupational physicians guide disabled workers who are absent from work through their disability period . These occupational physicians are employed by occupational health services that are paid for by the companies . The occupational physicians adhere to back pain management strategies that consist of advising workers on ergonomics , prevention , and return-to-work schedules and advising and communicating with other stakeholders ( such as health care providers and representatives of the workplace ) . Disabled workers who participated in the present study were assigned to either grade d activity or usual care within the context of the Dutch occupational health care setting . Grade d Activity The intervention group received the usual guidance from the occupational physician about work-related problems and barriers to return to work as well as the grade d activity intervention supervised by a physiotherapist . Three physiotherapists who worked in a private practice at Schiphol Airport provided the treatment according to the grade d activity protocol . Two of those physiotherapists were also trained as manual therapists , and 1 was also a human movement scientist . Before the study , the physiotherapists had been specifically trained to treat patients with low back pain according to behavioral principles . A research physiotherapist who was experienced in treating patients with chronic pain in rehabilitation centers instructed the physiotherapists in three 2-hour sessions and practice d patienttherapist interactions with them through role-play . Before the study , the physiotherapists treated several patients according to the grade d activity protocol to gain more experience . The physiotherapists made audiotapes of the intervention sessions before and during the study period . The contents of these audiotapes were assessed and discussed with the research physiotherapist in 3 additional meetings . Furthermore , the physiotherapists summarized the treatment after each session , and research ers used these summaries to review the sessions . The same physiotherapist treated participants each time , except for temporary st and -in sessions that were supervised by colleagues because of holidays or other reasons . Specific therapists were not systematic ally selected to treat specific participants ; selection was based on pragmatic reasons , such as the time available in the work schedules of the physiotherapists or the days of treatment preferred by the participants . Table 1 presents the concept and content of the grade d activity intervention . The intervention consisted of 1-hour exercise sessions that participants attended twice per week until they returned completely to regular work or until the maximum therapy duration of 3 months was reached . At the start of the intervention , the physiotherapist inquired about the participant 's medical history and completed a brief physical examination consisting of flexion , extension , and lateroflexion of the lumbar spine and a brief screening for nerve-root pain ( 10 ) . The purpose of the physical examination was to confirm the diagnosis of benign , nonspecific low back pain and to reduce participants ' fears about any presumed underlying disease . The participants were reassured that despite the annoying pain , nothing was seriously wrong with their backs . Subsequently , the physiotherapist and participant decided on a set of general exercises and individually tailored exercises . Both types of exercises had to be performed during each session . The general exercises were aerobic exercises , such as cycling or rowing , and strengthening exercises for large muscle groups , and most were carried out in a gym while using exercise equipment . The strengthening exercises were a floor abdominal sit-up exercise , a dynamic back extension exercise , a leg-press exercise , a latissimus pull-down exercise , and st and ing up from a low chair . Participants in the grade d activity group had to perform not only these general exercises but also individually tailored exercises , which imitated physical tasks at work or difficult and painful activities of daily living . For example , a participant who reported back problems while lifting and moving suitcases from a luggage wagon into an airplane might be given an exercise to practice lifting and moving a suitcase with a certain number of repetitions . During the first 3 sessions , the maximal performance ( for example , the maximum number of repetitions ) was assessed for each exercise separately , and the average score for each exercise over the 3 sessions was used as a baseline value for specifying a gradually progressive exercise scheme . Subsequently , the participant was asked to propose a date for full return to regular work , which would consequently be the end point of the physical exercise program . Before returning to full regular work , participants could return to work with modified hours and duties . Advised by the physiotherapist , the participant Study Design Low back pain patients seen in primary care were allocated r and omly to one of two educational interventions or to usual care . Objective To evaluate educational interventions design ed to improve the outcomes of primary care for low back pain . Summary of Background Data Patients with back pain are frequently dissatisfied with their medical care and identify lack of information as the most insufficient aspect . Methods In a large Health Maintenance Organization clinic , 293 subjects were allocated r and omly to receive usual care , an educational booklet , or a 15-minute session with a clinic nurse , including the booklet and a follow-up telephone call . Outcome measures included satisfaction with care , perceived knowledge , participation in exercise , functional status , symptom relief , and health care use . Outcomes were assessed 1 , 3 , 7 , and 52 weeks after the intervention . Results The nurse intervention result ed in higher patient satisfaction than usual care ( P < 0.001 ) and higher perceived knowledge ( P < 0.001 ) . Self-reported exercise participation was also higher in the nurse intervention group after a 1-week follow-up period ( 97 % vs. 65 % in the other groups ; P < 0.0001 ) . There were no significant differences among the three groups in worry , symptoms , functional status , or health care use at any follow-up interval . Differences in self-reported exercise and perceived knowledge were no longer significant after 7 weeks . Conclusions These findings challenge the value of purely educational approaches in reducing functional impact or health care use related to back pain and also challenge the value of fitness exercise in the most acute phase of back pain OBJECTIVES To evaluate the effects of a behavioral medicine intervention , relative to an attention control , in preventing chronic pain and disability in patients with first-onset , subacute low back pain ( LBP ) with limitations in work-role function . DESIGN A 2-group , experimental design with r and omization to behavioral medicine or attention control groups . SETTING Orthopedic clinic at a Naval Medical Center . PARTICIPANTS Sixty-seven participants with first-onset LBP of 6 to 10 weeks of duration and impairment in work function , of whom 50 completed all 4 therapy sessions and follow-up 6 months after pain onset . INTERVENTION Four 1-hour individual treatment sessions of either behavioral medicine , focused on back function and pain education , self-management training , grade d activity increases , fear reduction , and pain belief change ; or attention control condition , focused on empathy , support , and reassurance . MAIN OUTCOME MEASURES The primary outcome was proportion of participants classified as recovered , according to pre-established clinical cutoffs on st and ardized measures , signifying absence of chronic pain and disability at 6 months after pain onset . Secondary analyses were conducted on pain , disability , health status , and functional work category . Intervention credibility and pain belief manipulation checks were also evaluated . RESULTS Chi square analyses comparing proportions recovered at 6 months after pain onset for behavioral medicine and attention control participants found relative rates of 52 % versus 31 % in the modified intent-to-treat sample ( P=.09 ) and 54 % versus 23 % for those completing all 4 sessions and 6-month follow-up ( P=.02 ) . At 12 months , 79 % of recovered and 68 % of chronic pain participants still met criteria for their respective groups ( P<.0001 ) . Recovered participants also had higher rates of functional work status recovery at 12 months ( recovered : 96 % full duty and 4 % light duty ; chronic pain : 61 % full duty , 18 % light duty , and 21 % medical discharge , respectively ; P=.03 ) . CONCLUSIONS Early intervention using a behavioral medicine rehabilitation approach may enhance recovery and reduce chronic pain and disability in patients with first-onset , subacute LBP . Effects are stronger for participants attending all 4 sessions and the follow-up assessment Because back pain is a widespread and costly condition that tends to recur , treatment must focus on both the amelioration of acute symptoms and prevention over the long term . This paper reports a longitudinal evaluation of a program from a community hospital that emphasizes both these aspects . One hundred twenty patients routinely admitted to this program were r and omly assigned to treatment and control groups . These groups were assessed for differences in demonstrated physical strength , mobility , body mechanics , and self-care knowledge , and in levels of self-reported exercise , anxiety , and pain . There were significant immediate gains on physical measures of fitness and in observed body mechanics ; patients also reported significant gains in physical capabilities at home and in leisure activities . Self-care knowledge also improved . When assessed one year later , original gains in physical strength and mobility were being maintained , and self-reported physical capabilities also remained high . Although demonstrated knowledge of correct body mechanics declined over this period , it was still significantly greater than before the program . In light of these results , we believe that outpatient programs like the one reported here merit careful consideration in an era of concern about rising costs for primary health care QUESTION Does the addition of telephone coaching to usual physiotherapy care improve activity for people with non-chronic low back pain and low to moderate recovery expectations ? DESIGN R and omised trial with concealed allocation and intention-to-treat analysis . PARTICIPANTS People attending the physiotherapy department of a public hospital for treatment within eight weeks of onset of non-specific low back pain . Eligible participants had low to moderate recovery expectations , defined as a response of 7 or less to the question ' How certain are you that you will return to all of your usual activities one month from today ? ' on a scale from 0 ( not certain at all ) to 10 ( completely certain ) . INTERVENTION Five sessions of telephone coaching by a physiotherapist trained in health coaching techniques in addition to usual physiotherapy compared to usual physiotherapy alone . OUTCOME MEASURES The Patient Specific Functional Scale , Oswestry Disability Index , Pain Self Efficacy Question naire , and recovery expectation were measured at baseline , 4 , and 12 weeks . RESULTS 30 participants were recruited , with 26 completing all measures at 12 weeks . There were no significant differences between groups at 4 weeks . After 12 weeks the coaching group improved significantly more than the control group on two 10-point scales : the Patient Specific Functional Scale ( mean difference 3.0 points , 95 % CI 0.7 to 5.4 ) and recovery expectation ( mean difference 3.4 points , 95 % CI 1.1 to 5.7 ) . Estimates of effect sizes were moderate to large in favour of the intervention . CONCLUSION The addition of telephone health coaching to usual physiotherapy care for people with non-chronic non-specific low back pain led to clinical ly important improvements in activity and recovery expectation . TRIAL REGISTRATION ACTRN12607000458437 Study Design . A controlled r and omized clinical trial was performed . Objective . To investigate the effect of a light mobilization program on the duration of sick leave for patients with subacute low back pain . Summary of Background Data . Early intervention with information , diagnostics , and light mobilization may be a cost-effective method for returning patients quickly to normal activity . In this experiment , patients were referred to a low back pain clinic and given this simple and systematic program as an outpatient treatment . Methods . In this study , 457 patients sick-listed 8 to 12 weeks for low back pain , as recorded by the National Insurance Offices , were r and omized into two groups : an intervention group ( n = 237 ) and a control group ( n = 220 ) . The intervention group was examined at a spine clinic and given information and advice to stay active . The control group was not examined at the clinic , but was treated with conventional primary health care . Results . At 12-month follow-up assessment , 68.4 % in the intervention group had returned to full-duty work , as compared with 56.4 % in the control group . Conclusions . Early intervention with examination , information , and recommendations to stay active showed significant effects in reducing sick leave for patients with low back pain OBJECTIVE To evaluate the short-term effect of physical exercise and a cognitive intervention in low back pain . DESIGN R and omized controlled trial . SUBJECTS Ninety-three patients sick-listed for 8 - 12 weeks for sub-acute low back pain were r and omized to an exercise regime ( n = 30 ) , a cognitive intervention ( n = 34 ) or a control group ( n = 29 ) . METHODS Primary outcome measures were pain , disability , sick-listing and satisfaction with care . Secondary outcome measures were self-efficacy for pain and for function , fear-avoidance beliefs , emotional distress , generic health status and life satisfaction . RESULTS Eighteen percent of subjects dropped out . Drop-out was most frequent in the exercise group . At 18 weeks after inclusion fear-avoidance beliefs were reduced in both intervention groups . The cognitive group demonstrated significant improvement in disability , self-efficacy for pain , emotional distress , general health and life satisfaction . Patients in the exercise group were significantly more satisfied with the treatment , and patients following the exercise protocol reduced pain significantly . No effect on sick-listing was seen . CONCLUSION Cognitive intervention improved disability and may be feasible for most patients sick-listed in the sub-acute phase . Physical exercise reduced patients ' symptoms , but requires high motivation by patients . Despite positive effects in intervention groups on variables considered as negative prognostic factors for long-term disability and sickness absence , interventions had no effect on sick-listing Context Exercise and advice are common treatments for patients with subacute low back pain , but their effectiveness is unclear . Contribution In this trial , 259 adults with subacute low back pain received 12 real or sham physiotherapist-directed exercise sessions and 3 real or sham advice sessions over 6 weeks . Compared with sham exercise and sham advice , patients who received real exercise and real advice had the most benefit at 6 weeks . However , only a small benefit on patient-reported function persisted at 12 months . Implication Compared with no exercise or advice , a combination of physiotherapist-directed exercise and advice seems to improve pain and function in the short term for patients with subacute low back pain . The Editors Back pain is 1 of the most frequent reasons for consultation with a general practitioner ( 1 , 2 ) . Most treatment guidelines provide advice for patients on managing acute or recent-onset low back pain but not chronic pain ( 3 ) . This reflects the view that acute low back pain is typically self-limited and that only a small proportion of persons develop chronic pain . However , a recent systematic review of the prognosis of acute low back pain ( 4 ) showed that this view is inaccurate : Pain and disability are typically ongoing , and recurrences are common . Thus , effective treatments for patients whose pain and disability persist beyond the acute phase are needed . We are interested in the subacute phase , which is the transition period from acute ( duration < 6 weeks ) to chronic ( duration > 3 months ) low back pain . All treatment guidelines ( 3 ) endorse advice as a treatment for subacute low back pain , and advice is the most frequently administered treatment in general practice ( 1 ) . Exercise is the most common treatment for low back pain ( 2 , 5 , 6 ) , and some guidelines recommend it for subacute low back pain ( 3 ) . However , a systematic review of treatment for subacute low back pain ( 7 ) concluded that no high- quality evidence exists for the efficacy of any intervention . To address this knowledge gap , we conducted a factorial r and omized , placebo-controlled trial of the effect of exercise , advice , or both on pain , function , and global perceived effect . Methods Setting The trial was conducted at 7 physiotherapy clinics in Australia and New Zeal and , of which 6 were in university teaching hospitals and 1 was in a primary care clinic . There were 16 physiotherapists . Each clinic had 1 to 5 therapists providing treatment . We enrolled participants from January 2001 to June 2003 . The study protocol was approved by the institutional review boards of the University of Sydney , Sydney , Australia , and of each clinic . Participants We sought persons between 18 and 80 years of age with nonspecific low back pain lasting for at least 6 weeks but no longer than 12 weeks . Participants were recruited by direct referral to the trial by a health care professional ( n= 1 ) , invitations to patients on hospital waiting lists for physiotherapy treatment of low back pain ( n= 73 ) , and advertisements in newspapers ( n= 185 ) . Exclusion criteria were spinal surgery in the past 12 months , pregnancy , nerve root compromise , confirmed or suspected serious spinal abnormality ( for example , infection , fracture , or the cauda equina syndrome ) , contraindications to exercise , and poor comprehension of the English language . We did not exclude participants who were receiving low back pain treatment other than spinal surgery . Potential participants who reported osteoarthritis ; spondylitis ; spondylolysis ; spondylolisthesis ; disc protrusion , herniation , or prolapse ; or spinal stenosis were eligible . We asked participants not to take other treatments for low back pain during the 6-week treatment phase . Written informed consent was obtained from all participants before they enrolled in the trial . R and omization and Interventions After completing the baseline assessment , we r and omly allocated participants to 1 of 4 intervention groups : exercise and advice , exercise and sham advice , sham exercise and advice , or sham exercise and sham advice . The allocation schedule was generated by using the r and om-number function in Microsoft Excel ( Microsoft , Inc. , Redmond , Washington ) , and the allocation codes were placed in sequentially numbered , sealed , opaque envelopes . At each site , the trial coordinator or the physiotherapist allocated participants to groups by opening the next numbered envelope . This process ensured that allocation was concealed from participants , referring medical practitioners , trial staff who determined eligibility , and the assessor of outcomes . The 12 exercise or sham exercise sessions were delivered over 6 weeks : 3 sessions per week in weeks 1 and 2 , 2 sessions per week in weeks 3 and 4 , and 1 session per week in weeks 5 and 6 . In weeks 1 , 2 , and 4 , participants also received advice or sham advice . Sham treatments were design ed to provide similar contact time with the treating clinician . The clinicians who provided the sham treatments were the same ones who provided the real treatments . Registered physiotherapists who received training from an experienced clinical psychologist delivered treatment . Treatment consistency was promoted at the initial staff meeting and at regular trial treatment meetings , and by providing a treatment manual to all treatment providers . To assess treatment validity , an investigator recorded and assessed sample treatment sessions . In addition , 1 investigator regularly visited each treatment site to monitor delivery of treatment . The comprehensive treatment manual is in the Appendix . Appendix . Treatment Manual Exercise The exercise program was based on the program described by Lindstrm and colleagues ( 8) . It included an individualized , progressive , submaximal program design ed to improve the abilities of participants to complete functional activities that they specified as being difficult to perform because of low back pain . Each participant undertook aerobic exercise ( for example , a walking or cycling program ) ; stretches ; functional activities ; activities to build speed , endurance , and coordination ; and trunk- and limb-strengthening exercises . Physiotherapists used principles of cognitive-behavioral therapy , including setting goals of progressively increasing difficulty , encouraging self-monitoring of progress , and promoting self-reinforcement ( 9 ) . Physiotherapists provided individualized home exercise programs , which they regularly review ed , and they encouraged continuation of the home program after the intervention finished . Sham Exercise The control for the exercise intervention consisted of sham pulsed ultrasonography ( 5 minutes ) and sham pulsed short-wave diathermy ( 20 minutes ) . The sham units were identical to active units ( for example , the on and off lights illuminated and the output dial moved ) except that they did not provide output . To optimize treatment credibility , physiotherapists followed the usual clinical routine for delivering these treatments . The active forms of these treatments delivered in pulsed mode do not produce heat ; thus , previous experience with the treatments would not unblind participants . Participants allocated to exercise did not receive the active forms of these treatments . Advice Advice sessions were based on the program by Indahl and colleagues ( 10 ) and aim ed to encourage a grade d return to normal activities . The physiotherapist explained the benign nature of low back pain , addressed any unhelpful beliefs about back pain , and emphasized that being overly careful and avoiding light activity would delay recovery . Sham Advice During sham advice sessions , participants were given the opportunity to talk about their low back pain and any other problems . The physiotherapist responded in a warm and empathic manner , displaying genuine interest in the participant , but did not give advice about the low back pain ( 11 ) . Participants were told that the trial included active and placebo physiotherapy treatments and that they would receive 2 treatments , but they were not told whether the interventions they received were active or sham . Outcomes and Measurements We determined participants ' perceptions of the effectiveness of treatment at the beginning of the trial and at 12 months . We assessed treatment adherence by the number of appointments attended , session duration , and amount of time the physiotherapist spent with each participant . Participants were asked not to seek other treatments during the 6-week treatment period . Participants who discontinued treatment were encouraged to return for follow-up . Immediately before r and omization , we obtained baseline measurements . We collected additional data on work status , medication use , side effects , adverse events , and number and type of co- interventions at 6 weeks , 3 months , and 12 months after r and omization . We chose primary and secondary outcomes a priori . The primary outcomes were pain , global perceived effect , and functional ability at 6 weeks and 12 months . Secondary outcomes were pain , global perceived effect , and functional ability at 3 months ; number of health care contacts during the past 6 weeks ( determined at 12 months ) ; and disability and depression at 6 weeks , 3 months , and 12 months . We rated pain as average pain over the past week on a scale of 0 ( no pain ) to 10 ( worst pain possible ) ( 12 ) . We measured functional ability by using the Patient-Specific Functional Scale ( score range , 0 [ can not perform activity ] to 10 [ can perform activity at preinjury level ] ) ( 13 ) . We measured global perceived effect of treatment on an 11-point scale , ranging from 5 ( vastly worse ) to 5 ( completely recovered ) , with 0 being no change . We measured disability with the Rol and Morris Disability Question naire ( score range , 0 to 24 ) ( 14 ) . We measured depression , anxiety , and stress by using the 21-item Depression Anxiety Stress Scales ( DASS-21 ) ( score range for each subscale , 0 to 42 ) ( 15 ) . These measures have acceptable psychometric properties and are widely used in Background : Low back pain is a common medical and social problem associated with disability and absence from work . Knowledge on effective return to work ( RTW ) interventions is scarce . Objective : To determine the effectiveness of grade d activity as part of a multistage RTW programme . Design : R and omised controlled trial . Setting : Occupational healthcare . Subjects : 112 workers absent from work for more than eight weeks due to low back pain were r and omised to either grade d activity ( n = 55 ) or usual care ( n = 57 ) . Intervention : Grade d activity , a physical exercise programme aim ed at RTW based on operant-conditioning behavioural principles . Main outcome measures : The number of days off work until first RTW for more then 28 days , total number of days on sick leave during follow up , functional status , and severity of pain . Follow up was 26 weeks . Results : Grade d activity prolonged RTW . Median time until RTW was equal to the total number of days on sick leave and was 139 ( IQR = 69 ) days in the grade d activity group and 111 ( IQR = 76 ) days in the usual care group ( hazard ratio = 0.52 , 95 % CI 0.32 to 0.86 ) . An interaction between a prior workplace intervention and grade d activity , together with a delay in the start of the grade d activity intervention , explained most of the delay in RTW ( hazard ratio = 0.86 , 95 % CI 0.40 to 1.84 without prior intervention and 0.39 , 95 % CI 0.19 to 0.81 with prior intervention ) . Grade d activity did not improve pain or functional status clinical ly significantly . Conclusions : Grade d activity was not effective for any of the outcome measures . Different interventions combined can lead to a delay in RTW . Delay in referral to grade d activity delays RTW . In implementing grade d activity special attention should be paid to the structure and process of care Abstract We evaluated three different conservative treatment methods for acute low-back pain patients in groups following a manual therapy programme , an intensive training programme , or a general practitioner programme , the latter serving as the control group . Patients aged 19–64 years on sick leave for low-back pain with or without sciatica were included in a prospect i ve r and omised study evaluating outcomes such as impairment , pain , functional disability , socio-economic disability and satisfaction with the treatment or explanations . Evaluation by unbiased observers was performed at 1 , 3 and 12 months . The three treatment groups were comparable at baseline . With regard to satisfaction , the patients in the manual therapy programme and those in the intensive training programme were more satisfied with the treatment than those in the general practitioner programme at all follow-ups . With regard to the explanations of current low-back pain episodes , the patients in the manual therapy programme were more satisfied than those in the general practitioner programme at all follow-ups . The manual therapy programme group were also more satisfied with the explanations than those in the intensive training programme at the 1-month follow-up . However , no differences were revealed between the groups with respect to outcomes on measures of impairment , pain , functional disability or socio-economic disability . All three study groups showed rapid improvement . After 1 month a significant improvement was noted in all outcome values compared with the values on entry to the study . Within the limitations discussed in our study , it is concluded that ( 1 ) patients sick listed with acute low-back pain , with or without sciatica , will be significantly improved after 1 month regardless of conservative treatment programme ; ( 2 ) they will be more satisfied with the treatment if they are referred to a manual treatment programme or a training treatment programme ; ( 3 ) they will be more satisfied with the explanations of the acute low-back problem if they are referred to one of the above groups , especially the manual treatment group ; ( 4 ) they will not show any other differences with respect to subjective and objective variables , either at short-term or at long-term follow-ups BACKGROUND CONTEXT Musculoskeletal disorders of the spine in the US military account for the single largest proportion of the absence of sickness causes leading to early termination . We explored if selected psychological and physical factors were associated with poor outcome after episodes of low back pain ( LBP ) . PURPOSE To identify clinical , demographic , and psychological factors predictive of work duty status after a complaint of LBP . STUDY DESIGN A prospect i ve clinical cohort of US Navy personnel treated for LBP . PATIENT SAMPLE Eligible cases were active duty US Navy or Marine Corps personnel presenting to an emergency clinic or primary care clinic with a complaint of LBP , where the index episode of LBP was no more than 12 weeks duration before enrollment . OUTCOME MEASURES The subject 's work status ( full duty , light duty , sick in quarters [ SIQ ] , limited duty , or medically released to full duty ) was abstract ed from the subject 's electronic medical record at approximately 4 weeks and then again 12 weeks after study enrollment . Work status in this study population is assigned by a Navy health-care provider at the time of a clinical visit and based on the health-care provider 's determination of medical fitness for duty . This study collapsed work status into two groups , " full duty " ( consisting of " full duty " and " medically released to full duty " ) and " not at full duty " ( consisting of " light duty , " " SIQ , " and " limited duty " ) . METHODS Volunteers completed a baseline question naire consisting of recommended well-vali date d measures , including attitudes and beliefs about LBP and work ( Fear-Avoidance Beliefs Question naire [ FABQ ] and the Tampa Scale of Kinesiophobia ) , distress ( the Pain Catastrophizing Scale ) , clinical depression ( The Center for Epidemiologic Studies Depression scale ) , a numeric pain intensity scale , self-perceived disability ( Oswestry Disability Index ) , and general health status ( 12-Item Short Form Health Survey ) . Navy health-care providers conducted a back pain-specific medical evaluation . Associations are expressed as multivariate-adjusted prevalence ratios ( PRs ) estimated using Poisson regression . RESULTS Two hundred fifty-three participants were enrolled . Work status outcome was collected for 239 participants . Predictors of " not at full duty " at 4 weeks after enrollment included having back pain for 4 weeks or less before study enrollment ( PR , 2.69 ; 95 % CI , 1.21 - 5.97 ) and increased FABQ Work subscale score ( PR , 1.05 ; 95 % CI , 1.01 - 1.08 ) . The sole predictor of work status at 12 weeks after enrollment was increased FABQ Physical Activity ( FABQ Physical ) subscale score ( PR=1.14 ; 95 % CI , 1.00 - 1.30 ) . CONCLUSIONS The findings that fear-avoidance beliefs were predictive of subsequent work status among active duty service personnel in this study population ( after adjusting for clinical , demographic , and psychological covariates ) suggest the clinical utility of addressing these factors during treatment of back pain episodes in the military . These findings reflect the important role that psychological factors may play in the return to work process in an active duty military population Patients with nonspecific mechanical low back pain ( n = 103 ) , examined by an orthopaedic surgeon and a social worker , were r and omized to an activity group ( n = 51 ) and a control group ( n = 52 ) . Patients with defined orthopaedic , medical , or psychiatirc diagnoses were excluded before r and omization . No patients were excluded due to place of birth or difficulties in speaking or underst and ing the Swedish language . The purpose of the study was to compare mobility , strength and fitness after traditional care and after traditional care plus a grade d activity program with a behavioral therapy approach . A grade d activity program , with a behavioral therapy approach was given under the guidance of a physical therapist . The endpoint of the grade d activity program was return to work . This program significantly increased mobility , strength , and fitness more than could be explained by only a time recovery effect , especially in males . The patients in the activity group returned to work earlier than did the patients in the control group . Spinal rotation , abdominal muscle endurance time and lifting capacity were significantly correlated to rate of return to work . Traditional care plus a grade d activity program were superior to only traditional care , evaluated in terms of mobility , strength and fitness . The grade d activity program proved to be a successful method of restoring occupational function and facilitating return to work in subacute low back pain patients . The patients in the grade d activity program learned that it is safe to move , while regaining function Introduction In an earlier study , Gatchel et al. ( J Occup Rehabil 13:1–9 , 2003 ) demonstrated that participants at high risk for developing chronic low back pain disability ( CLBPD ) , who received a biopsychosocial early intervention treatment program , displayed significantly more symptom improvement , as well as cost savings , relative to participants receiving st and ard care . The purpose of the present study was to exp and on these results by examining whether the addition of a work-transition component would further strengthen the effectiveness of this early intervention treatment . Methods Using an existing algorithm , participants were identified as being high-risk ( HR ) or low-risk ( LR ) for developing CLBPD . HR participants were then r and omly assigned to one of three groups : early intervention ( EI ) ; early intervention with work transition ( EI/WT ) ; or st and ard care ( SC ) . Participants provided information regarding pain , disability , work status , and psychosocial functioning at baseline , periodically during treatment , and again 1 year following completion of treatment . Results At 1-year follow-up , no significant differences were found between the EI and EI/WT groups in terms of occupational status , self-reports of pain and disability , coping ability or psychosocial functioning . However , significant differences in all these outcomes were found comparing these groups to st and ard care . Conclusion The addition of a work transition component to an early intervention program for the treatment of ALBP did not significantly contribute to improved work outcomes . However , results further support the effectiveness of early intervention for high-risk ALBP patients OBJECTIVES --The aim was to combat occurrence of chronic occupational back pain . METHODS --A multidisciplinary model to manage back pain that includes both clinical and ergonomic approaches has been developed . Early detection , early clinical and ergonomic evaluations , and early active treatment make up the cornerstone of management . Detection of cases starts after four weeks of absence from work . An ergonomic intervention is implemented at six weeks . A medical specialist is involved at eight weeks . If return to work is not possible after 12 weeks , a functional recovery therapy followed by a therapeutic return to work is implemented . A multidisciplinary team decides if return to original or modified work is possible or if vocational rehabilitation is necessary . This model has been implemented by the investigators in the Sherbrooke ( Quebec , Canada ) area , and is presently being evaluated through a r and omised trial in 31 industrial settlements ( about 20,000 workers ) . A cluster r and omisation of industries and workers will allow separate testing of ergonomic and clinical interventions . RESULTS --One year after implementation , 31 of 35 of the eligible industrial sites participated in the study and 79 of 88 of the eligible workers affected by recent back pain had agreed to participate . Ergonomic and clinical interventions have been implemented as planned . Only three workers dropped out . Hence this global clinical and ergonomic management programme has been shown to be feasible in a general population . CONCLUSION --A global management programme of back pain joining ergonomic and clinical intervention with a multidisciplinary approach has not been tested yet . Linking these two strategies in a same multidisciplinary team represents a systemic approach to this multifactorial ailment . During the first year of this trial we did not find any conflict between these two interventions from the employer 's or worker 's point of view Study Design . A r and omized comparative study with single-blind outcome assessment s. Objectives . To compare the efficacy of a multimodal treatment emphasizing proprioceptive training ( ACTIVE ) with activated home exercises ( HOME ) and recommendation of exercise ( CONTROL ) in patients with nonspecific chronic neck pain . Summary of Background Data . The efficacy of active exercises and passive physiotherapy for neck trouble has been somewhat disappointing in the previous few studies . Methods . Seventy-six patients ( 22 men , 54 women ) with chronic , nonspecific neck pain participated . Sixty-two participated the 1-year follow-up . Subjective pain and disability , cervical ranges of motion , and pressure pain threshold in the shoulder region were measured at baseline , at 3 months , and at 12 months . The ACTIVE treatment consisted of 24 sessions of proprioceptive exercises , relaxation , and behavioral support . The HOME regimen included a neck lecture and two sessions of practical training for home exercises and instructions for maintaining a diary of progress . The CONTROL treatment included a lecture regarding care of the neck with a recommendation to exercise . Results . The average self-experienced total benefit was highest in the ACTIVE group , and the HOME group rated over the CONTROL group ( P < 0.001 ) . Differences between the groups in favor of the ACTIVE treatment were recorded in reduction of neck symptoms and improvements in general health and self-experienced working ability ( P < 0.01–0.03 ) . Changes in measures of mobility and pressure pain threshold were minor . Conclusions . Regarding self-experienced benefit , the multimodal treatment was more efficacious than activated home exercises that were clearly more efficacious than just advising . No major differences were noted in objective measurements of cervical function between the groups , but the content validity of these assessment s in chronic neck trouble can be question ed Study Design . A controlled clinical trial . Objectives . To examine the long‐term effect of an informative approach to low back pain . Summary of Background Data . In management and prevention of low back pain , back school based on an ergonomic approach have played an important role . The effect of such informative interventions is not clear . Methods . A 5‐year follow‐up study was done on patients included in a previous study . The outcome was measured by return to work or still on sick leave . The patients were allocated to an intervention group ( n = 245 ) and a control group ( n = 244 ) . Only the intervention group was called in for examination and intervention and answered a battery of tests for psychological and health factors . The intervention apart from the clinical examination consisted of education in a " mini back school . " The program was based on a new medical model for low back pain . Results . Forty‐seven ( 19 % ) of the patients in the intervention group , compared with 84 patients ( 34 % ) in the control group , were still on sick leave after 5 years ( P < 0.001 ) . There were fewer recurrences of sick leave ( P < 0.03 ) in the intervention group than in the control group . Based on Internal Health Locus of Control , number of children , and income , 75 % were correctly classified as nonreturners in the intervention group . Conclusions . This study indicates that subchronic low back pain may be managed successfully with an approach that includes clinical examination combined with information for patients about the nature of the problem , provided in a manner design ed to reduce fear and give them reason to resume light activity The aim of this paper was to study the physical performance , pain , pain behavior and disability in patients with subacute low back pain ( LBP ) . The patients were blue-collar workers and had been sick-listed for 8 weeks due to subacute low back pain . A total of 103 patients were r and omized , 51 of them to the intervention group and the other to a control group . Recordings of physical performance and complaints of LBP were done before and after treatment in the intervention group . The proportion of patients with no complaints of LBP was significantly greater in the intervention group than in the control group at the one-year follow-up . The patients who intra-individually improved their physical performance also intra-individually decreased their complaints of LBP . The intra-individual improvements were suggested to be important for the individual return to work Study Design . R and omized controlled trial . Objectives . To Investigate the long-term effectiveness , costs , and effect modifiers of a mini-intervention , provided in addition to the usual care , and the incremental effect of a worksite visit for patients with subacute disabling low back pain ( LBP ) . Summary of Background Data . A mini-intervention was earlier proved to be an effective treatment for subacute LBP . Whether the beneficial effect is sustained is not known . Furthermore , modifiers of a treatment effect are largely unknown . Methods . A total of 164 patients with subacute LBP r and omized into a mini-intervention ( A , n = 56 ) , a mini-intervention plus a worksite visit ( B , n = 51 ) , or the usual care ( C , n = 57 ) . Mini-intervention consisted of a detailed assessment of the patients ’ history , beliefs , and physical findings by a physician and a physiotherapist , followed by recommendations and advice . The usual care patients received the conventional care . Pain , disability , health-related quality of life , satisfaction with care , days on sick leave , and health care consumption and costs were measured during a 24-month follow-up . Thirteen c and i date modifiers were tested for each outcome . Results . There were no differences between the three treatment arms regarding the intensity of pain , the perceived disability , or the health-related quality of life . However , mini-intervention decreased occurrence of daily ( A vs. , C , P = 0.01 ) and bothersome ( A vs. C , P < 0.05 ) pain and increased treatment satisfaction . Costs result ing from LBP were lower in the intervention groups ( A 4670 Euros , B 5990 Euros ) than in C ( C 9510 Euros ) ( A vs. C , P = 0.04 ; and B vs. C , not significant ) . The average number of days on sick leave was 30 in A , 45 in B , and 62 in C ( A vs. C , P = 0.03 ; B vs. C , not significant ) . The perceived risk for not recovering was the strongest modifier of treatment effect . Mental and mental-physical workers in A and B were less often on sick leave than those in C. Conclusions . Mini-intervention is an effective treatment for subacute LBP . Despite lack of a significant effect on intensity of low back pain and perceived disability , mini-intervention , including proper recommendations and advice , according to the “ active approach , ” is able to reduce LBP-related costs . The perceived risk of not recovering was the strongest modifier of treatment effect . In alleviating pain , the intervention was most effective among the patients with a high perceived risk of not recovering In a r and omized controlled study multimodal cognitive behavioral treatment ( MMCBT ) , including physical treatment , cognitive behavioral modification , education , and examination of the work situation for each patient , was given to patients sick-listed for musculoskeletal pain ( n = 469 ) . Patients were recruited through the National Insurance System . After a pre-test by an independent physiotherapist the patients were allocated at r and om to the intervention group ( n = 312 ) or the control group ( n = 157 ) . The MMBCT program lasted for 4 weeks . The control group returned to their general practitioners , without any feedback or advice on therapy from the project . At the one year follow-up the MMCBT group had not returned to work at a higher rate than the control group receiving ordinary treatment available through their general practitioners . However , the MMCBT group had improved their ergonomic behavior , work potential , life quality , physical , and psychological health Objective . This r and omized clinical trial was design ed to determine the effect of treating low back pain as a benign , self limiting condition by light normal activity . Methods . Patients on sickness leave from work for more than 8 weeks were r and omized into two groups : intervention ( n = 463 ) and control ( n = 512 ) . Those in the intervention group were examined , provided information , and given instruction . Outcome was measured by return or failure to return to work ( still on sickness leave ) . Results . Survival analysis showed a highly significant ( P = 0.000 ) reduction in sickness leave in the intervention group as compared with the control group . At 200 days 60 % were still on sickness leave in the control group vs. 30 % in the intervention group . A multivariate analysis with age , sex , and treatment as cofactors showed that sex had no effect on length of sickness leave and that treatment retained its effect when adjusting for differences in age composition . Conclusion . This study indicates that low back pain treated as a benign , self limiting condition recommended to light mobilization gives superior results as compared to treatment within a conventional medical system CONTEXT Common pain conditions appear to have an adverse effect on work , but no comprehensive estimates exist on the amount of productive time lost in the US workforce due to pain . OBJECTIVE To measure lost productive time ( absence and reduced performance due to common pain conditions ) during a 2-week period . DESIGN AND SETTING Cross-sectional study using survey data from the American Productivity Audit ( a telephone survey that uses the Work and Health Interview ) of working adults between August 1 , 2001 , and July 30 , 2002 . PARTICIPANTS R and om sample of 28 902 working adults in the United States . MAIN OUTCOME MEASURES Lost productive time due to common pain conditions ( arthritis , back , headache , and other musculoskeletal ) expressed in hours per worker per week and calculated in US dollars . RESULTS Thirteen percent of the total workforce experienced a loss in productive time during a 2-week period due to a common pain condition . Headache was the most common ( 5.4 % ) pain condition result ing in lost productive time . It was followed by back pain ( 3.2 % ) , arthritis pain ( 2.0 % ) , and other musculoskeletal pain ( 2.0 % ) . Workers who experienced lost productive time from a pain condition lost a mean ( SE ) of 4.6 ( 0.09 ) h/wk . Workers who had a headache had a mean ( SE ) loss in productive time of 3.5 ( 0.1 ) h/wk . Workers who reported arthritis or back pain had mean ( SE ) lost productive times of 5.2 ( 0.25 ) h/wk . Other common pain conditions result ed in a mean ( SE ) loss in productive time of 5.5 ( 0.22 ) h/wk . Lost productive time from common pain conditions among active workers costs an estimated 61.2 billion dollars per year . The majority ( 76.6 % ) of the lost productive time was explained by reduced performance while at work and not work absence . CONCLUSIONS Pain is an inordinately common and disabling condition in the US workforce . Most of the pain-related lost productive time occurs while employees are at work and is in the form of reduced performance BACKGROUND Recommendations for the management of low back pain in primary care emphasise the importance of recognising and addressing psychosocial factors at an early stage . We compared the effectiveness of a brief pain-management programme with physiotherapy incorporating manual therapy for the reduction of disability at 12 months in patients consulting primary care with subacute low back pain . METHODS For this pragmatic , multicentre , r and omised clinical trial , eligible participants consulted primary care with non-specific low back pain of less than 12 weeks ' duration . They were r and omly assigned either a programme of pain management ( n=201 ) or manual therapy ( n=201 ) . The primary outcome was change in the score on the Rol and and Morris disability question naire at 12 months . Analysis was by intention to treat . FINDINGS Of 544 patients assessed for eligibility , 402 were recruited ( mean age 40.6 years ) and 329 ( 82 % ) reached 12-month follow-up . Mean disability scores were 13.8 ( SD 4.8 ) for the pain-management group and 13.3 ( 4.9 ) for the manual-therapy group . The mean decreases in disability scores were 8.8 ( 6.4 ) and 8.8 ( 6.1 ) at 12 months ( difference 0 [ 95 % CI -1.3 to 1.4 ] , p=0.99 ) , and median numbers of physiotherapy visits per patient were three ( IQR one to five ) and four ( two to five ) , respectively ( p=0.001 ) . One adverse reaction ( an exacerbation of pain after the initial assessment ) was recorded . INTERPRETATION Brief pain management techniques delivered by appropriately trained clinicians offer an alternative to physiotherapy incorporating manual therapy and could provide a more efficient first-line approach for management of non-specific subacute low back pain in primary care Study Design . R and omized clinical trial of 2 interventions in 351 employees sick listed due to low back pain ( LBP ) and a subsequent validation study ( n = 120 ) to vali date results from subgroup analyses in the original study . Objective . To compose health economic analyses ( cost-effectiveness- and cost-benefit analyses ) of multidisciplinary versus brief intervention by calculating health care sector costs and sick leave benefits . Summary of Background Data . Both brief and multidisciplinary interventions have been reported to be superior relative to usual care when comparing intervention costs with saved costs for sick leave benefits . We reported similar return to work rates in a brief and a multidisciplinary intervention group , but different return to work rates in subgroups . Methods . The brief intervention comprised clinical examination and reassuring advice . The multidisciplinary intervention was conducted by a case manager and a team of specialists . The costs of medicine , health care services , and sick leave benefits were calculated on the basis of registers . Results . The mean intervention cost per patient was & OV0556;1377 higher in the multidisciplinary intervention ( n = 176 ) than in the brief intervention group ( n = 175 ) , and sick leave was not averted . However , sick leave was averted in a subgroup receiving the multidisciplinary intervention and the mean incremental intervention cost for 1 saved sick leave week in this subgroup ( n = 60 ) of patients , who thought they were at risk of losing their job or had little influence on their work situation was & OV0556;217 . The latter finding was verified in the validation study ( n = 28 ) . Conclusion . The brief intervention result ed in fewer sick leave weeks and was less expensive than the multidisciplinary intervention . The multidisciplinary intervention only outperformed the brief intervention in terms of costs in a subgroup of sick-listed employees who thought they were at risk of losing their job or had little influence on their work situation . Level of Evidence : Study design . Population -based r and omized controlled trial . Objective . To assess the effectiveness of workplace intervention and grade d activity , separately and combined , for multidisciplinary rehabilitation of low back pain ( LBP ) . Summary of Background Data . Effective components for multidisciplinary rehabilitation of LBP are not yet established . Methods . Participants sick-listed 2 to 6 weeks due to nonspecific LBP were r and omized to workplace intervention ( n = 96 ) or usual care ( n = 100 ) . Workplace intervention consisted of workplace assessment , work modifications , and case management involving all stakeholders . Participants still sick-listed at 8 weeks were r and omized for grade d activity ( n = 55 ) or usual care ( n = 57 ) . Grade d activity comprised biweekly 1-hour exercise sessions based on operant-conditioning principles . Outcomes were lasting return to work , pain intensity and functional status , assessed at baseline , and at 12 , 26 , and 52 weeks after the start of sick leave . Results . Time until return to work for workers with workplace intervention was 77 versus 104 days ( median ) for workers without this intervention ( P = 0.02 ) . Workplace intervention was effective on return to work ( hazard ratio = 1.7 ; 95 % CI , 1.2–2.3 ; P = 0.002 ) . Grade d activity had a negative effect on return to work ( hazard ratio = 0.4 ; 95 % CI , 0.3–0.6 ; P < 0.001 ) and functional status . Combined intervention had no effect . Conclusion . Workplace intervention is advised for multidisciplinary rehabilitation of subacute LBP . Grade d activity or combined intervention is not advised In this multicentre intervention study , we compared an integrated group treatment program which combines psychological and education methods into a more active training approach , with the traditional individual approach of physiotherapy and physical procedures for sub-chronic and chronic low back pain . Our 411 patients had a 4-week inpatient treatment : 243 patients in an experimental program and 168 in a traditional program . Outcomes of 283 patients were assessed 3 months and 1 year after entry . The dropout rate was 31.1 % . Both conditions demonstrated favourable initial effects on functional and psychological parameters , but the integrated approach showed better long-term results for work rehabilitation than the traditional approach . The most successful patients ( n = 58 ) were younger and had a higher educational level in comparison to the unsuccessful subgroup ( n = 71 ) . The main conclusion is that an integrated approach promoting self control and behaviour change through educational measures achieves better long-term results than the traditional individual physiotherapy approach OBJECTIVE Guidelines for the management of acute low back pain in primary care recommend early intervention to address psychosocial risk factors associated with long-term disability . We assessed the cost utility and cost effectiveness of a brief pain management program ( BPM ) targeting psychosocial factors compared with physical therapy ( PT ) for primary care patients with low back pain of < 12 weeks ' duration . METHODS A total of 402 patients were r and omly assigned to BPM or PT . We adopted a health care perspective , examining the direct health care costs of low back pain . Outcome measures were quality -adjusted life years ( QALYs ) and 12-month change scores on the Rol and and Morris disability question naire . Re source use data related to back pain were collected at 12-month followup . Cost effectiveness was expressed as incremental ratios , with uncertainty assessed using cost-effectiveness planes and acceptability curves . RESULTS There were no statistically significant differences in mean health care costs or outcomes between treatments . PT had marginally greater effectiveness at 12 months , albeit with greater health care costs ( BPM 142 pounds , PT 195 pounds ) . The incremental cost-per-QALY ratio was 2,362 pounds . If the UK National Health Service were willing to pay 10,000 pound per additional QALY , there is only a 17 % chance that BPM provides the best value for money . CONCLUSION PT is a cost-effective primary care management strategy for low back pain . However , the absence of a clinical ly superior treatment program raises the possibility that BPM could provide an additional primary care approach , administered in fewer sessions , allowing patient and doctor preferences to be considered OBJECTIVE To identify subgroups of workers absent from work due to low back pain who are more or less likely to return to work earlier as a result of a grade d activity intervention , and to investigate whether this intervention is effective in reducing pain-related fears and if so , whether these reductions in pain-related fears mediate return to work . METHODS A subgroup analysis was conducted on data from a previous r and omized controlled trial of 134 Dutch airline workers , which found that a behaviorally-oriented grade d activity intervention was more effective than usual care in stimulating return to work . The subgroup analyses added interaction terms to a Cox regression model that described the relationship between treatment allocation and return to work over 12 months of followup . Furthermore , we studied the effects of grade d activity on pain-related fears and added variables indicating a reduction in pain-related fears to the model in order to investigate their influence on return to work . RESULTS Statistically significant interactions were found for disability , fear-avoidance beliefs about physical activity , and fear-avoidance beliefs about work . No indication was found that the reduction in pain-related fears in the grade d activity group mediated more favorable return-to-work results in this group . CONCLUSION Workers who perceive their disability to be moderate and workers with moderate scores for fear-avoidance beliefs return to work more rapidly as a result of the grade d activity intervention than workers with higher scores . The return to work of workers receiving the grade d activity intervention is possibly independent from the reductions in pain-related fears caused by this intervention Introduction In Denmark , the magnitude and impact of work disability on the individual worker and society has prompted the development of a new “ coordinated and tailored work rehabilitation ” ( CTWR ) approach . The aim of this study was to compare the effects of CTWR with conventional case management ( CCM ) on return-to-work of workers on sick leave due to musculoskeletal disorders ( MSDs ) . Methods The study was a r and omized controlled trial with economic evaluation undertaken with workers on sick leave for 4–12 weeks due to MSDs . CTWR consists of a work disability screening by an interdisciplinary team followed by the collaborative development of a RTW plan . The primary outcome variable was registered cumulative sickness absence hours during 12 months follow-up . Secondary outcomes were work status as well as pain intensity and functional disability , measured at baseline , 3 and 12 months follow-up . The economic evaluation ( intervention costs , productivity loss , and health care utilization costs ) was based on administrative data derived from national registries . Results For the time intervals 0–6 months , 6–12 months , and the entire follow-up period , the number of sickness absence hours was significantly lower in the CTWR group as compared to the control group . The total costs saved in CTWR participants compared to controls were estimated at US $ 1,366 per person at 6 months follow-up and US $ 10,666 per person at 12 months follow-up . Conclusions Workers on sick leave for 4–12 weeks due to MSD who underwent “ CTWR ” by an interdisciplinary team had fewer sickness absence hours than controls . The economic evaluation showed that — in terms of productivity loss — CTWR seems to be cost saving for the society BACKGROUND AND METHODS There are few data on the relative effectiveness and costs of treatments for low back pain . We r and omly assigned 321 adults with low back pain that persisted for seven days after a primary care visit to the McKenzie method of physical therapy , chiropractic manipulation , or a minimal intervention ( provision of an educational booklet ) . Patients with sciatica were excluded . Physical therapy or chiropractic manipulation was provided for one month ( the number of visits was determined by the practitioner but was limited to a maximum of nine ) ; patients were followed for a total of two years . The bothersomeness of symptoms was measured on an 11-point scale , and the level of dysfunction was measured on the 24-point Rol and Disability Scale . RESULTS After adjustment for base-line differences , the chiropractic group had less severe symptoms than the booklet group at four weeks ( P=0.02 ) , and there was a trend toward less severe symptoms in the physical therapy group ( P=0.06 ) . However , these differences were small and not significant after transformations of the data to adjust for their non-normal distribution . Differences in the extent of dysfunction among the groups were small and approached significance only at one year , with greater dysfunction in the booklet group than in the other two groups ( P=0.05 ) . For all outcomes , there were no significant differences between the physical-therapy and chiropractic groups and no significant differences among the groups in the numbers of days of reduced activity or missed work or in recurrences of back pain . About 75 percent of the subjects in the therapy groups rated their care as very good or excellent , as compared with about 30 percent of the subjects in the booklet group ( P<0.001 ) . Over a two-year period , the mean costs of care were $ 437 for the physical-therapy group , $ 429 for the chiropractic group , and $ 153 for the booklet group . CONCLUSIONS For patients with low back pain , the McKenzie method of physical therapy and chiropractic manipulation had similar effects and costs , and patients receiving these treatments had only marginally better outcomes than those receiving the minimal intervention of an educational booklet . Whether the limited benefits of these treatments are worth the additional costs is open to question Aims : Analysing and presenting data on different outcomes after sick-leave is challenging . The use of extended statistical methods supplies additional information and allows further exploitation of data . Methods : Four hundred and fifty-seven patients , sick-listed for 8—12 weeks for low back pain , were r and omized to intervention ( n=237 ) or control ( n=220 ) . Outcome was measured as : ` ` sick-listed ' ' , ` ` returned to work ' ' , or ` ` disability pension ' ' . The individuals shifted between the three states between one and 22 times ( mean 6.4 times ) . In a multi-state model , shifting between the states was set up in a transition intensity matrix . The probability of being in any of the states was calculated as a transition probability matrix . The effects of the intervention were modelled using a non-parametric model . Results : There was an effect of the intervention for leaving the state sick-listed and shifting to returned to work ( relative risk (RR)=1.27 , 95 % confidence interval ( CI ) 1.09— 1.47 ) . The nonparametric estimates showed an effect of the intervention for leaving sick-listed and shifting to returned to work in the first 6 months . We found a protective effect of the intervention for shifting back to sick-listed between 6 and 18 months . The analyses showed that the probability of staying in the state returned to work was not different between the intervention and control groups at the end of the follow-up ( 3 years ) . Conclusions : We demonstrate that these alternative analyses give additional results and increase the strength of the analyses . The simple intervention did not decrease the probability of being on sick-leave in the long term ; however , it decreased the time that individuals were on sick-leave |
13,733 | 25,925,586 | Conclusion : Consolidation RT could significantly improve outcomes of DLBCL patients who achieved a CR to RCHOP . | Background : The current st and ard therapy for patients with diffuse large B-cell lymphoma ( DLBCL ) is rituximab plus cyclophosphamide , doxorubicin , vincristine and prednisone ( RCHOP ) .
The role of radiotherapy ( RT ) after complete response ( CR ) to RCHOP in patients with DLBCL remains unclear .
This systematic review with a meta- analysis is an attempt to evaluate this role . | BACKGROUND The role of rituximab in combination with different CHOP ( cyclophosphamide , doxorubicin , vincristine , and prednisone)-like chemotherapy regimens in young patients with good-prognosis diffuse large-B-cell lymphoma remains to be defined . We aim ed to compare CHOP-like chemotherapy and rituximab with CHOP-like chemotherapy alone in these patients . METHODS 824 patients who were from 18 countries ; aged 18 - 60 years ; and who had no risk factors or one risk factor according to age-adjusted International Prognostic Index ( IPI ) , stage II-IV disease , or stage I disease with bulk were enrolled . These patients were r and omly assigned to six cycles of CHOP-like chemotherapy and rituximab ( n=413 ) or to six cycles of CHOP-like chemotherapy alone ( n=411 ) . Bulky and extranodal sites received additional radiotherapy . The primary endpoint was event-free survival ; secondary endpoints were response , progression under therapy , progression-free survival , overall survival , and frequency of toxic effects . Analyses were done by intention to treat and per protocol . This trial is registered at http://www . clinical trials.gov , NCT 00064116 . FINDINGS After a median follow-up of 34 months ( range 0.03 - 61 ) , patients assigned chemotherapy and rituximab had increased 3-year event-free survival compared with those assigned chemotherapy alone ( 79 % [ 95 % CI 75 - 83 ] vs 59 % [ 54 - 64 ] ; difference between groups 20 % [ 13 - 27 ] , log-rank p<0.0001 ) , and had increased 3-year overall survival ( 93 % [ 90 - 95 ] vs 84 % [ 80 - 88 ] ; difference between groups 9 % [ 3 - 13 ] , log-rank p=0.0001 ) . Event-free survival was affected by treatment group , presence of bulky disease , and age-adjusted IPI : after chemotherapy and rituximab , a favourable subgroup ( ie , IPI=0 , no bulk ) could be defined from a less-favourable subgroup ( ie , IPI=1 or bulk , or both ) . Groups did not differ in the frequency of adverse events . INTERPRETATION Rituximab added to six cycles of CHOP is an effective treatment for young patients with good-prognosis diffuse large-B-cell lymphoma . The definition of two prognostic subgroups allows for a more refined therapeutic approach for these patients PURPOSE To compare low-dose ( 30 Gy ) radiotherapy ( RT ) with observation ( OBS ) in limited-stage aggressive lymphoma patients achieving complete remission ( CR ) after chemotherapy , and to measure conversion from partial response ( PR ) to CR with high-dose ( 40 Gy ) RT . PATIENTS AND METHODS From 1984 to 1992 , stage I ( with risk factors ) and II adults with diffuse aggressive lymphoma in CR after eight cycles of cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) were r and omly assigned to 30 Gy involved-field RT or OBS . PR patients received 40 Gy RT . RESULTS Among 172 CR patients , the 6-year disease-free survival ( DFS ) was 73 % for low-dose RT versus 56 % for OBS ( two-sided P = .05 ) . Failure-free survival ( two-sided P = .06 ) , and time to progression ( two-sided P = .06 ) also favored RT . Intent-to-treat analyses yielded similar results . No survival differences were observed . Three RT versus 15 OBS patients relapsed in initial disease sites . At 6 years , failure-free survival was 63 % in PR patients ; conversion to CR did not significantly influence clinical outcome . CONCLUSION For patients in CR after CHOP , low-dose RT prolonged DFS and provided local control , but no survival benefit was observed . The majority of PR patients were event-free at 6 years despite residual radiographic abnormalities . Future efforts should be directed toward improved imaging and more effective systemic therapies PURPOSE Chemoradiotherapy has been considered st and ard treatment for patients with limited-stage aggressive lymphoma on the basis of trials conducted before the introduction of the International Prognostic Index . To evaluate this approach in elderly patients with low-risk localized lymphoma , we conducted a trial comparing chemoradiotherapy with chemotherapy alone . PATIENTS AND METHODS Previously untreated patients older than 60 years with localized stage I or II histologically aggressive lymphoma and no adverse prognostic factors of the International Prognostic Index were r and omly assigned to receive either four cycles of cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) plus involved-field radiotherapy ( 299 patients ) or chemotherapy alone with four cycles of CHOP ( 277 patients ) . RESULTS With a median follow-up time of 7 years , event-free and overall survival did not differ between the two treatment groups ( P = .6 and P = .5 , respectively ) . The 5-year estimates of event-free survival were 61 % for patients receiving chemotherapy alone and 64 % for patients receiving CHOP plus radiotherapy ; the 5-year estimates of overall survival were 72 % and 68 % , respectively . In a multivariate analysis , overall survival was affected by stage II disease ( P < .001 ) and male sex ( P = .03 ) . CONCLUSION In this large prospect i ve study , CHOP plus radiotherapy did not provide any advantage over CHOP alone for the treatment of low-risk localized aggressive lymphoma in elderly patients BACKGROUND The MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP ( cyclophosphamide , doxorubicin , vincristine , and prednisone)-like regimen in young patients with good-prognosis diffuse large-B-cell lymphoma . Extended follow-up was needed to establish long-term effects . METHODS In the r and omised open-label MInT study , patients from 18 countries ( aged 18 - 60 years with none or one risk factor according to the age-adjusted International Prognostic Index [ IPI ] , stage II-IV disease or stage I disease with bulk ) were r and omly assigned to receive six cycles of a CHOP-like chemotherapy with or without rituximab . Bulky and extranodal sites received additional radiotherapy . R and omisation was done central ly with a computer-based tool and was stratified by centre , bulky disease , age-adjusted IPI , and chemotherapy regimen by use of a modified minimisation algorithm that incorporated a stochastic component . Patients and investigators were not masked to treatment allocation . The primary endpoint was event-free survival . Analyses were by intention to treat . This observational study is a follow-up of the MInT trial , which was stopped in 2003 , and is registered at Clinical Trials.gov , number NCT00400907 . FINDINGS The intention-to-treat population included 410 patients assigned to chemotherapy alone and 413 assigned to chemotherapy plus rituximab . After a median follow-up of 72 months ( range 0·03 - 119 ) , 6-year event-free survival was 55·8 % ( 95 % CI 50·4 - 60·9 ; 166 events ) for patients assigned to chemotherapy alone and 74·3 % ( 69·3 - 78·6 ; 98 events ) for those assigned to chemotherapy plus rituximab ( difference between groups 18·5 % , 11·5 - 25·4 , log-rank p<0·0001 ) . Multivariable analyses showed that event-free survival was affected by treatment group , presence of bulky disease , and age-adjusted IPI and that overall survival was affected by treatment group and presence of bulky disease only . After chemotherapy and rituximab , a favourable subgroup ( IPI=0 , no bulk ) could be defined from a less favourable subgroup ( IPI=1 or bulk , or both ; event-free survival 84·3 % [ 95 % CI 74·2 - 90·7 ] vs 71·0 % [ 65·1 - 76·1 ] , log-rank p=0·005 ) . 18 ( 4·4 % , 95 % CI 2·6 - 6·9 ) second malignancies occurred in the chemotherapy-alone group and 16 ( 3·9 % , 2·2 - 6·2 ) in the chemotherapy and rituximab group ( Fisher 's exact p=0·730 ) . INTERPRETATION Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for young patients with good-prognosis diffuse large-B-cell lymphoma . The definition of two prognostic subgroups allows a more refined therapeutic approach to these patients than does assessment by IPI alone . FUNDING Hoffmann-La Roche PURPOSE To evaluate the effect of rituximab in limited-stage diffuse large B-cell lymphoma ( DLBCL ) , we conducted a multicenter phase II trial combining rituximab with three cycles of CHOP ( cyclophosphamide , doxorubicin , vincristine , and prednisone ; R-CHOP ) followed by involved-field radiation therapy ( IFRT ) . PATIENTS AND METHODS Southwest Oncology Group ( SWOG ) study S0014 enrolled patients with newly diagnosed , aggressive , CD20-expressing non-Hodgkin 's lymphoma ( NHL ) . Patients had limited-stage disease and at least one adverse risk factor as defined by the stage-modified International Prognostic Index ( nonbulky stage II disease , age > 60 years , WHO performance status of 2 , or elevated serum lactate dehydrogenase ) . Four doses of rituximab were infused on days -7 , 1 , 22 , and 43 , and CHOP was administered on days 3 , 24 , and 45 , followed 3 weeks later by 40 to 46 Gy of IFRT . RESULTS Sixty patients with aggressive NHL were eligible . With the median follow-up of 5.3 years , treatment result ed in a progression-free survival ( PFS ) of 93 % at 2 years and 88 % at 4 years . Overall survival ( OS ) was 95 % at 2 years and 92 % at 4 years . These results were compared with those from a historic group of patients treated without rituximab on S8736 , demonstrating PFS of 78 % and OS of 88 % at 4 years . CONCLUSION In limited-stage DLBCL , the addition of rituximab to three cycles of CHOP plus IFRT met prespecified study criteria of efficacy , with 2-year PFS of at least 84 % , meriting further investigation . There is a pattern of continuing relapse with modest survival gains . We hypothesize that such a pattern may be the result of biologic differences between limited- and advanced-stage lymphoma PURPOSE To analyze the long-term outcome of patients included in the Lymphome Non Hodgkinien study 98 - 5 ( LNH98 - 5 ) comparing cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) to rituximab plus CHOP ( R-CHOP ) in elderly patients with diffuse large B-cell lymphoma . PATIENTS AND METHODS LNH98 - 5 was a r and omized study that included 399 previously untreated patients , age 60 to 80 years , with diffuse large B-cell lymphoma . Patients received eight cycles of classical CHOP ( cyclophosphamide 750 mg/m(2 ) , doxorubicin 50 mg/m(2 ) , vincristine 1.4 mg/m(2 ) , and prednisone 40 mg/m(2 ) for 5 days ) every 3 weeks . In R-CHOP , rituximab 375 mg/m(2 ) was administered the same day as CHOP . Survivals were analyzed using the intent-to-treat principle . RESULTS Median follow-up is 5 years at present . Event-free survival , progression-free survival , disease-free survival , and overall survival remain statistically significant in favor of the combination of R-CHOP ( P = .00002 , P < .00001 , P < .00031 , and P < .0073 , respectively , in the log-rank test ) . Patients with low-risk or high-risk lymphoma according to the age-adjusted International Prognostic Index have longer survivals if treated with the combination . No long-term toxicity appeared to be associated with the R-CHOP combination . CONCLUSION Using the combination of R-CHOP leads to significant improvement of the outcome of elderly patients with diffuse large B-cell lymphoma , with significant survival benefit maintained during a 5-year follow-up . This combination should become the st and ard for treating these patients PURPOSE To evaluate the usefulness of adjuvant radiotherapy to sites of previous bulky disease in patients with advanced diffuse large cell lymphoma ( DLCL ) who were in complete remission after chemotherapy . METHODS AND MATERIAL Two-hundred and eighteen patients were initially treated with combined chemotherapy CEOP-bleo ( cyclophosphamide , epirubicin , vincristine , prednisone , bleomycin ) alternating with DAC ( dexamethasone , cytosine arabinoside , and cisplatinum ) . One hundred and fifty-five patients achieved complete remission . Eighty-eight patients with initial bulky disease were r and omly assigned to either received ( 43 patients ) or not received radiotherapy ( 45 patients ) . Dose ranged from 40 - 50 Gy . RESULTS The median time to treatment failure has not been reached in patients who received radiotherapy . At 5 years 72 % of the patients treated with the combined therapy remain alive disease in free compared to only 35 % in the control group . Projected survival at 5 years was better in the patients with adjuvant radiotherapy : 81 % compared to 55 % in the patients who received no radiotherapy . Toxicity was mild and manageable . No lethal toxicities were observed . CONCLUSION This treatment sequence produced durable control disease in patients with disseminated DLCL and bulky disease with acceptable toxicity . The role of radiation therapy in patients with disseminated DLCL will be confirmed in large clinical trials , but we felt that this sequence of treatment could be useful in patients with this clinical condition RETRACTED PURPOSE R-CHOP ( rituximab plus cyclophosphamide , doxorubicin , vincristine , and prednisone ) is st and ard care for aggressive B-cell lymphoma . A prospect i ve trial was conducted to investigate the role of additive radiotherapy ( RT ) to bulky and extralymphatic disease . PATIENTS AND METHODS The best arm of the RICOVER-60 trial ( 6 × R-CHOP-14 + 2R [ R-CHOP administered once every 2 weeks plus two additional applications of rituximab ] plus involved-field RT [ 36 Gy ] to sites of initial bulky [ ≥ 7.5 cm ] disease and extralymphatic involvement ) was compared with a cohort receiving the same immunochemotherapy but without RT in an amendment to the RICOVER-60 trial ( RICOVER-noRTh ) in a prospect i ve fashion . RESULTS After a median observation time of 39 months , 164 of 166 RICOVER-noRTh patients were evaluable . In a multivariable analysis of the intention-to-treat population adjusting for International Prognostic Index risk factors and age ( > 70 years ) , event-free survival ( EFS ) of patients with bulky disease was inferior without additive RT ( hazard ratio [ HR ] , 2.1 ; 95 % CI , 1.3 to 3.5 ; P = .005 ) , with trends for inferior progression-free ( PFS ; HR , 1.8 ; 95 % CI , 1.0 to 3.3 ; P = .058 ) and overall survival ( OS ; HR , 1.6 ; 95 % CI , 0.9 to 3.1 ; P = .127 ) . In a per- protocol analysis with 11 patients in RICOVER-noRTh excluded for receiving unplanned RT , multivariable analysis revealed HRs of 2.7 ( 95 % CI , 1.3 to 5.9 ; P = .011 ) for EFS , 4.4 ( 95 % CI , 1.8 to 10.6 ; P = .001 ) for PFS , and 4.3 ( 95 % CI , 1.7 to 11.1 ; P = .002 ) for OS for patients not receiving RT to bulky disease . CONCLUSION Additive RT to bulky sites abrogates bulky disease as a risk factor and improves outcome of elderly patients with aggressive B-cell lymphoma . Whether RT can be spared in patients with ( metabolic ) complete remission after immunochemotherapy must be addressed in appropriately design ed prospect i ve trials BACKGROUND Chemoradiotherapy is st and ard treatment for localized aggressive lymphoma . To determine the optimal therapy for nonelderly persons with low-risk localized lymphoma , we conducted a r and omized trial comparing chemoradiotherapy with chemotherapy alone . METHODS Previously untreated patients less than 61 years old with localized stage I or II aggressive lymphoma and no adverse prognostic factors according to the International Prognostic Index were r and omly assigned to three cycles of cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) plus involved-field radiotherapy ( 329 patients ) or chemotherapy alone with dose-intensified doxorubicin , cyclophosphamide , vindesine , bleomycin , and prednisone ( ACVBP ) plus sequential consolidation ( 318 patients ) . RESULTS With a median follow-up of 7.7 years , event-free and overall survival rates were significantly higher in the group given chemotherapy alone than in the group given CHOP plus radiotherapy ( P<0.001 and P=0.001 , respectively ) . The five-year estimates of event-free survival were 82 percent ( 95 percent confidence interval , 78 to 87 percent ) for patients receiving chemotherapy alone and 74 percent ( 95 percent confidence interval , 69 to 78 percent ) for those receiving chemoradiotherapy . The respective five-year estimates of overall survival were 90 percent ( 95 percent confidence interval , 87 to 93 percent ) and 81 percent ( 95 percent confidence interval , 77 to 86 percent ) . In a multivariate analysis , event-free and overall survival rates were affected by treatment group , independently of tumor stage and the presence or absence of bulky disease . CONCLUSIONS In patients under 61 years of age , chemotherapy with three cycles of ACVBP followed by sequential consolidation is superior to three cycles of CHOP plus radiotherapy for the treatment of low-risk localized lymphoma BACKGROUND Patients with clinical ly localized , intermediate- or high- grade non-Hodgkin 's lymphoma usually receive initial treatment with a doxorubicin-containing regimen such as cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) . Pilot studies suggest that eight cycles of CHOP alone or three cycles of CHOP followed by involved-field radiotherapy are effective in such patients . METHODS We compared these two approaches in a prospect i ve , r and omized , multi-institutional study . The end points were progression-free survival , overall survival , and life-threatening or fatal toxic effects . Two hundred eligible patients were r and omly assigned to receive CHOP plus radiotherapy , and 201 received CHOP alone . RESULTS Patients treated with three cycles of CHOP plus radiotherapy had significantly better progression-free survival ( P=0.03 ) and overall survival ( P=0.02 ) than patients treated with CHOP alone . The five-year estimates of progression-free survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 77 percent and 64 percent , respectively . The five-year estimates of overall survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 82 percent and 72 percent , respectively . The adverse effects included one death in each treatment group . Life-threatening toxic effects of any type were seen in 61 of 200 patients treated with CHOP plus radiotherapy and in 80 of 201 patients treated with CHOP alone ( P=0.06 ) . The left ventricular function was decreased in seven patients who received CHOP alone , whereas no cardiac events were recorded in the group receiving CHOP plus radiotherapy ( P=0.02 ) . CONCLUSIONS Three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone for the treatment of localized intermediate- and high- grade non-Hodgkin 's lymphoma PURPOSE To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody Rituxan ( rituximab , IDEC-C2B8 ; Genentech Inc , South San Francisco , CA ) and cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) chemotherapy in patients with aggressive non-Hodgkin 's lymphoma ( NHL ) . PATIENTS AND METHODS Thirty-three patients with previously untreated advanced aggressive B-cell NHL received six infusions of Rituxan ( 375 mg/m2 per dose ) on day 1 of each cycle in combination with six doses of CHOP chemotherapy given on day 3 of each cycle . RESULTS The ORR by investigator assessment confirmed by the sponsor was 94 % ( 31 of 33 patients ) . Twenty patients experienced a complete response ( CR ) ( 61 % ) , 11 patients had a partial response ( PR ) ( 33 % ) , and two patients were classified as having progressive disease . In the 18 patients with an International Prognostic Index ( IPI ) score > or = 2 , the combination of Rituxan plus CHOP achieved an ORR of 89 % and CR of 56 % . The median duration of response and time to progression had not been reached after a median observation time of 26 months . Twenty-nine of 31 responding patients remained in remission during this follow-up period , including 15 of 16 patients with an IPI score > or = 2 . The most frequent adverse events attributed to Rituxan were fever and chills , primarily during the first infusion . Rituxan did not seem to compromise the ability of patients to tolerate CHOP ; all patients completed the entire six courses of the combination . The bcl-2 translocation of blood or bone marrow was positive at baseline in 13 patients ; 11 patients had follow-up specimens obtained ( eight CR , three PR ) , and all had a negative bcl-2 status after therapy . Only one patient has reconverted to bcl-2 positivity , and all patients remain in clinical remission . CONCLUSION This is the first report to demonstrate the safety and efficacy of the Rituxan chimeric anti-CD20 antibody in combination with st and ard-dose CHOP in the treatment of aggressive B-cell lymphoma . The clinical responses are at least comparable to those achieved with CHOP alone with no significant added toxicity . The presence or absence of the bcl-2 translocation did not affect the ability of patients to achieve a CR with this regimen . The ability to achieve sustained remissions in patients with an IPI score > or = 2 warrants further investigation with a r and omized study The effects of radiotherapy ( RT ) after chemotherapy in patients with diffuse large B-cell lymphoma ( DLBCL ) remain unclear ; several trials have yielded conflicting results . This study examined the effect of RT after cyclophosphamide , doxorubicin , vincristine , and prednisone + rituximab ( R-CHOP ) treatment on event-free ( EFS ) and overall ( OS ) survival . Data from 216 patients with DLBCL who were enrolled in two clinical trials at Italian Lymphoma Study Group sites and were subjected to six R-CHOP cycles and involved-field radiotherapy ( IFRT ) were retrospectively analyzed . IFRT treatment yielded significant EFS benefit , with a 66 % reduction in the risk of death and /or disease progression . Cox analysis , when adjusted for age , gender , stage , performance status ( PS ) , lactate dehydrogenase ( LDH ) , and disease bulk , confirmed the significant EFS benefit of IFRT . The role of RT in DLBCL in the rituximab era is unclear . Future studies must take into account new radiation techniques and the response to chemotherapy based on functional imaging . Prospect i ve r and omized trials incorporating response-adapted therapy and modern radiation techniques are needed |
13,734 | 28,029,715 | Age was identified as a likely modifier of the association between antidepressant use and some form of cognitive impairment or AD/dementia .
Antidepressant drug usage is associated with AD/dementia and this is particularly evident if usage begins before age 65 .
This association may arise due to confounding by depression or depression severity .
However , biological mechanisms potentially linking antidepressant exposure to dementia have been described , so an etiological effect of antidepressants is possible . | OBJECTIVE To determine if antidepressant drug usage is associated with cognitive impairment or dementia , including Alzheimer disease ( AD ) . | 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 Studies on humans show that depressive disorder is associated with an increased risk of developing cognitive dysfunction , and animal studies suggest that antidepressants may have neuroprotective abilities . On the basis of these observations , it was hypothesized that treatment with antidepressants may decrease the risk of developing dementia in patients with depression . We investigated whether continued treatment with antidepressants is associated with a decreased rate of dementia in a population of patients discharged from psychiatric healthcare service with a diagnosis of depression . We used register data on all prescribed antidepressants in all patients discharged from psychiatric healthcare service with a diagnosis of depression and with subsequent diagnoses of dementia in Denmark from 1995 to 2005 . A total of 37 658 patients with a diagnosis of depression at their first psychiatric contact and who were exposed to antidepressants after discharge were included in the study . A total of 2007 patients ( 5.3 % ) were subsequently diagnosed with dementia of any kind . The rate of dementia decreased during periods of two or more prescriptions of older antidepressants compared with the period of only one prescription of older antidepressants [ relative risk (RR)=0.83 ( 95 % confidence interval (CI)=0.70–0.98 ) ] . This finding was replicated with Alzheimer ’s disease as the outcome [ RR=0.66 ( 95 % CI=0.47–0.94 ) ] but not with dementia of other kinds as the outcome [ RR=0.88 ( 95 % CI=0.73–1.06 ) ] . In contrast , during periods of continued use of selective serotonin reuptake inhibitors or newer nonselective serotonin reuptake inhibitors , the rate of dementia was not decreased , regardless of the subtype of dementia . It was concluded that continued long-term treatment with older antidepressants is associated with a reduced rate of dementia in patients treated in psychiatric healthcare setting s , whereas continued treatment with other kinds of antidepressants is not . Method ological reasons for these findings can not be excluded because of the nonr and omized nature of data CONTEXT Adjunctive restorative therapies administered during the first few months after stroke , the period with the greatest degree of spontaneous recovery , reduce the number of stroke patients with significant disability . OBJECTIVE To examine the effect of escitalopram on cognitive outcome . We hypothesized that patients who received escitalopram would show improved performance in neuropsychological tests assessing memory and executive functions than patients who received placebo or underwent Problem Solving Therapy . DESIGN R and omized trial . SETTING Stroke center . PARTICIPANTS One hundred twenty-nine patients were treated within 3 months following stroke . The 12-month trial included 3 arms : a double-blind placebo-controlled comparison of escitalopram ( n = 43 ) with placebo ( n = 45 ) , and a nonblinded arm of Problem Solving Therapy ( n = 41 ) . OUTCOME MEASURES Change in scores from baseline to the end of treatment for the Repeatable Battery for the Assessment of Neuropsychological Status ( RBANS ) and Trail-Making , Controlled Oral Word Association , Wechsler Adult Intelligence Scale-III Similarities , and Stroop tests . RESULTS We found a difference among the 3 treatment groups in change in RBANS total score ( P < .01 ) and RBANS delayed memory score ( P < .01 ) . After adjusting for possible confounders , there was a significant effect of escitalopram treatment on the change in RBANS total score ( P < .01 , adjusted mean change in score : escitalopram group , 10.0 ; nonescitalopram group , 3.1 ) and the change in RBANS delayed memory score ( P < .01 , adjusted mean change in score : escitalopram group , 11.3 ; nonescitalopram group , 2.5 ) . We did not observe treatment effects in other neuropsychological measures . CONCLUSIONS When compared with patients who received placebo or underwent Problem Solving Therapy , stroke patients who received escitalopram showed improvement in global cognitive functioning , specifically in verbal and visual memory functions . This beneficial effect of escitalopram was independent of its effect on depression . The utility of antidepressants in the process of poststroke recovery should be further investigated . Trial Registration clinical trials.gov Identifier : NCT00071643 A prospect i ve analysis of risk factors for Alzheimer 's disease was a major objective of the Canadian Study of Health and Aging , a nationwide , population -based study . Of 6,434 eligible subjects aged 65 years or older in 1991 , 4,615 were alive in 1996 and participated in the follow-up study . All participants were cognitively normal in 1991 when they completed a risk factor question naire . Their cognitive status was reassessed 5 years later by using a similar two-phase procedure , including a screening interview , followed by a clinical examination when indicated . The analysis included 194 Alzheimer 's disease cases and 3,894 cognitively normal controls . Increasing age , fewer years of education , and the apolipoprotein E epsilon4 allele were significantly associated with increased risk of Alzheimer 's disease . Use of nonsteroidal anti-inflammatory drugs , wine consumption , coffee consumption , and regular physical activity were associated with a reduced risk of Alzheimer 's disease . No statistically significant association was found for family history of dementia , sex , history of depression , estrogen replacement therapy , head trauma , antiperspirant or antacid use , smoking , high blood pressure , heart disease , or stroke . The protective associations warrant further study . In particular , regular physical activity could be an important component of a preventive strategy against Alzheimer 's disease and many other conditions CONTEXT Although depression is a risk factor for dementia in the general population , its association with dementia among patients with diabetes mellitus has not been well studied . OBJECTIVE To determine whether comorbid depression in patients with type 2 diabetes increases the risk of development of dementia . DESIGN The Diabetes and Aging Study was a cohort investigation that surveyed a racially/ethnically stratified r and om sample of patients with type 2 diabetes . SETTING A large , integrated , nonprofit managed care setting in Northern California . PARTICIPANTS A sample of 19,239 diabetes registry members 30 to 75 years of age . MAIN OUTCOME MEASURES The Patient Health Question naire 8 , International Classification of Diseases , Ninth Revision ( ICD-9 ) diagnoses of depression , and /or antidepressant prescriptions in the 12 months prior to baseline were used to identify prevalent cases of depression . Clinical ly recognized dementia was identified among subjects with no prior ICD-9 Clinical Modification ( ICD-9-CM ) diagnoses of dementia . To exclude the possibility that depression was a prodrome of dementia , dementia diagnoses were only based on ICD-9-CM diagnoses identified in years 3 to 5 postbaseline . The risk of dementia for patients with depression and diabetes relative to patients with diabetes alone was estimated using Cox proportional hazard regression models that adjusted for sociodemographic , clinical , and health risk factors and health use . RESULTS During the 3- to 5-year period , 80 of 3766 patients ( 2.1 % ) with comorbid depression and diabetes ( incidence rate of 5.5 per 1000 person-years ) vs 158 of 15,473 patients ( 1.0 % ) with diabetes alone ( incidence rate of 2.6 per 1000 person-years ) had 1 or more ICD-9-CM diagnoses of dementia . Patients with comorbid depression had a 100 % increased risk of dementia during the 3 to 5 years postbaseline ( adjusted hazard ratio , 2.02 ; 95 % confidence interval , 1.73 - 2.35 ) . CONCLUSION Depression in patients with diabetes was associated with a substantively increased risk for development of dementia compared with those with diabetes alone Background : Subsyndromal symptoms of depression ( SSD ) in patients with schizophrenia are common and clinical ly important . While treatment of depression in major depressive disorder may partially ameliorate cognitive deficits , the cognitive effects of antidepressant medications in patients with schizophrenia or schizoaffective disorder and SSD are unknown . Methods : The goal of this study was to assess the impact of SSD and their treatment on cognition in participants with schizophrenia or schizoaffective disorder aged ≧40 years . Participants were r and omly assigned to a flexible dose treatment with citalopram or placebo augmentation of their current medication for 12 weeks . An ANCOVA compared improvement in the cognitive composite scores , and a linear model determined the moderation of cognition on treatment effects based on the Hamilton Depression Rating Scale and the Calgary Depression Rating Scale scores between treatment groups . Results : There were no differences between the citalopram and placebo groups in changes in cognition . Baseline cognitive status did not moderate antidepressant treatment response . Conclusions : Although there are other cogent reasons why SSD in schizophrenia warrant direct intervention , treatment does not substantially affect the level of cognitive functioning . Given the effects of cognitive deficits associated with schizophrenia on functional disability , there remains an ongoing need to identify effective means of directly ameliorating them BACKGROUND It has been suggested that antidepressants may have neuroprotective abilities but it has newer been investigated lately whether treatment with antidepressants reduces the risk of dementia . METHOD Linkage of registers of all prescribed antidepressants and diagnoses of dementia in Denmark during a period from 1995 to 2005 . RESULTS Persons who purchased antidepressants once ( N=687,552 ) had an increased rate of dementia compared to persons unexposed to antidepressants ( N=779,831 ) . Nevertheless , the rate of dementia changed over time ; thus during the initial prescription periods the rate increased with the number of prescriptions but continued long-term antidepressants treatment was associated with a reduction in the rate of dementia , however , not to the same level as the rate for the general population . This pattern was found for all classes of antidepressants ( SSRIs , newer non-SSRI antidepressants and older antidepressants ) . All findings were replicated in sub-analyses with Alzheimer 's disease as outcome . LIMITATIONS Method ological reasons for the findings can not be excluded due to the non-r and omized nature of data . CONCLUSIONS Continued long-term antidepressant treatment was associated with a reduced rate of dementia , however , not to the same level as the rate for the general population BACKGROUND It remains unknown whether depression and apolipoprotein E genotype are risk factors for incident mild cognitive impairment ( MCI ) . OBJECTIVE To determine whether elderly individuals with depression ( measured by the short Geriatric Depression Scale ) are at increased risk of developing incident MCI . DESIGN Prospect i ve cohort study . SETTING Primary care clinic . PARTICIPANTS A cohort of 840 cognitively normal elderly subjects without depression at recruitment who were followed up prospect ively for a median of 3.5 years ( range , 0.4 - 12.8 years ) . Subjects who developed depression ( score of > /=6 on the short Geriatric Depression Scale ; depression cohort ) were compared with all remaining subjects ( referent cohort ) . MAIN OUTCOME MEASURES Incidence of MCI ( primary outcome ) and incidence of MCI or dementia ( composite secondary outcome ) . RESULTS Individuals in the depression cohort were at significantly increased risk of subsequent incident MCI ( hazard ratio [ HR ] , 2.2 ; 95 % confidence interval [ CI ] , 1.2 - 4.1 ) after adjusting for age ( time scale ) , sex , and education , and considering dementia as a competing outcome . The association was stronger in men but did not vary by severity of depression . We observed a synergistic interaction between apolipoprotein E genotype ( epsilon3/epsilon4 or epsilon4/epsilon4 ) and depression ( joint effect HR , 5.1 ; 95 % CI , 1.9 - 13.6 ; test for additive interaction , P = .03 ) . We found a similar association between depression and the subsequent composite outcome of incident MCI or dementia ( HR , 2.6 ; 95 % CI , 1.6 - 4.3 ) . CONCLUSIONS Cognitively normal elderly individuals who develop depression are at increased risk of subsequent MCI . We found a synergistic interaction between depression and apolipoprotein E genotype Three definitions of atypical depression are evaluated with respect to the effects of monoamine oxidase inhibitors ( MAOIs ) and tricyclic antidepressants ( TCAs ) on the basis of pooled data from several double-blind studies . Those three definitions of atypical depression are depression with associated panic , depression secondary to a diagnosis of anxiety , and depression with reversed vegetative change . In none of these forms was a drug difference observed . However , when gender was taken into account , MAOIs were superior to TCAs in depressed women with panic attacks , whereas TCAs were superior to MAOIs in depressed men with panic attacks |
13,735 | 27,430,287 | We found support for the existence of independent associations between teamwork , clinician occupational well-being and patient safety . | Background There is growing evidence that teamwork in hospitals is related to both patient outcomes and clinician occupational well-being .
Furthermore , clinician well-being is associated with patient safety .
Despite considerable research activity , few studies include all three concepts , and their interrelations have not yet been investigated systematic ally .
To advance our underst and ing of these potentially complex interrelations we propose an integrative framework taking into account current evidence and research gaps identified in a systematic review . | Purpose Staff behaviours to optimise patient safety may be influenced by burnout , depression and strength of the safety culture . We evaluated whether burnout , symptoms of depression and safety culture affected the frequency of medical errors and adverse events ( selected using Delphi techniques ) in ICUs . Methods Prospect i ve , observational , multicentre ( 31 ICUs ) study from August 2009 to December 2011 . Results Burnout , depression symptoms and safety culture were evaluated using the Maslach Burnout Inventory ( MBI ) , CES-Depression scale and Safety Attitudes Question naire , respectively . Of 1,988 staff members , 1,534 ( 77.2 % ) participated . Frequencies of medical errors and adverse events were 804.5/1,000 and 167.4/1,000 patient-days , respectively . Burnout prevalence was 3 or 40 % depending on the definition ( severe emotional exhaustion , depersonalisation and low personal accomplishment ; or MBI score greater than −9 ) . Depression symptoms were identified in 62/330 ( 18.8 % ) physicians and 188/1,204 ( 15.6 % ) nurses/nursing assistants . Median safety culture score was 60.7/100 [ 56.8–64.7 ] in physicians and 57.5/100 [ 52.4–61.9 ] in nurses/nursing assistants . Depression symptoms were an independent risk factor for medical errors . Burnout was not associated with medical errors . The safety culture score had a limited influence on medical errors . Other independent risk factors for medical errors or adverse events were related to ICU organisation ( 40 % of ICU staff off work on the previous day ) , staff ( specific safety training ) and patients ( workload ) . One-on-one training of junior physicians during duties and existence of a hospital risk-management unit were associated with lower risks . Conclusions The frequency of selected medical errors in ICUs was high and was increased when staff members had symptoms of depression The presence of hope has been found to influence an individual 's ability to cope with stressful situations . The objective of this study is to evaluate the relationship between medical errors , hope and burnout among practicing physicians using vali date d metrics . Prospect i ve cohort study was conducted among hospital based physicians practicing in Japan ( N = 836 ) . Measures included the vali date d Burnout Scale , self- assessment of medical errors and Herth Hope Index ( HHI ) . The main outcome measure was the frequency of self-perceived medical errors , and Poisson regression analysis was used to evaluate the association between hope and medical error . A total of 361 errors were reported in 836 physician-years . We observed a significant association between hope and self-report of medical errors . Compared with the lowest tertile category of HHI , incidence rate ratios ( IRRs ) of self-perceived medical errors of physicians in the highest category were 0.44 ( 95%CI , 0.34 to 0.58 ) and 0.54 ( 95%CI , 0.42 to 0.70 ) respectively , for the 2nd and 3rd tertile . In stratified analysis by hope score , among physicians with a low hope score , those who experienced higher burnout reported higher incidence of errors ; physicians with high hope scores did not report high incidences of errors , even if they experienced high burnout . Self-perceived medical errors showed a strong association with physicians ' hope , and hope modified the association between physicians ' burnout and self-perceived medical errors AIMS We examined the impact of workplace relationships ( perceived organizational support , supervisor-nurse relationships and teamwork ) on the engagement , well-being , organizational commitment and turnover intentions of nurses working in Australian and USA hospitals . BACKGROUND In a global context of nurse shortages , knowledge about factors impacting nurse retention is urgently sought . We postulated , using the Social Exchange Theory , that nurses ' turnover intentions would be affected by several factors and especially their relationships at work . DESIGN Based on the literature review , data were collected via a self-report survey to test the hypotheses . METHODS A self-report survey was used to gather data in 2010 - 2012 from 510 r and omly chosen nurses from Australian hospitals and 718 nurses from US hospitals . A multi-group structural equation modelling analysis identified significant paths and compared the impact between countries . RESULTS The findings indicate that this model was more effective in predicting the correlations between variables for nurses in Australia compared with the USA . Most paths predicted were confirmed for Australia , except for the impact of teamwork on organizational commitment and turnover , plus the impact of engagement on turnover . In contrast , none of the paths related to supervisor-subordinate relationships was significant for the USA ; neither were the paths from teamwork to organizational commitment or turnover . CONCLUSION Our findings suggest that well-being is a predictor of turnover intentions , meaning that healthcare managers need to consider nurses ' well-being in everyday decision-making , especially in the cost-cutting paradigm that pervades healthcare provision in nearly every country . This is important because nurses are in short supply and this situation will continue to worsen , because many countries have an ageing population RATIONALE The stressful work environment of ICUs can lead to burnout . Burnout can impact on the welfare and performance of caregivers , and may lead them to resign their job . The shortage of ICU caregivers is becoming a real threat for health care leaders . OBJECTIVES To investigate the factors associated with burnout on a national level in order to determine potential important factors . METHODS Prospect i ve , multicenter , observational survey of all caregivers from 74 of the 92 Swiss ICUs , measuring the prevalence of burnout among the caregivers and the pre-specified center- , patient- and caregiver-related factors influencing its prevalence . MEASUREMENTS AND MAIN RESULTS Out of the 4322 question naires distributed from March 2006 to April 2007 , 3052 ( 71 % ) were returned , with a response rate of 72 % by center , 69 % from nurse-assistants , 73 % from nurses and 69 % from physicians . A high proportion of female nurses among the team was associated with a decreased individual risk of high burnout ( OR 0.98 , 95 % CI:0.97 - 0.99 for every % ) . The caregiver-related factors associated with a high risk of burnout were being a nurse-assistant , being a male , having no children and being under 40 years old . CONCLUSIONS The findings of this study seem to open a new frontier concerning burnout in ICUs , highlighting the importance of team composition . Our results should be confirmed in a prospect i ve multicenter , multinational study . Whether our results can be exported to other medical setting s where team-working is pivotal remains to be investigated CONTEXT Medical errors are associated with feelings of distress in physicians , but little is known about the magnitude and direction of these associations . OBJECTIVE To assess the frequency of self-perceived medical errors among resident physicians and to determine the association of self-perceived medical errors with resident quality of life , burnout , depression , and empathy using vali date d metrics . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve longitudinal cohort study of categorical and preliminary internal medicine residents at Mayo Clinic Rochester . Data were provided by 184 ( 84 % ) of 219 eligible residents . Participants began training in the 2003 - 2004 , 2004 - 2005 , and 2005 - 2006 academic years and completed surveys quarterly through May 2006 . Surveys included self- assessment of medical errors and linear analog scale assessment of quality of life every 3 months , and the Maslach Burnout Inventory ( depersonalization , emotional exhaustion , and personal accomplishment ) , Interpersonal Reactivity Index , and a vali date d depression screening tool every 6 months . MAIN OUTCOME MEASURES Frequency of self-perceived medical errors was recorded . Associations of an error with quality of life , burnout , empathy , and symptoms of depression were determined using generalized estimating equations for repeated measures . RESULTS Thirty-four percent of participants reported making at least 1 major medical error during the study period . Making a medical error in the previous 3 months was reported by a mean of 14.7 % of participants at each quarter . Self-perceived medical errors were associated with a subsequent decrease in quality of life ( P = .02 ) and worsened measures in all domains of burnout ( P = .002 for each ) . Self-perceived errors were associated with an odds ratio of screening positive for depression at the subsequent time point of 3.29 ( 95 % confidence interval , 1.90 - 5.64 ) . In addition , increased burnout in all domains and reduced empathy were associated with increased odds of self-perceived error in the following 3 months ( P=.001 , P<.001 , and P=.02 for depersonalization , emotional exhaustion , and lower personal accomplishment , respectively ; P=.02 and P=.01 for emotive and cognitive empathy , respectively ) . CONCLUSIONS Self-perceived medical errors are common among internal medicine residents and are associated with substantial subsequent personal distress . Personal distress and decreased empathy are also associated with increased odds of future self-perceived errors , suggesting that perceived errors and distress may be related in a reciprocal cycle PURPOSE To investigate if differences in antecedents of severe and nonsevere medication errors exist . DESIGN A longitudinal study of 6 months of data from 279 nursing units in 146 r and omly selected hospitals in the United States ( US ) . METHODS Antecedents of severe and nonsevere medication errors included work environment factors ( work dynamics and RN hours ) , team factors ( communication with physicians and nurses ' expertise ) , person factors ( nurses ' education and experience ) , patient factors ( age , health status , and previous hospitalization ) , and medication-related support services . Generalized estimating equations with a negative binomial distribution were used with nursing units as the unit of analysis . FINDINGS None of the antecedents allowed predicting both types of medication errors . Nurses ' expertise had a negative and medication-related support services had a positive association with nonsevere medication errors . Nurses ' educational level had a significant nonlinear relationship with severe medication errors only : As the percentage of unit BSN-prepared nurses increased , severe medication errors decreased until the percentage of BSN-prepared nurses reached 54 % . In contrast , RN experience had a statistically significant relationship with nonsevere medication errors only and nursing units with more experienced nurses reported more nonsevere medication errors . CONCLUSIONS Severe and nonsevere medication errors might have different antecedents . CLINICAL RELEVANCE Error prevention and management strategies should be targeted to specific types of medication errors for best results AIM Whether mental stress negatively impacts team performance during cardio-pulmonary resuscitation ( CPR ) remains controversial ; this may partly be explained by differences in stress measures used in previous studies . Our aim was to compare self-reported , biochemical and physiological stress measures in regard to CPR performance . METHODS This prospect i ve , observational study was conducted at the simulator center of the University Hospital Basel , Switzerl and . Self-reported ( feeling stressed and overwhelmed [ stress/overload ] ) , biochemical ( plasma cortisol ) and physiological ( heart rate , heart rate variability ) stress measures were assessed in 28 residents ( teams of 2 ) before , during and after resuscitation . Team performance was defined as time to start CPR and h and s-on time during the first 180 s. RESULTS At baseline , significant negative correlations of heart rate variability with stress/overload and heart rate , as well as positive correlations of heart rate and cortisol were found . During resuscitation , self-reported , biochemical and physiological stress measures did not correlate significantly . There was no association of baseline stress measures with performance . During CPR , stress/overload was significantly associated with time to start CPR ( regression coefficient 12.01 ( 95 % CI 0.65 , 23.36 ) , p=0.04 ) , while heart rate was negatively associated with time to start CPR ( regression coefficient -0.78 ( 95 % CI -1.44 , -0.11 ) , p=0.027 ) and positively with h and s-on time ( regression coefficient 2.22 ( 95 % CI 0.53 , 3.92 ) , p=0.015 ) . CONCLUSIONS Self-reported stress ( stress/overload ) was the only predictor for low CPR performance . Biochemical measures showed no association , and physiological measures ( heart rate ) showed an inverse association , which may be due to physical activity , limiting its value as a mental stress marker in this acute setting The influence of teammates ' shared mental models on team processes and performance was tested using 56 undergraduate dyads who " flew " a series of missions on a personal-computer-based flight-combat simulation . The authors both conceptually and empirically distinguished between teammates ' task- and team-based mental models and indexed their convergence or " sharedness " using individually completed paired-comparisons matrices analyzed using a network-based algorithm . The results illustrated that both shared-team- and task-based mental models related positively to subsequent team process and performance . Furthermore , team processes fully mediated the relationship between mental model convergence and team effectiveness . Results are discussed in terms of the role of shared cognitions in team effectiveness and the applicability of different interventions design ed to achieve such convergence Patient care in hospital setting s requires coordinated team performance . Studies in other industries show that successful teams adapt their coordination processes to the situational task requirements . This prospect i ve field study aim ed to test a new observation system and investigate patterns of adaptive coordination within operating room teams . A trained observer recorded coordination activities during 24 cardiac surgery procedures . The study tested whether different patterns occur during different phases of and between different types of surgical procedures ( two-way multivariate ANOVA with repeated measure ) . A statistically significant increase was found in clinical and coordination activities in phases of the operation with high task interdependence . The highest level of ‘ coordination via the work environment ’ ( i.e. an implicit coordination mechanism ) was recorded during the actual procedure on the beating heart . These findings prove the sensitivity of the observation system developed and evaluated in this study and provide insight into patterns of adaptive coordination in cardiac anaesthesia . This study furthers our underst and ing of adaptive coordination as a cornerstone of effective team performance in complex work environments . Using a new observation system , it describes patterns employed by health care professionals in response to changing task dem and s in an acute patient care setting CONTEXT Fatigue and distress have been separately shown to be associated with medical errors . The contribution of each factor when assessed simultaneously is unknown . OBJECTIVE To determine the association of fatigue and distress with self-perceived major medical errors among resident physicians using vali date d metrics . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve longitudinal cohort study of categorical and preliminary internal medicine residents at Mayo Clinic , Rochester , Minnesota . Data were provided by 380 of 430 eligible residents ( 88.3 % ) . Participants began training from 2003 to 2008 and completed surveys quarterly through February 2009 . Surveys included self- assessment of medical errors , linear analog self- assessment of overall quality of life ( QOL ) and fatigue , the Maslach Burnout Inventory , the PRIME-MD depression screening instrument , and the Epworth Sleepiness Scale . MAIN OUTCOME MEASURES Frequency of self-perceived , self-defined major medical errors was recorded . Associations of fatigue , QOL , burnout , and symptoms of depression with a subsequently reported major medical error were determined using generalized estimating equations for repeated measures . RESULTS The mean response rate to individual surveys was 67.5 % . Of the 356 participants providing error data ( 93.7 % ) , 139 ( 39 % ) reported making at least 1 major medical error during the study period . In univariate analyses , there was an association of subsequent self-reported error with the Epworth Sleepiness Scale score ( odds ratio [ OR ] , 1.10 per unit increase ; 95 % confidence interval [ CI ] , 1.03 - 1.16 ; P = .002 ) and fatigue score ( OR , 1.14 per unit increase ; 95 % CI , 1.08 - 1.21 ; P < .001 ) . Subsequent error was also associated with burnout ( ORs per 1-unit change : depersonalization OR , 1.09 ; 95 % CI , 1.05 - 1.12 ; P < .001 ; emotional exhaustion OR , 1.06 ; 95 % CI , 1.04 - 1.08 ; P < .001 ; lower personal accomplishment OR , 0.94 ; 95 % CI , 0.92 - 0.97 ; P < .001 ) , a positive depression screen ( OR , 2.56 ; 95 % CI , 1.76 - 3.72 ; P < .001 ) , and overall QOL ( OR , 0.84 per unit increase ; 95 % CI , 0.79 - 0.91 ; P < .001 ) . Fatigue and distress variables remained statistically significant when modeled together with little change in the point estimates of effect . Sleepiness and distress , when modeled together , showed little change in point estimates of effect , but sleepiness no longer had a statistically significant association with errors when adjusted for burnout or depression . CONCLUSION Among internal medicine residents , higher levels of fatigue and distress are independently associated with self-perceived medical errors Objective To determine the prevalence of depression and burnout among residents in paediatrics and to establish if a relation exists between these disorders and medication errors . Design Prospect i ve cohort study . Setting Three urban freest and ing children ’s hospitals in the United States . Participants 123 residents in three paediatric residency programmes . Main outcome measures Prevalence of depression using the Harvard national depression screening day scale , burnout using the Maslach burnout inventory , and rate of medication errors per resident month . Results 24 ( 20 % ) of the participating residents met the criteria for depression and 92 ( 74 % ) met the criteria for burnout . Active surveillance yielded 45 errors made by participants . Depressed residents made 6.2 times as many medication errors per resident month as residents who were not depressed : 1.55 ( 95 % confidence interval 0.57 to 4.22 ) compared with 0.25 ( 0.14 to 0.46 , P<0.001 ) . Burnt out residents and non-burnt out residents made similar rates of errors per resident month : 0.45 ( 0.20 to 0.98 ) compared with 0.53 ( 0.21 to 1.33 , P=0.2 ) . Conclusions Depression and burnout are major problems among residents in paediatrics . Depressed residents made significantly more medical errors than their non-depressed peers ; however , burnout did not seem to correlate with an increased rate of medical errors Background Team-based interventions are effective for improving safety and quality of healthcare . However , context ual factors , such as team functioning , leadership , and organizational support , can vary significantly across teams and affect the level of implementation success . Yet , the science for measuring context is immature . The goal of this study is to vali date measures from a short instrument tailored to track dynamic context and progress for a team-based quality improvement ( QI ) intervention . Methods Design : Secondary cross-sectional and longitudinal analysis of data from a clustered r and omized controlled trial ( RCT ) of a team-based quality improvement intervention to reduce central line-associated bloodstream infection ( CLABSI ) rates in intensive care units ( ICUs ) . Setting : Forty-six ICUs located within 35 faith-based , not-for-profit community hospitals across 12 states in the U.S. Population : Team members participating in an ICU-based QI intervention . Measures : The primary measure is the Team Check-up Tool ( TCT ) , an original instrument that assesses context and progress of a team-based QI intervention . The TCT is administered monthly . Validation measures include CLABSI rate , Team Functioning Survey ( TFS ) and Practice Environment Scale ( PES ) from the Nursing Work Index . Analysis : Temporal stability , responsiveness and validity of the TCT . Results We found evidence supporting the temporal stability , construct validity , and responsiveness of TCT measures of intervention activities , perceived group-level behaviors , and barriers to team progress . Conclusions The TCT demonstrates good measurement reliability , validity , and responsiveness . By having more vali date d measures on implementation context , research ers can more readily conduct rigorous studies to identify context ual variables linked to key intervention and patient outcomes and strengthen the evidence base on successful spread of efficacious team-based interventions . QI teams participating in an intervention should also find data from a vali date d tool useful for identifying opportunities to improve their own implementation Objective : The objective of this study was to explore the theoretical relationship between the social reputation and the perceived safety of a hospital . Subjects and Methods : A r and om sample of 316 patients and 27 relatives of patients who were unable to respond themselves at four public hospitals in Madrid , Barcelona and Alicante were interviewed to establish a measure of reputation and perceived safety . Results : There were no different perceptions between patients and relatives regarding hospital reputation or safety perception ( p > 0.05 ) . The perception of patients or relatives of health professionals ' competence ( β = 0.07 , 95 % CI 0.01 - 0.12 ) , the perception of a positive treatment output of surgical or medical treatment ( β = 0.35 , 95 % CI 0.22 - 0.49 ) and hospital reputation ( β = 0.08 , 95 % CI 0.02 - 0.14 ) were directly and positively associated with their perception that the hospital was a safe clinical environment in which few clinical errors are committed . Conclusions : The data suggested that the social reputation of these hospitals and the perceptions of patients or relatives of patient safety were indeed correlated . Future research should assess whether efforts to enhance hospital reputation , by improving patients ' perceptions of clinical safety , may contribute to reducing the frequency of litigation cases 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 To determine whether team performance in a simulated emergency is related to generic teamwork skills and behaviours . METHODS Design - Cross-sectional analysis of data from the Simulation and Fire-drill Evaluation ( SaFE ) r and omised controlled trial . Setting - Six secondary and tertiary Maternity Units in Southwest Engl and . Participants - 140 healthcare professionals , in 24 teams . Assessment - Blinded analysis of recorded simulations . Main outcome measures - Correlation of team performance ( efficiency conducting key clinical actions , including the administration of an essential drug , magnesium ) , and generic teamwork scores ( using a vali date d tool that assesses skills and behaviours , by Weller et al. ) . RESULTS There was significant positive correlation between clinical efficiency and teamwork scores across all three dimensions ; skills ( Kendall 's tau(b)=0.54 , p<0.001 ) , behaviours ( tau(b)=0.41 , p=0.001 ) , and overall score ( tau(b)=0.51 , p<0.001 ) . Better teams administered the essential drug 2½min more quickly ( Mann-Whitney U , p<0.001 ) . CONCLUSIONS The clinical conduct of a simulated emergency was strongly linked to generic measures of teamwork . Further studies are needed to eluci date which aspects of team working are critical for team performance , to better inform training programs for multi-professional team working BACKGROUND : Our goal in this study was to test the relationship between speaking up — i.e . , question ing , correcting , or clarifying a current procedure— and technical team performance in anesthesia . Hypothesis 1 : team members ’ higher levels of speaking up are related to higher levels of technical team performance . Hypothesis 2 : team members will react to speaking up by either clarifying their procedure or initiating a procedural change . Hypothesis 3 : higher levels of speaking up during an earlier phase of teamwork will be related to higher levels of speaking up during a later phase . METHODS : This prospect i ve observational study involved 2-person ad hoc anesthesia teams performing simulated inductions of general anesthesia with minor nonroutine events ( e.g. , bradycardia ) in a large teaching hospital . Subjects were registered anesthesia nurses and residents . Each team consisted of 1 nurse and 1 resident . Synchronized video and vital parameter recordings were obtained . Two trained observers blinded to the hypotheses coded speaking up and further team communication and coordination behavior on the basis of 12 distinct categories . All teamwork measures were quantified as percentage of total time spent on the respective teamwork category . Two experienced staff anesthesiologists blinded to the hypotheses evaluated technical team performance using a Delphi-vali date d rating checklist . Hypotheses 1 and 3 were tested using linear regression with residents ’ and nurses ’ levels of speaking up as 2 separate predictor variables . Hypothesis 2 was analyzed using lag sequential analysis , result ing in Z values representing the extent to which the observed value for a conditional transition significantly differs from its unconditional value . RESULTS : Thirty-one nurses and 31 residents participated . Technical team performance could be predicted by the level of speaking up from nurses ( R2 = 0.18 , P = 0.017 ) but not from residents ( R2 = 0.19 , P = 0.053 ) ; this result supports Hypothesis 1 for nurses . Supporting Hypothesis 2 , residents reacted to speaking up with clarifying the procedure by providing information ( Z = 18.08 , P < 0.001 ) , initiating procedural change by giving instructions ( Z = 4.74 , P < 0.001 ) and team member monitoring ( Z = 3 , P = 0.0013 ) . Likewise , nurses reacted with clarifying the procedure by providing or evaluating information ( Z = 16.09 , P < 0.001 ; Z = 3.72 , P < 0.001 ) and initiating procedural change by providing assistance ( Z = 0.57 , P < 0.001 ) . Indicating a trend for Hypothesis 3 , nurses ’ level of speaking up before intubation predicted their level of speaking up during intubation ( R2 = 0.15 , P = 0.034 ) , although this did not reach the Bonferroni-corrected significance level of P = 0.025 . No respective relationship was found for residents ( R2 = 0.15 , P = 0.096 ) . CONCLUSIONS : This study provides empirical evidence and shows mechanisms for the positive relationship between speaking-up behavior and technical team performance BACKGROUND Disruptions in surgical flow have the potential to increase the occurrence of surgical errors ; however , little is known about the frequency and nature of surgical flow disruptions and their effect on the etiology of errors , which makes the development of evidence -based interventions extremely difficult . The goal of this project was to study surgical errors and their relationship to surgical flow disruptions in cardiovascular surgery prospect ively to underst and better the effect of these disruptions on surgical errors and ultimately patient safety . METHODS A trained observer recorded surgical errors and flow disruptions during 31 cardiac surgery operations over a 3-week period and categorized them by a classification system of human factors . Flow disruptions were then review ed and analyzed by an interdisciplinary team of experts in operative and human factors . RESULTS Flow disruptions consisted of teamwork/communication failures , equipment and technology problems , extraneous interruptions , training-related distractions , and issues in re source accessibility . Surgical errors increased significantly with increases in flow disruptions . Teamwork/communication failures were the strongest predictor of surgical errors . CONCLUSION These findings provide preliminary data to develop evidence -based error management and patient safety programs within cardiac surgery with implication s to other related surgical programs In this quasi-experimental study among staff of 29 oncology wards , the authors evaluated the effects of a team-based burnout intervention program combining a staff support group with a participatory action research approach . Nine wards were r and omly selected to participate in the program . Before the program started ( Time 1 ) , directly after the program ended ( Time 2 ) , and 6 months later ( Time 3 ) , study participants filled out a question naire on their work situation and well-being . Results of multilevel analyses showed that staff in the experimental wards experienced significantly less emotional exhaustion at both Time 2 and Time 3 and less depersonalization at Time 2 , compared with the control wards . Moreover , changes in burnout levels were significantly related to changes in the perception of job characteristics over time AIM To investigate impacts of practice environment factors and burnout at the nursing unit level on job outcomes and nurse-assessed quality of care in acute hospital nurses . BACKGROUND Prior research has consistently demonstrated correlations between nurse practice environments and nurses ' job satisfaction and health at work , but somewhat less evidence connects practice environments with patient outcomes . The relationship has also been more extensively documented using hospital-wide measures of environments as opposed to measures at the nursing unit level . DESIGN Survey . METHOD Data from a sample of 546 staff nurses from 42 units in four Belgian hospitals were analysed using a two-level ( nursing unit and nurse ) r and om intercept model . Linear and generalised linear mixed effects models were fitted including nurse practice environment dimensions measured with the Revised Nursing Work Index and burnout dimensions of the Maslach Burnout Inventory as independent variables and job outcome and nurse-assessed quality of care variables as dependent variables . RESULTS Significant unit-level associations were found between nurse practice environment and burnout dimensions and job satisfaction , turnover intentions and nurse-reported quality of care . Emotional exhaustion is a predictor of job satisfaction , nurse turnover intentions and assessed quality of care as well besides various nurse work practice environment dimensions . Nurses ' ratings of unit-level management and hospital-level management and organisational support had effects in opposite directions on assessment s of quality of care at the unit ; this suggests that nurses ' perceptions of conditions on their nursing units relative to their perceptions of their institutions at large are potentially influential in their overall job experience . CONCLUSION Nursing unit variation of the nurse practice environment and feelings of burnout predicts job outcome and nurse-reported quality of care variables . RELEVANCE TO CLINICAL PRACTICE The team and environmental context s of nursing practice play critical roles in the recruitment and retention of nurses , and as well as in the quality of care delivered . Widespread burnout as a nursing unit characteristic , reflecting a response to chronic organisational stressors , merits special attention from staff nurses , physicians , managers and leaders Introduction France is facing a shortage of available physicians due to a greying population and the lack of a proportional increase in the formation of doctors . Emergency physicians are the medical system 's first line of defence . Methods The authors prepared a comprehensive question naire using established scales measuring various aspects of working conditions , satisfaction and health of salaried physicians and pharmacists . It was made available online , and the two major associations of emergency physicians promoted its use . 3196 physicians filled out the question naire . Among them were 538 emergency physicians . To avoid bias , 1924 physicians were r and omly selected from the total data base to match the demographic characteristics of France 's physician population : 42.5 % women , 57.5 % men , 8.2 % < 35 years old , 33.8 % 35–44 years old , 34.5 % 45–54 years old and 23.6 % ≥55 years old . The distribution of physicians in the 23 administrative regions and by speciality was also precisely taken into account . This representative sample was used to compare subgroups of physicians by speciality . Results The outcomes indicate that the intent to leave the profession ( ITL ) was quite prevalent across French physicians and even more so among emergency physicians ( 17.4 % and 21.4 % respectively ) , and burnout was highly prevalent ( 42.4 % and 51.5 % , respectively ) . Among the representative sample and among emergency physicians , work – family conflict ( OR=4.47 and OR=6.14 , respectively ) and quality of teamwork ( OR=2.21 and OR=5.44 , respectively ) were associated with burnout in a multivariate analysis , and these risk factors were more prevalent among emergency physicians than other types . A serious lack of quality of teamwork appears to be associated with a higher risk of ITL ( OR=3.92 among the physicians in the representative sample and OR=4.35 among emergency physicians ) , and burnout doubled the risk of ITL in multivariate analysis . Conclusions In order to prevent the premature departure of French doctors , it is important to improve work – family balance , working processes through collaboration , multidisciplinary teamwork and to develop team training approaches and ward design to facilitate teamwork |
13,736 | 16,235,359 | Oxygen improved breathlessness , SaO2/PaO2 and VE at isotime with endurance exercise testing .
Oxygen improved SaO2/PaO2 and reduced VE at Isotime .
This review provides some evidence from small , single assessment studies that ambulatory oxygen improves exercise performance in people with moderate to severe COPD . | BACKGROUND Ambulatory oxygen is defined as the use of supplemental oxygen during exercise and activities of daily living .
Ambulatory oxygen therapy is often used for patients on long term oxygen therapy during exercise , or for non long term oxygen therapy users who achieve some subjective and /or objective benefit from oxygen during exercise .
The evidence for the use of ambulatory oxygen therapy is extrapolated from two sources : longer term studies and single assessment studies .
Longer term studies assess the impact of ambulatory oxygen therapy used at home during activities of daily living .
Single assessment studies compare performance during an exercise test using oxygen with performance during an exercise test using placebo air .
OBJECTIVES To determine the efficacy of ambulatory oxygen in patients with COPD using single assessment studies . | BACKGROUND Supplemental oxygen in patients with chronic obstructive pulmonary disease ( COPD ) and exercise hypoxaemia improves exercise capacity and dyspnoea . However , the benefit of oxygen during pulmonary rehabilitation in these patients is still unknown . METHODS Twenty five patients with stable COPD ( mean ( SD ) forced expiratory volume in one second ( FEV1 ) 0.76 ( 0.29 ) l and 30.0 (9.89)% predicted , arterial oxygen tension ( Pao 2 ) 8.46 ( 1.22 ) kPa , arterial carbon dioxide tension ( Paco 2 ) 6.32 ( 1.01 ) kPa ) and significant arterial desaturation on exercise ( 82.0 (10.4)% ) were entered onto a pulmonary rehabilitation programme . Patients were r and omised to train whilst breathing oxygen ( OT ) ( n = 13 ) or air ( AT ) ( n = 12 ) , both at 4 l/min . Assessment s included exercise tolerance and associated dyspnoea using the shuttle walk test ( SWT ) and Borg dyspnoea score , health status , mood state , and performance during daily activities . RESULTS The OT group showed a significant reduction in dyspnoea after rehabilitation compared with the AT group ( Borg mean difference –1.46 ( 95 % CI –2.72 to –0.19 ) ) but there were no differences in other outcome measures : SWT difference –23.6 m ( 95 % CI –70.7 to 23.5 ) , Chronic Respiratory Disease Question naire 3.67 ( 95 % CI –7.70 to 15.1 ) , Hospital Anxiety and Depression Scale 1.73 ( 95 % CI –2.32 to 5.78 ) , and London Chest Activity of Daily Living Scale –2.18 ( 95 % CI –7.15 to 2.79 ) . At baseline oxygen significantly improved SWT ( mean difference 27.3 m ( 95 % CI 14.7 to 39.8 ) and dyspnoea ( –0.68 ( 95 % CI –1.05 to –0.31 ) ) compared with placebo air . CONCLUSIONS This study suggests that supplemental oxygen during training does little to enhance exercise tolerance although there is a small benefit in terms of dyspnoea . Patients with severe disabling dyspnoea may find symptomatic relief with supplemental oxygen Supplemental oxygen improves exercise tolerance of normoxemic and hypoxemic chronic obstructive pulmonary disease ( COPD ) patients . We determined whether nonhypoxemic COPD patients undergoing exercise training while breathing supplemental oxygen achieve higher intensity and therefore improve exercise capacity more than patients breathing air . A double-blinded trial was performed involving 29 nonhypoxemic patients ( 67 years , exercise SaO2 > 88 % ) with COPD ( FEV1 = 36 % predicted ) . All exercised on cycle ergometers for 45 minutes , 3 times per week for 7 weeks at high-intensity targets . During exercise , they received oxygen ( 3 L/minute ) ( n = 14 ) or compressed air ( 3 L/minute ) ( n = 15 ) . Both groups had a higher exercise tolerance after training and when breathing oxygen . However , the oxygen-trained group increased the training work rate more rapidly than the air-trained group . The mean + /- SD work rate during the last week was 62 + /- 19 W ( oxygen-trained group ) and 52 + /- 22 W ( air-trained group ) ( p < 0.01 ) . After training , endurance in constant work rate tests increased more in the oxygen-trained group ( 14.5 minutes ) than in the air-trained group ( 10.5 minutes ) ( p < 0.05 ) . At isotime , the breathing rate decreased four breaths per minute in the oxygen-trained group and one breath per minute in the air-trained group ( p = 0.001 ) . We conclude that supplemental oxygen provided during high-intensity training yields higher training intensity and evidence of gains in exercise tolerance in laboratory testing PURPOSE To quantify the effects of acute oxygen supplementation on lower limb blood flow ( QLEG ) , O2 delivery ( QO2LEG ) , and O2 uptake ( VO2LEG ) during exercise and to determine whether the metabolic capacity of the lower limb is exhausted at peak exercise during room air breathing in patients with COPD . METHODS Oxygen ( FIO2 = 0.75 ) and air were r and omly administered to 14 patients with COPD ( FEV1 : 35 + /- 2 % pred , mean + /- SEM ) during two symptom-limited incremental cycle exercise tests . Before exercise , a cannula was installed in a radial artery and a thermodilution catheter inserted in the right femoral vein . At each exercise step , five-breath averages of respiratory rate , tidal volume , and ventilation ( VE ) , dyspnea and leg fatigue scores , arterial and venous blood gases , and QLEG were obtained . From these measurements , VO2LEG was calculated . RESULTS Peak exercise capacity increased from 46 + /- 3 W in room air to 59 + /- 5 W when supplemental oxygen was used ( P < 0.001 ) . QLEG , QO2LEG , and VO2LEG were greater at peak exercise with O2 than with air ( P < 0.05 ) . During submaximal exercise , dyspnea score and VE were significantly reduced with O2 ( P < 0.05 ) , whereas QLEG , VO2LEG , and leg fatigue were similar under both experimental conditions . The improvement in peak exercise work rate correlated with the increase in peak QO2LEG ( r = 0.66 , P < 0.01 ) , peak VO2LEG ( r = 0.53 , P < 0.05 ) , and reduction in dyspnea at iso-exercise intensity ( r = 0.56 , P < 0.05 ) . CONCLUSION The improvement in peak exercise capacity with oxygen supplementation could be explained by the reduction in dyspnea at submaximal exercise and the increases in QO2LEG and VO2LEG , which enabled the exercising muscles to perform more external work . These data indicate that the metabolic capacity of the lower limb muscles was not exhausted at peak exercise during room air breathing in these patients with COPD BACKGROUND Oxygen conserving devices may lead to substantial increases in the duration of oxygen provided . A study was undertaken to compare the performance of a pulsed dose oxygen delivery ( PDOD ) system with continuous flow oxygen or air during a maximal walking test . METHODS Fourteen patients with chronic obstructive pulmonary disease ( COPD ) and arterial oxygen desaturation on exercise ( mean ( SD ) forced expiratory volume in one second ( FEV1 ) 0.83 ( 0.28 ) l , arterial oxygen pressure ( Pao 2 ) 8.38 ( 1.24 ) kPa , arterial carbon dioxide pressure ( Paco 2 ) 5.95 ( 0.86 ) kPa ) were r and omised to perform a walking test using air administered via a cylinder or continuous flow oxygen at 2 l/min or by a PDOD system . RESULTS There was no significant difference in the mean arterial oxygen saturation ( Sao 2 ) using the PDOD system or with continuous flow oxygen ( p = 0.33 ) . Patients showed greatest desaturation whilst walking with the air cylinder ( Sao 2 79.2 (8.59)% ) which was significantly different from the desaturation with both continuous flow oxygen ( 87.6 (5.85)% , p = 0.001 ) and PDOD ( 85.6 (7.36)% , p = 0.004 ) . There was no significant difference between the distance walked using oxygen delivered at 2 l/min by continuous flow or via the PDOD ( p = 0.72 ; CI 0.34 to 1.08 ) . The mean ( SD ) distance walked on continuous flow oxygen ( 203.6 ( 106.1 ) m ) and PDOD ( 207.9 ( 109.8 ) m ) was significantly greater than the distance walked with the air cylinder ( 188.6 ( 110.02 ) m ) ; ( 1.12 fold increase in distance , CI 1.01 to 1.23 , p = 0.02 , and 1.14 fold increase in distance , CI 1.01 to 1.28 , p = 0.03 , respectively ) . CONCLUSIONS These findings suggest that the pulsed dose oxygen conserving device was as effective as continuous flow oxygen in maintaining arterial oxygen saturation and that the use of this device was associated with similar improvements in exercise tolerance to patients taking continuous flow oxygen therapy A r and omized , controlled , single-blind study was performed on 20 patients with chronic obstructive pulmonary disease and exercise-induced hypoxaemia . Ten patients each were r and omly assigned to one of two groups , one training with air and the other training with oxygen . There were no significant differences between the groups regarding values measured prior to the study . The patients trained 3 times per week for 30 minutes each time for a duration of 8 weeks . The training consisted of interval walking on a treadmill ( intensity set according to Borg ratings ) with either air or oxygen administered through a nasal cannula at a rate of 5 l/min . Training significantly improved the 6-minute walking distance by 20 % and 14 % in the air and oxygen group , respectively , when the patients were tested on air . In the same test the air group significantly decreased Borg ratings for perceived exertion . Borg ratings for dyspnoea and perceived exertion significantly decreased in the oxygen group when they were tested on oxygen . It was concluded that oxygen supplementation did not further improve the training effect , compared with training with air , in patients with chronic obstructive pulmonary disease and exercise-induced hypoxaemia Supplemental oxygen has acute beneficial effects on exercise performance in patients with chronic obstructive pulmonary disease ( COPD ) . The purpose of this study was to investigate whether oxygen-supplemented training enhances the effects of training while breathing room air in patients with severe COPD . A r and omized controlled trial was performed in 24 patients with severe COPD who developed hypoxaemia during incremental cycle exercise ( arterial oxygen saturation ( Sa , O2 ) < 90 % at peak exercise ) . All patients participated in an in-patient pulmonary rehabilitation programme of 10 weeks duration . They were assigned either to general exercise training while breathing room air ( GET/RA group : forced expiratory volume in one second ( FEV1 ) 38 % of predicted ; arterial oxygen tension ( Pa , O2 ) 10.5 kPa at rest ; Pa , O2 7.3 kPa at peak exercise ) , or to GET while breathing supplemental oxygen ( GET/O2 group : FEV1 29 % pred ; Pa , O2 10.2 kPa at rest ; Pa , O2 7.2 kPa at peak exercise ) . Sa , O2 was not allowed to fall below 90 % during the training . The effects on exercise performance while breathing air and oxygen , and on quality of life were compared . Maximum workload ( Wmax ) significantly increased in the GET/RA group ( mean ( SD ) 17 ( 15 ) W , p<0.01 ) , but not in the GET/O2 group ( 7 ( 25 ) W ) . Six minute walking distance ( 6MWD ) , stair-climbing , weight-lifting exercise ( all while breathing room air ) and quality of life significantly increased in both groups . Acute administration of oxygen improved exercise performance before and after training . Training significantly increased Wmax , peak carbon dioxide production ( V'CO2 ) and 6MWD while breathing oxygen in both groups . Differences between groups were not significant . Pulmonary rehabilitation improved exercise performance and quality of life in both groups . Supplementation of oxygen during the training did not add to the effects of training on room air In 159 chronic obstructive pulmonary disease ( COPD ) patients ( 139 males , mean age 62 + /- 8 yrs , arterial oxygen tension ( PaO2 ) 7.2 + /- 0.9 kPa ) , on long-term oxygen therapy ( LTOT ) , we evaluated the effects of portable oxygen therapy both on the daily duration of oxygen therapy and on daily activities . They were given two types of LTOT at r and om : group A ( n = 75 ) , oxygen concentrators only ( OC ) ; group B ( n = 84 ) , either small oxygen cylinders plus OC ( B1 = 51 ) or liquid oxygen ( B2 = 33 ) . The patients were followed-up for one year by means of : a ) medical examination every three months ; b ) monthly home interviews concerning the daily duration of oxygen therapy , the utilization of the devices and the daily activities of the patients ; c ) a measurement of the daily oxygen usage . The results show that : 1 ) there are no significant clinical and functional differences between groups A and B at the onset of and throughout the study ; 2 ) in group B the daily use of oxygen therapy is significantly longer than in group A ( 17 + /- 3.5 h.day-1 vs 14 + /- 3 h.day-1 , p less than 0.01 ) without any difference between groups B1 and B2 ; 3 ) outdoor walking activities are different between groups A and B , at least in those patients using oxygen more than 18 h.day-1 . Only 60 % of patients in group B ( 55 % of B1 ; 67 % of B2 ) use their portable devices outdoors and for walking . No strict predictive criterion of this use is found in our study . ( ABSTRACT TRUNCATED AT 250 WORDS STUDY OBJECTIVES To compare , in clinical conditions , the efficacy of refilled oxygen cylinders ( O2-HFs ) in improving oxygenation and exercise capacity of patients with COPD during a 6-min walking test . DESIGN Prospect i ve r and omized study with a cross-over design . SETTING A university teaching hospital . PATIENTS Ten patients with COPD , in a stable state and previously treated with long-term domiciliary oxygen therapy . Baseline characteristics were as follows : age , 65 + /- 7 years ; PaO2 on room air , 55.4 + /- 6.3 mm Hg ; PaCO2 on room air , 46.2 + /- 7.4 mm Hg ; FEV1/vital capacity , 47 + /- 7 % ; and FEV1 , 30 + /- 7 % of predicted value ( mean + /- SD ) . DESIGN All patients performed three successive 6-min walking tests , the first test in room air and the other tests in a r and omized order with either a conventional oxygen cylinder ( O2-C ) or an O2-HF . MEASUREMENTS AND RESULTS The fraction of inspired oxygen ( FIO2 ) delivered by O2-HFs was significantly lower than the FIO2 delivered by O2-Cs ( 94.2 + /- 2.6 % vs 98.8 + /- 4.9 % , p = 0.02 ) . Mean O2-HF and O2-C weights before the walking tests were similar ( 3,510 + /- 251 g and 3,770 + /- 142 g , respectively ; p = 0.09 ) . Mean transcutaneous oxygen saturation was similarly improved with both oxygen delivery systems . Mean distances with O2-C ( 373.5 + /- 81 m ) and O2-HF ( 375 + /- 97 m ) were not different but significantly improved , as compared with room air ( 334.5 + /- 90 m ; p = 0.03 and 0.02 , respectively ) . Dyspnea sensations were similar for the three tests . CONCLUSION O2-HFs are as efficient as O2-Cs for performing short-term exercises . Because of a lower cost , pressurizing units may be worthwhile for improving ambulatory oxygen therapy and pulmonary rehabilitation programs It is unknown whether acute response to ambulatory oxygen ( O2 ) predicts longer term improvement in health-related quality of life ( HRQL ) in chronic obstructive pulmonary disease ( COPD ) patients . The aims of this study were 1 ) to assess the short-term clinical impact , as determined by HRQL , of ambulatory O2 in a 12-week , double-blind , r and omised crossover study of O2 ( versus cylinder compressed air ) of dyspnoeic but not chronically hypoxic COPD patients with exertional desaturation ≤88 % ( n=41 ) , and 2 ) to determine whether either baseline characteristics or acute response to O2 predicts short-term ( 12 weeks ) response . Primary outcome measures were Chronic Respiratory Question naire ( CRQ ) , Hospital Anxiety and Depression scale and the short form (SF)-36 . Improvements were seen in all domains of the CRQ for cylinder O2 compared with cylinder air . Significant improvements were also noted in anxiety and depression and in certain domains of the SF-36 . There were 28 ( 68 % ) acute responders to cylinder O2 ( defined as increase in 6‐min walk ≥54 m or decrease in post-Borg dyspnoea ≥1 ) and 23 ( 56 % ) short-term responders ( defined as clinical ly significant improvement in CRQ ) . However , acute and short-term responses were not correlated with no predictors of short-term response identified . At study completion , 14 ( 41 % ) of acute or short-term responders did not want to continue therapy , with 11 citing poor acceptability or tolerability . Short-term ambulatory oxygen is associated with significant improvements in health-related quality of life . These benefits can not be predicted by baseline characteristics or acute response . Despite acute or short-term response , a substantial proportion of patients declined ambulatory oxygen BACKGROUND : Liquid oxygen is available for portable use and may have advantages over gas cylinders . METHODS : The use and acceptability of liquid and gaseous oxygen was compared in 15 patients with chronic lung disease who had shown an improvement of at least 10 % in assessment s of exercise tolerance and breathlessness with st and ard portable oxygen . Gaseous and liquid portable oxygen were provided in r and om order for two eight week periods , and assessment s consisted of six minute walking tests , lung function tests , chronic respiratory disease index question naires , and diary cards . RESULTS : The walking distance was not significantly affected by the weight of the equipment with either system . Patients used the liquid oxygen for significantly longer ( 23.5 hours a week ) than the gas cylinder ( 10 hours a week ) . When using liquid oxygen patients went out of the house on average for 19.5 hours a week , compared with 15.5 hours a week with gaseous oxygen . The liquid oxygen system was preferred because the oxygen lasted longer , filling was easier , and the canister was easier to carry . CONCLUSIONS : Liquid oxygen for portable treatment may be of benefit in selected patients with chronic lung disease BACKGROUND : Provision of ambulatory oxygen using an intermittent pulsed flow regulated by a dem and oxygen delivery system ( DODS ) greatly increases the limited supply time of st and ard portable gaseous cylinders . The efficacy of such a system has not previously been studied during submaximal exercise in subjects with severe chronic obstructive pulmonary disease ( COPD ) in whom desaturation is likely to be great and where usage is often most appropriate . METHODS : Fifteen subjects with severe COPD and oxygen desaturation underwent six minute walk tests performed in r and om order to compare the efficacy of a dem and oxygen delivery system ( DODS ) with continuous flow oxygen . Walk distance , breathlessness , oxygen saturation , resting time , and recovery time ( objective and subjective ) were recorded and compared for each walk . RESULTS : Breathing continuous oxygen compared with baseline air breathing improved mean walk distance ( 295 m versus 271 m ) and recovery time ( 47 seconds versus 112 seconds ) , whilst the lowest recorded saturation ( 81 % versus 74 % ) and time desaturated below 90 % ( 201 seconds versus 299 seconds ) were reduced . When the DODS was compared with air breathing only the walk distance changed ( 283 m versus 271 m ) . A comparison of the DODS with continuous oxygen breathing showed the DODS to be less effective at oxygenating subjects with inferior lowest saturation ( 78 % versus 81 % ) , time spent below 90 % ( 284 seconds versus 201 seconds ) , time to objective recovery ( 83 seconds versus 47 seconds ) , and walk distance ( 283 m versus 295 m ) . CONCLUSIONS : Neither of the delivery systems was able to prevent desaturation in these subjects . The use of continuous flow oxygen , however , was accompanied by improvements in oxygenation , walk distance , and recovery time compared with air breathing . The DODS produced only a small increase in walk distance without elevation of oxygen saturation , but was inferior to continuous flow oxygen in most of the measured variables when compared directly Dynamic hyperinflation contributes to exertional breathlessness and reduced exercise tolerance in chronic obstructive pulmonary disease ( COPD ) patients . This study examined whether oxygen supplementation results in a dose-dependent decrease in hyperinflation associated with functional and symptomatic improvement . Ten severe COPD patients without clinical ly significant oxygen ( O2 ) desaturation during exercise , and seven healthy subjects , performed five exercise tests at 75 % of maximally tolerated work rate . Inspired oxygen fraction ( FI , O2 ) was varied ( 0.21 , 0.3 , 0.5 , 0.75 and 1.0 ) among tests in a r and omized order . Ventilation ( V'E ) was measured , and end-inspiratory ( EILV ) and end-expiratory ( EELV ) lung volume changes were assessed from inspiratory capacity manoeuvres . In the patients , compared to room air , endurance time increased with FI , O2=0.3 ( mean+/-SEM 92+/-20 % ) and increased further with FI , O2=0.5 ( 157+/-30 % ) . At isotime , compared to room air , there were significant reductions in dyspnoea score , EELV , EILV , V'E and respiratory frequency ( fR ) with FI , O2=0.3 . Improved endurance time negatively correlated with change in EELV ( r=0.48 , p=0.002 ) and EILV ( r=0.43 , p=0.005 ) . The dyspnoea rating decrease correlated with fR decrease . In healthy subjects , smaller V'E and fR decreases were observed at FI , O2=0.5 , accompanied by more modestly increased endurance . Oxygen supplementation during exercise induced dose-dependent improvement in endurance and symptom perception in nonhypoxaemic chronic obstructive pulmonary disease patients , which may be partly related to decreased hyperinflation and slower breathing pattern . This effect is maximized at an inspired oxygen fraction of 0.5 The effect of oxygen on breathlessness and exercise tolerance was examined in " pink and puffing " patients with fixed airways obstruction . When breathing oxygen , patients were less breathless and walked further . This was true whether the cylinder was carried by the patient or by an assistant . It was not possible to identify those patients who would benefit most . The best method of assessing improvement was by comparing breathlessness on a st and ardised progressive exercise test on a treadmill . Four patients had a greater than 30 % reduction in breathlessness on submaximum exercise when breathing oxygen . Breathing oxygen for five or fifteen minutes before exercise but not during exercise ( predose ) result ed in a similar improvement in exercise tolerance . For short periods of exercise predosing with oxygen provides a convenient alternative to continuous oxygen . For longer periods of exercise the benefits of portable oxygen in selected patients have been previously underestimated We have examined the hypothesis that hypoxaemia contributes to breathlessness by a mechanism distinct from its action as a ventilatory stimulant . Five patients who developed arterial oxygen desaturation during incremental exercise were studied . Exercise tests were performed on a cycle-ergometer . Breathlessness was measured by using a visual analogue scale technique . All five patients had considerable previous experience of these procedures . Two identical exercise tests were performed by each patient , breathing either room air or 60 % oxygen in a blind r and omized study . Breathing air , arterial saturation at rest was 93 % and fell by 7 % during exercise . Breathing 60 % oxygen , resting saturation was 98 % and there was no fall during exercise . Breathing oxygen , ventilation for a given work load was reduced and exercise duration was increased when compared with air breathing . In each of the five patients the relationship between breathlessness and minute ventilation was the same whether breathing air or 60 % oxygen , despite the reduction in ventilation for a given work rate 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 The provision of domiciliary oxygen to patients hypoxic at hospital discharge has been termed short-term oxygen therapy ( STOT ) . This practice appears widespread , although there is a paucity of literature and no evidence -based guidelines . We undertook this audit to examine the prescription of STOT and determine the proportion fulfilling for long-term oxygen therapy ( LTOT ) 2 months post-discharge . STOT was defined prospect ively : resting PaO2 < or = 7.3 kPa ( 55 mmHg ) or PaO2 between 7.3 and 8.0 kPa ( 60 mmHg ) with any of the following : clinical evidence of cor pulmonale ( pedal oedema or jugular venous distension ) , ECG evidence of pulmonale , echocardiogram evidence of pulmonary hypertension , haematocrit > 0.55 ( adapted directly from LTOT criteria ) . Patients were evaluated for LTOT 2 months post-discharge when clinical ly stable on optimal medical management . All referrals to the Auckl and Regional Oxygen Service between July 1998 and 1999 were systematic ally review ed . The majority 289/405 ( 71 % ) of new referrals were for the prescription of STOT/LTOT in patients with chronic lung disease : 160/289 ( 55 % ) derived from hospitalized patients with the majority 130 ( 81 % ) fulfilling criteria for STOT , median age 73 , range 24 - 96 years . Mean hospital stay was 10.2 days . Two months after discharge 22/127 ( 17 % ) of STOT patients had died , comparable with 4/22 ( 18 % ) not fulfilling criteria for STOT . A total of 123 patients were assessed for LTOT at 2 months ; 76 ( 62 % ) fulfilled criteria for LTOT . The prescription of oxygen at hospital discharge represented a considerable proportion of our referral load . There was a high mortality in the 2-month follow-up period . A significant proportion of STOT patients did not subsequently fulfill criteria for LTOT . Further prospect i ve studies are required in order to develop evidence -based guidelines STUDY OBJECTIVES To assess oxygen desaturation during activities and to evaluate the short-term effects of supplemental O(2 ) use in patients with severe COPD who do not qualify for long-term O(2 ) therapy . DESIGN A double-blind , r and omized , placebo-controlled trial . SETTING Out patients from the pulmonary diseases division of a tertiary-care university hospital . PATIENTS Twenty patients with stable COPD with FEV(1)/FVC ratios of < 50 % , FEV(1 ) levels < 55 % of the predicted normal value , and PaO(2 ) levels of > 60 mm Hg when resting . INTERVENTIONS Patients were initially evaluated with pulmonary function tests , blood gas analysis , and Doppler echocardiography , and they underwent the following three 6-min walking tests ( WTs ) in a r and om sequence : basal WT ( BWT ) ; WT while breathing compressed air ( CAWT ) ; and WT while breathing O(2 ) ( O(2)WT ) . MEASUREMENTS AND RESULTS The distance walked was recorded in meters . Dyspnea was measured by Borg scale measurement before and after the tests , and arterial oxygen saturation measured by pulse oximetry ( SpO(2 ) ) was continuously monitored . Results were analyzed by grouping patients in the following manner : desaturators ( DSs ) ( ie , patients with a drop in SpO(2 ) of at least 5 % and < 90 % during the WT ) vs nondesaturators ( NDSs ) ; and O(2 ) responders ( ie , patients with an increase of at least 10 % in the distance walked and /or a decrease of at least 3 points in Borg index score ) vs nonresponders . During the BWT , 11 of 20 patients ( 55 % ) were defined as desaturators . During the O(2)WT , the SpO(2 ) remained at > 90 % in every patient . The distance walked increased by 22 % ( p < 0.02 ) , and dyspnea decreased 36 % ( p < 0.01 ) in DS patients . In NDS patients , O(2 ) administration reduced dyspnea by 47 % ( p < 0.001 ) , but the distance walked did not improve . Responses were markedly different from one patient to another . No significant differences were noticed between the results of the BWT and CAWT in any of the groups . Thirteen O(2 ) responders did not differ from 7 nonresponders either in basal data or in desaturation measure during the BWT , except that all walking responders ( five patients ) were above the median of basal left ventricle performance . CONCLUSIONS Most of the studied COPD patients desaturated during the BWT . O(2 ) administration avoided desaturation and could increase the distance walked and reduce dyspnea , but these effects were not related to walking desaturation in individual cases . Improvements were not a placebo effect . The therapeutic role of O(2 ) during activities in some patients with severe COPD needs to be individually assessed Oxygen supplementation is known to improve exercise capacity in patients with chronic obstructive pulmonary disease ( COPD ) . Although some COPD patients use oxygen after exercise to relieve dyspnea , the effect of oxygen during recovery from exercise is not clearly understood . Exercise duration and dyspnea recovery time were studied in 18 patients with stable COPD . Patients exercised at a constant submaximal work rate on a treadmill ergometer until they no longer wished to continue . Oxygen , room air and compressed air were r and omly administered in three consecutive post-exercise recovery periods . Dyspnea was scored on a 100 mm visual analog scale at 30 s intervals until return to baseline . An additional 20 minute post-recovery resting period was allowed between each test . No significant differences were found in dyspnea recovery time breathing oxygen ( 271 s ) , room air ( 290 s ) or compressed air ( 311 s ) When the groups were sorted by sequence of testing , there was a highly significant increase in recovery time ( 208 s , 307 s and 358 s for the first , second and third tests ; P < 0.005 ) and a non-statistically significant decrease in exercise duration ( 89 s , 79 s and 76 s ) . Post-exercise oxygen supplementation had no effect on dyspnea recovery time in these COPD patients . Repeated bouts of exercise increased dyspnea recovery time and tended to decrease exercise duration . These findings suggest that , despite recovery of symptoms , physiological recovery from prior exercise is incomplete We verified the utility of an oxygen economizer ( Pendant Oxymizer ) in assuring greater protection than nasal prongs against worsening of oxyhemoglobin resting desaturation ( delta SaO2 ) induced by muscular exercise in 16 patients ( ten with chronic obstructive pulmonary disease [ COPD ] and six with restrictive pulmonary disease ) . This worsening was quantified as desaturation surface accumulated within five minutes of exercise and was expressed in arbitrary units ( au ) . Each patient carried out the same exercise three times , in a r and omized fashion ( breathing air or breathing supplemental oxygen [ 3 L/min ] delivered by either nasal prongs or by oxygen economizer ) . In patients with obstructive disease , delta SaO2 was reduced from 38 + /- 12.0 au when they were breathing air to 18.1 + /- 11.7 au when breathing oxygen by nasal prongs ( p less than 0.001 ) and to 10.1 + /- 9.5 au when breathing oxygen by economizer ( p less than 0.001 ) . In patients with restrictive disease , delta SaO2 was reduced from 35.6 + /- 9.9 au when breathing air to 14.9 + /- 10.2 au breathing oxygen by nasal prongs ( p less than 0.01 ) and to 13.7 + /- 10.3 au breathing oxygen by economizer ( p less than 0.01 ) . The difference between breathing by economizer and nasal prongs was significant ( paired t-test ; p less than 0.01 ) only in patients with COPD . One explanation could lie in the different values of the respiratory rate , which was significantly greater in patients with restrictive disease ( 20.7 + /- 1.2 breaths per minute at rest and 25.8 + /- 1.5 with exercise ) than in patients with obstructive disease ( 15.3 + /- 1.2 breaths per minute at rest and 20.8 + /- 1.4 with exercise ) The purpose of this study was to determine if there is a relationship between improvement in exercise capacity with supplemental oxygen and the magnitude of hypoxic ventilatory drive in patients with CAO . We hypothesized that those patients with the highest hypoxic drives would be the most likely to have increased exercise tolerance with supplemental oxygen . Seventeen patients with CAO ( mean FEV1 = 0.99 + /- 0.45 L ) underwent identical maximal cycle ergometry exercise tests on two occasions 45 minutes apart while breathing either air or 30 percent oxygen in a r and omized single-blind fashion . With supplemental oxygen , the ventilation decreased and the PaCO2 increased significantly at rest . The patients had a significantly greater exercise tolerance on supplemental oxygen ( 76.7 vs 69.1 watts , p less than 0.005 ) but no increase in the maximal ventilation . When the nine patients who improved were compared to the eight patients who did not improve , the two groups were basically identical . Specifically , there were no significant differences in the mean ventilatory or mouth occlusion responses to hypoxia or in the blood gases . The patients who did improve tended to have a greater reduction in their ventilatory response to exercise while exercising on oxygen as compared to when they were exercising on room air . From this study , it was concluded that measurements of hypoxic ventilatory drive are not helpful in predicting which patients with CAO are likely to have improved exercise capability while breathing supplemental oxygen BACKGROUND : The development of portable liquid oxygen systems , capable of delivering high flow rate oxygen for long periods , justifies re assessment of the value of supplemental oxygen to aid exercise tolerance in patients with chronic respiratory insufficiency . The type of exercise test and the low oxygen flow rates previously used may account for the variable and often poor responses to supplemental oxygen reported in earlier studies . METHODS : The walking tolerance of 30 patients with severe respiratory disability was measured while they were breathing air and increasing doses of supplemental oxygen ( 2 , 4 , 6 1/min ) by using both the st and ard six minute walking test and an endurance walking test . To assess the initial learning effect and repeatability of the walking tests , three six minute walks and three endurance walks were performed on day 1 and a single walk of each type on days 2 , 3 , and 14 . In addition , oxygen dosing studies were performed on days 2 and 3 after the initial baseline walking tests . Each dosing study comprised four endurance walking tests or four six minute walking tests with patients breathing either air at a flow rate of 4 1/min from a portable cylinder or supplemental oxygen at a flow rate of 2 , 4 or 6 1/min from a portable liquid oxygen supply . The order of the tests was r and omised . Walking distance with each flow rate of oxygen was compared with walking distance with patients carrying cylinder air and for the initial unburdened walks . Breathlessness was assessed by visual analogue scoring on completion of each walk . RESULTS : Exercise ability and breathlessness were significantly improved with supplemental oxygen and this benefit outweighed the reduction in performance result ing from carrying the portable device . Supplemental oxygen at flow rates of 2 , 4 , and 6 1/min increased mean endurance walking distances by 37.9 % , 67.7 % and 85.0 % and six minute walking distances by 19.2 % , 34.5 % , and 36.3 % by comparison with distances when the patient was carrying air with a flow rate of 4 1/min . The additional work of carrying the portable gas supply reduced endurance walking distance by 22.2 % and six minute walking distance by 14.1 % by comparison with a baseline unburdened walk . Comparison of supplemental oxygen at 2 , 4 , and 6 1/min with the baseline unburdened performance showed increased endurance walking distances of 7.3 % , 30.4 % , and 43.9 % and six minute walking distances of 2.3 % , 15.5 % , and 17.0 % . Walking distance was increased by more than 50 % by comparison with an unburdened walk in seven patients with the endurance walking test but in only three patients with the six minute walking test . The benefit was similar in patients with obstructive and with interstitial lung disease . Individual responses were variable and only desaturation during the baseline walk in patients with obstructive lung disease had any predictive value for benefit with oxygen . CONCLUSION : As there was no clear relation between response to oxygen therapy and the patients ' characteristics , assessment for supplemental oxygen therapy will depend on exercise testing . It is suggested that portable oxygen should be considered only if a patient shows a 50 % improvement in exercise ability with high flow rate oxygen ( 4 - 6 1/min ) by comparison with an unburdened walk It is unclear whether short-term benefits from supplemental oxygen translate into improved quality of life in patients with severe COPD . In a 12 wk double-blind r and omized crossover study , we assessed the effects of supplemental air and oxygen on exercise performance ( step tests and 6 min walking distance [ 6MWD ] ) initially and after two 6 wk periods at home using exertional cylinder air or oxygen . We measured quality of life at baseline and after the two 6 wk domiciliary periods . The 26 patients ( 24 males ) had a mean age of 73 + /- 6 yr ; mean FEV1 , 0.9 + /- 0.4 L ; mean DLCO , 10.6 + /- 2.4 ml/min/mm Hg ; mean resting PO2 , 69 + /- 8.5 ( range 58 to 82 ) mm Hg ; mean PCO2 , 41 + /- 3.3 mm Hg ; and mean resting SaO2 , 94 + /- 2.1 ( mean + /- SD ) . Laboratory tests were performed breathing intranasal air or oxygen at 4 L/min , and measurements were made of SaO2 and Borg dysnea scores . Supplemental oxygen increased 6MWD and steps by small , statistically significant increments acutely at baseline and after 6 and 12 wk , without corresponding falls in Borg score . Degree of desaturation at baseline did not correlate with increase in 6MWD or steps achieved at baseline or at 6 or 12 wk , nor with the domiciliary gas used . There was no difference in 6MWD or steps achieved while breathing supplemental oxygen after 6 wk of domiciliary oxygen compared with domiciliary air . Small improvements in quality of life indices were found after domiciliary oxygen , and mastery also improved after domiciliary air . There were no differences in quality of life , however , when domiciliary oxygen was compared with domiciliary air . Although oxygen supplementation induced small acute increments in laboratory exercise performance , such improvements had little impact on the patients ' daily lives In order to evaluate the benefits of O2 supplementation during exercise , slowly incremental treadmill exercise tests were performed twice with 30 minutes interval rest in fourteen patients with severe COPD . The patients breathed room air . 31/min of compressed air by nasal prongs , and 31/min of supplemental oxygen in single blind fashion at r and om . The patients who developed arterial desaturation below 88 % on exercise , group D , showed slight but significant increase in walked distance ( 397 m vs 424 m ) and significant decrease in breathlessness ( 22.9 vs 16.9 ) on oxygen as compared to on air . On the other h and in patients without significant arterial desaturation , group S , there was no improvement in those parameters . The increase in walked distance on oxygen was closely related with the decrease in mean inspiratory flow ( VT/Ti ) , blood lactate level , and CO2 production at identical work load . Plasma human atrial natriuretic peptide ( h-ANP ) levels in group D increased with exercise from a resting value of 27.6 + /- 6.9 to 44.0 + /- 9.0 on compressed air whereas the increase was significantly suppressed to 35.4 + /- 9.0 on oxygen . In group S there was no difference in the increase of plasma h-ANP levels between air and oxygen breathing during exercise ( 33.1 + /- 5.1 vs 31.9 + /- 9.6 ) . A close correlation ( r = 0.908 ) was found between mean pulmonary artery pressures and plasma h-ANP levels at rest and during exercise performed in four patients breathing air and oxygen . Those findings suggested that arterial plasma h-ANP levels reflected the right ventricular afterload and that they could be used to evaluate the effectiveness of O2-supplementation during exercise . ( ABSTRACT TRUNCATED AT 250 WORDS In a prospect i ve , r and omized study we examined the effect of ( i ) ambulatory oxygen and ( ii ) a portable , inspiratory pressure support ( IPS ) device on the endurance shuttle walk test ( ESWT ) in patients with severe chronic obstructive pulmonary disease ( COPD ) . Ten out patients [ median ( range ) FEV1 0.60 l(0.35 , 1.45 ) ] performed the ESWT under five test conditions : baseline walk ( no assistance ) , IPS at 14 cmH2O from a portable ventilator ( the HIPPY , Friday Medical , U.K. ) , sham IPS ( < 8 cmH2O ) , ambulatory oxygen at 2 l min(-1 ) , and sham oxygen ( carrying the portable oxygen cylinder and breathing air ) . There were significant improvements in the ESWT with ambulatory oxygen , but a negative effect with the HIPPY device [ mean ( SD ) time : baseline 172 ( 48 ) sec ; oxygen 242 ( 62 ) sec ; HIPPY 84 ( 35 ) sec ] . The ESWT appeared sensitive to the effect of cylinder weight although differences in endurance capacity were not significant [ sham oxygen 151 ( 45 ) sec ] . The ESWT was sensitive to the acute application of oxygen , demonstrating a beneficial effect on endurance performance in patients with severe COPD . The ESWT could form the basis of a st and ardized assessment for ambulatory oxygen Ventilatory muscle function was examined at rest and during exercise on a cycle ergometer in 8 patients with moderate to severe chronic air-flow limitation ( FEV1 , 32 + /- 4 % predicted ) in air and in oxygen . The diaphragmatic electromyogram ( EMG ) was measured using an esophageal electrode . In addition , measurements of esophageal ( Pes ) , gastric ( Pga ) , and transdiaphragmatic ( Pdi ) pressures and abdominal wall movements were made . Patients exercised to exhaustion at a constant submaximal workload ( 80 % of maximal power output ) inspiring air or 40 % O2 in r and om order on separate days . At end-exercise in air , tidal inspiratory Pes swings were 36 + /- 4 % of static maximal inspiratory Pes , and inspiratory Pdi swings were 45 + /- 7 % of the static maximal Pdi . Arterial oxygen saturation decreased from 91 + /- 2 % at rest to 80 + /- 5 % at end-exercise in air . During exercise in air , 5 patients demonstrated a persistent and greater than 20 % fall in the ratio of high frequency ( 150 to 350 Hz ) to low frequency ( 20 to 46 Hz ) power ( H/L ) of the diaphragmatic EMG , indicating impending diaphragmatic fatigue , and 2 patients had paradoxical motion of the abdominal wall . Exercise time at the same constant work load increased from 3.0 + /- 0.6 min in air to 6.4 + /- 1.2 min in O2 ( p less than 0.005 ) . At the comparable time during exercise in O2 to end-exercise in air , minute ventilation was less by 13 % ( p less than 0.005 ) , which was entirely attributable to a lower frequency of breathing . Mean inspiratory and expiratory flows and heart rate were all significantly lower . ( ABSTRACT TRUNCATED AT 250 WORDS Oxygen ( O2 ) has been reported to improve exercise tolerance in some patients with chronic obstructive pulmonary disease ( COPD ) despite only mild resting hypoxemia ( PaO2 greater than 60 mm Hg ) . To confirm these prior studies and evaluate potential mechanisms of benefit , we measured dyspnea scores by numeric rating scale during cycle ergometry endurance testing and correlated the severity of dyspnea with right ventricular systolic pressure ( RVSP ) measured by Doppler echocardiography during a separate supine incremental exercise test . Both sets of exercise were performed according to a r and omized double-blind crossover protocol in which patients breathed compressed air or 40 % O2 . We studied 12 patients with severe COPD ( FEV1 0.89 + /- 0.09 L [ mean + /- SEM ] , FEV1/FVC 37 + /- 2 % , DLCO 9.8 + /- 1.5 ml/min/mm Hg[47 % of predicted ] , PaO2 71 + /- 2.6 mm Hg ) . With endurance testing on compressed air , PaO2 did not change significantly in the group as whole ( postexercise PaO2 63 + /- 5.1 mm Hg , p = NS ) , but did fall to less than 55 mm Hg in four patients from this group . Duration of exercise increased on 40 % O2 from 10.3 + /- 1.6 to 14.2 + /- 1.5 min ( p = 0.005 ) , and the rise in dyspnea scores was delayed . Oxygen delayed the rise in RVSP with incremental exercise in all patients and lowered the mean RVSP at maximum exercise from 71 + /- 8 to 64 + /- 7 mm Hg ( p less than 0.03 ) . Improvement in duration of exercise correlated with decrease in dyspnea ( r2 = 0.66 , p = 0.001 ) but not with decreases in heart rate , minute ventilation , or RVSP . ( ABSTRACT TRUNCATED AT 250 WORDS We studied interrelationships between exercise endurance , ventilatory dem and , operational lung volumes , and dyspnea during acute hyperoxia in ventilatory-limited patients with advanced chronic obstructive pulmonary disease ( COPD ) . Eleven patients with COPD ( FEV(1.0 ) = 31 + /- 3 % predicted , mean + /- SEM ) and chronic respiratory failure ( Pa(O(2 ) ) 52 + /- 2 mm Hg , Pa(CO(2 ) ) 48 + /- 2 mm Hg ) breathed room air ( RA ) or 60 % O(2 ) during two cycle exercise tests at 50 % of their maximal exercise capacity , in r and omized order . Endurance time ( T(lim ) ) , dyspnea intensity ( Borg Scale ) , ventilation ( V E ) , breathing pattern , dynamic inspiratory capacity ( IC(dyn ) ) , and gas exchange were compared . Pa(O(2 ) ) at end-exercise was 46 + /- 3 and 245 + /- 10 mm Hg during RA and O(2 ) , respectively . During O(2 ) , T(lim ) increased 4.7 + /- 1.4 min ( p < 0.001 ) ; slopes of Borg , V E , V CO(2 ) , and lactate over time fell ( p < 0.05 ) ; slopes of Borg-V E , V E-V CO(2 ) , V E-lactate were unchanged . At a st and ardized time near end-exercise , O(2 ) reduced dyspnea 2.0 + /- 0.5 Borg units , V CO(2 ) 0.06 + /- 0.03 L/min , V E 2.8 + /- 1.0 L/min , and breathing frequency 4.4 + /- 1.1 breaths/min ( p < 0.05 each ) . IC(dyn ) and inspiratory reserve volume ( IRV ) increased throughout exercise with O(2 ) ( p < 0.05 ) . Increased IC(dyn ) was explained by the combination of increased resting IRV and decreased exercise breathing frequency ( r(2 ) = 0.83 , p < 0.0005 ) . In conclusion , improved exercise endurance during hyperoxia was explained , in part , by a combination of reduced ventilatory dem and , improved operational lung volumes , and dyspnea alleviation Oxygen therapy improves submaximal exercise tolerance in hypoxemic patients with chronic obstructive pulmonary disease ( COPD ) . This study compared the st and ard nasal cannula , reservoir nasal cannula , and a dem and flow device in 15 male hypoxemic patients with COPD . On six separate occasions each subject used , in a r and omized order , all three systems while completing incremental cycle ergometry and a test circuit composed of tasks that simulate activities of daily living . Oxygen flow required during exercise was 1.8 + /- 0.9 and 2.8 + /- 0.7 L/min for reservoir nasal cannula and st and ard nasal cannula use , respectively ( p < 0.0001 ) . The effect of the three oxygen delivery systems on oxygen saturation ( Spo2 ) during the last 30 s of exercise varied with type of activity . Only during dem and flow device use while undressing and dressing was the subjects ' Spo2 ( 90 + /- 3 % ) significantly lower ( p = 0.019 ) . There was a trend toward lower Spo2 with the dem and flow device ( p = 0.103 ) during arm work above shoulder level . Although not statistically significant , reservoir nasal cannula use result ed in consistently lower tidal volume and minute ventilation during test circuit activities . Exercise tolerance was not significantly different between the three oxygen delivery systems The absence of st and ardized assessment protocol s with well- defined measurement properties limits comparison of outcomes among those receiving long-term oxygen therapy ( LTOT ) . We describe simple protocol s for a hospital test , a simulated home test , and an actual home test , their reliability and relationship to each other . Stable patients with exercise hypoxemia participated . In 74 patients who completed four exercise tests , correlations between tests ranged from 0.85 to 0.78 . Of these 27.0 % had the same prescription from all four tests . In 46 % prescriptions were within 1 L/ min and in 27 % within 2 L/min . During exercise the hospital tests suggested slightly higher oxygen prescriptions than did the simulated home tests ( 2.5 L/min versus 2.0 L/min , p < 0.001 ) . In 23 patients who participated in actual home assessment s , the correlations between the home test , the hospital , and the simulated home tests were 0.22 ( 95 % CI -0.24 to 0.67 ) and 0.27 ( 95 % CI -0.18 to 0.72 ) . In conclusion , st and ardizing tests for the assessment of LTOT is important . We describe simple hospital and simulated home tests that are reproducible , easy to carry out , and correlate well with each other Breathing 30 % oxygen during exercise alleviated arterial hypoxaemia and reduced minute ventilation in patients with severe chronic bronchitis . A similar level of oxygen ( 2 or 4 litres of oxygen/minute ) from nasal prongs also increased their exercise tolerance , as assessed by the distance that they could walk on the level in 12 minutes . Nevertheless , a single-blind controlled study showed that the effort of carrying their portable supply of liquid oxygen , in the Union Carbide Oxygen Walker , abolished this gain in exercise tolerance . The improvement in walking distance was restored when oxygen on exercise was provided by wheeling the oxygen walker on a light-weight shopping trolley The mechanisms of exertional dyspnea relief in response to supplemental oxygen ( O2 ) in chronic airflow limitation ( CAL ) are not precisely known and are likely multifactorial . To explore factors contributing to the relief of dyspnea after oxygen administration , 11 patients with severe CAL ( FEV1.0 = 39 + /- 3 % predicted , mean + /- SEM ) and mild hypoxemia ( resting PaO2 = 74 + /- 2 mm Hg ) breathed room air ( RA ) and 60 % O2 during exercise at approximately 50 % of their maximal incremental exercise capacity . Breathlessness ratings ( Borg scale ) , endurance time , respiratory drive ( change in mouth occlusion pressure over the first 0.1 s of inspiration , P0.1 ) , ventilation ( VE ) , breathing pattern , operational lung volumes , gas exchange , and metabolic parameters were compared during RA and 60 % O2 . PaO2 at exercise cessation during RA and 60 % O2 was 65 + /- 3 mm Hg and 226 + /- 12 mm Hg , respectively ( p < 0.001 ) . With 60 % O2 , the mean of individual Borg/time slopes fell significantly ( p < 0.05 ) by 23 + /- 12 % and was associated with a 35 + /- 11 % increase ( p < 0.01 ) in endurance time ( r = -0.64 , p < 0.05 ) . During 60 % O2 , slopes of P0.1 and lactate over time also fell significantly ( p < 0.05 ) , whereas delta PaCO2/time did not change significantly . At a st and ardized time near end-exercise , Borg , VE , and P0.1 changed during 60 % O2 by -0.8 + /- 0.3 ( p < 0.05 ) , -4.1 + /- 2.0 L/min ( p = 0.07 ) , and -1.3 + /- 0.5 cm H2O/s ( p < 0.05 ) , respectively . Slopes of Borg/VE , Borg/lactate , and VE/lactate were essentially superimposable during tests on RA and O2 : Borg , lactate , and VE all fell proportionally during hyperoxia . In patients with CAL and mild exercise hypoxemia , relief of exertional breathlessness during hyperoxia is explained by reduced ventilatory dem and in association with reduced blood lactate levels SUMMARY Nine patients with severe chronic obstructive lung disease with clinical and electrocardiographic evidence of cor pulmonale were selected . They had a mean resting PaO 2 of 53 mm Hg , which fell to 49 mm Hg on maximal exercise ( P Portable liquid air breathing , compared to the control period before starting to use the portable gas apparatus , result ed in no changes in spirometric findings , gas diffusion , heart rate , exercise tolerance , distance walked per day ( pedometer ) , ECG at rest and exercise , or arterial blood gas levels at rest and exercise . All patients stated that they " felt better " with than without the portable gas apparatus . While receiving liquid oxygen , the group as a whole showed a significant fall in resting heart rate ( P 2 during oxygen breathing increased to 84 mm Hg ( P 2 at rest to 71 mm Hg ( P 2 on maximal exertion to 65 mm Hg ( P All nine patients stated that they " felt better " with the portable gas apparatus than during the control period . Only three could clearly tell that they received something different during each five-week period . It was these patients who stated that the liquid air was " not as good . " They were the only patients to show an increase in distance walked per day by pedometer readings . The only distinguishing feature of this group was a greater fall in PaO 2 during exercise in the control period . Portable liquid oxygen therapy is of more than placebo value in a highly selected group of patients with COPD , cor pulmonale , and hypoxemia at rest and exercise BACKGROUND A deficiency of alpha-1 antitrypsin ( AAT ) can lead to pulmonary disease in middle-aged adults in whom dyspnea management can be a significant issue . OBJECTIVE The research addressed whether short-term oxygen ( O2 ) administration during activities might decrease dyspnea and improve exercise performance in nonhypoxemic patients with emphysema caused by a deficiency of alpha-1 antitrypsin . METHOD This was a double-blind , r and omized crossover study of 31 subjects with a deficiency of AAT ( mean + SD , age = 47 + /- 7 ) , moderate emphysema and a resting PaO2 > 70 mm Hg . Oxygen saturation ( SpO2 ) , 6-minute walk distance , and end of walk dyspnea were measured during three practice walks and during walks with nasal cannula administration of O2 ( intervention ) and compressed air ( control ) . RESULTS Repeated measures analysis of variance ( ANOVA ) showed significant differences across the walks for SpO ( F= 18.9 , p = 0.0001 ) , 6-minute walk distance ( F= 6.07 , p = 0.004 ) , and dyspnea ( F= 4.44 , p = 0.016 ) . Using post hoc contrasts , SpO2 was the only variable that differed between 20 , and compressed air ( p < 0.0001 ) . There was , however , an interaction effect of gender with O2 for dyspnea ( F= 9.85 , p = 0.004 ) . Mean values showed that men did not benefit from O2 ( p = 0.87 ) . However , women experienced less dyspnea when receiving O2 as compared with compressed air ( p = 0.0025 ) , and although not statistically significant , the lower dyspnea with O2 corresponded with an increased walk distance of 79 feet . CONCLUSIONS O2 administration may be useful for reducing dyspnea during exercise in selected population What is meant by intention-to-treat ? Why should data be analyzed in controlled trials in a way that all participants are included in the group to which they were r and omly assigned , regardless of whether they completed the intervention given to the group ? In this Tutorial , the logic of the intention-to-treat principle is outlined . It is shown that study results may be biased by excluding patients post hoc thus producing spurious effects that do not exist in the population under study . The intention-to-treat strategy avoids this bias |
13,737 | 25,985,709 | In the microbiota of allergic children whose intestinal microbiota was assessed at the onset of allergic symptoms , there was a higher count of Bacteroides ; a lower count of Akkermansia muciniphila , Faecalibacterium prausnitzii , and Clostridium ; a higher prevalence of B. adolescentis ; a lower prevalence of B. catenulatum and Staphylococcus aureus ; and a lower bacterial diversity | Evidence suggests that possible imbalances in intestinal microbiota composition may be implicated in the occurrence of allergic diseases .
Although several studies published until 2006 indicated a correlation between microbiota composition and allergic symptoms , it has not been possible to distinguish protective microorganisms from those associated with increased risk of allergic diseases .
Therefore , the objective of this study was to review the studies published since 2007 that address the intestinal microbiota in allergic diseases . | Background : The objective is to study the effect of after-birth oral colonization by a probiotic Escherichia coli strain in infants of allergic mothers to reduce occurrence of allergy later in life . Methods : In a controlled clinical trial , 158 infants were r and omly divided into groups of ( i ) 56 colonized infants of allergic mothers , ( ii ) 57 control infants of allergic mothers , and ( iii ) 45 control infants of healthy mothers . Incidence rates of bacterial pathogens in stool and levels of anti-E. coli immunoglobulins and some cytokines in serum were determined , and secretory IgA was monitored in stool filtrates and maternal milk . Clinical check-ups of infants aged 4 days , 3 and 6 months , 2 , 3 and 5 years were carried out and clinical symptoms of allergy were monitored . One milliliter of the probiotic E. coli strain was administered to infants of allergic mothers at first within 48 h after birth and subsequently 3 times a week over a period of 4 weeks . Control infants of allergic and healthy mothers were monitored in these intervals as well . Results : Presence of the E. coli strain was monitored in stool sample s throughout the study . At the conclusion of the study , allergy symptoms were found in 14 infants of control allergic mothers , 7 infants of healthy mothers , and in 2 colonized infants of allergic mothers . Colonization affected levels of several cytokines and specific anti-E. coli antibodies . Conclusions : After birth , targeted colonization of the intestine by a probiotic E. coli strain can be an effective means of allergy prevention in infants of allergic mothers Background The ' hygiene hypothesis ' suggests that early exposure to microbes can be protective against atopic disease . The intestinal microbial flora could operate as an important postnatal regulator of the Th1/Th2 balance . The aim of the study was to investigate the association between early intestinal colonisation and the development of asthma in the first 3 years of life . Methods In a prospect i ve birth cohort , 117 children were classified according to the Asthma Predictive Index . A positive index included wheezing during the first three years of life combined with eczema in the child in the first years of life or with a parental history of asthma . A faecal sample was taken at the age of 3 weeks and cultured on selective media . Results Asthma Predictive Index was positive in 26/117 ( 22 % ) of the children . The prevalence of colonisation with Bacteroides fragilis was higher at 3 weeks in index+ compared to index- children ( 64 % vs. 34 % p < 0,05 ) . Bacteroides fragilis and Total Anaerobes counts at 3 weeks were significantly higher in children with a positive index as compared with those without . After adjusting for confounders a positive association was found between Bacteroides fragilis colonisation and Asthma Predictive Index ( odds ratio : 4,4 ; confidence interval : 1,7 – 11,8 ) . Conclusion Bacteroides fragilis colonisation at age 3 weeks is an early indicator of possible asthma later in life . This study could provide the means for more accurate targeting of treatment and prevention and thus more effective and better controlled modulation of the microbial milieu BACKGROUND It is debated whether a low total diversity of the gut microbiota in early childhood is more important than an altered prevalence of particular bacterial species for the increasing incidence of allergic disease . The advent of powerful , cultivation-free molecular methods makes it possible to characterize the total microbiome down to the genus level in large cohorts . OBJECTIVE We sought to assess microbial diversity and characterize the dominant bacteria in stool during the first year of life in relation to atopic eczema development . METHODS Microbial diversity and composition were analyzed with barcoded 16S rDNA 454-pyrosequencing in stool sample s at 1 week , 1 month , and 12 months of age in 20 infants with IgE-associated eczema and 20 infants without any allergic manifestation until 2 years of age ( Clinical Trials.gov ID NCT01285830 ) . RESULTS Infants with IgE-associated eczema had a lower diversity of the total microbiota at 1 month ( P = .004 ) and a lower diversity of the bacterial phylum Bacteroidetes and the genus Bacteroides at 1 month ( P = .02 and P = .01 ) and the phylum Proteobacteria at 12 months of age ( P = .02 ) . The microbiota was less uniform at 1 month than at 12 months of age , with a high interindividual variability . At 12 months , when the microbiota had stabilized , Proteobacteria , comprising gram-negative organisms , were more abundant in infants without allergic manifestation ( Empirical Analysis of Digital Gene Expression in R [ edgeR ] test : P = .008 , q = 0.02 ) . CONCLUSION Low intestinal microbial diversity during the first month of life was associated with subsequent atopic eczema Background A modest number of prospect i ve studies of the composition of the intestinal microbiota and eczema in early life have yielded conflicting results . Objective To examine the relationship between the bacterial diversity of the gut and the development of eczema in early life by methods other than stool culture . Methods Fecal sample s were collected from 21 infants at 1 and 4 months of life . Nine infants were diagnosed with eczema by the age of 6 months ( cases ) and 12 infants were not ( controls ) . After conducting denaturating gradient gel electrophoresis ( DGGE ) of stool sample s , we compared the microbial diversity of cases and controls using the number of electrophoretic b and s and the Shannon index of diversity ( H ' ) as indicators . Results Control subjects had significantly greater fecal microbial diversity than children with eczema at ages 1 ( mean H ' for controls = 0.75 vs. 0.53 for cases , P = 0.01 ) and 4 months ( mean H ' for controls = 0.92 vs. 0.59 for cases , P = 0.02 ) . The increase in diversity from 1 to 4 months of age was significant in controls ( P = 0.04 ) but not in children who developed eczema by 6 months of age ( P = 0.32 ) . Conclusion Our findings suggest that reduced microbial diversity is associated with the development of eczema in early life BACKGROUND Alterations in intestinal microflora have been linked to the development of allergic disease . Recent studies suggest that healthy infant immune development may depend on the establishment of a diverse gut microbiota rather than the presence or absence of specific microbial strains . OBJECTIVES We investigated the relationship between diversity of gut microbiota in the early postnatal period and subsequent development of eczema and atopy in the first year of life . METHODS Fecal sample s were collected 1 wk after birth from 98 infants at high risk of allergic disease , who were followed prospect ively to age 12 months . Fecal microbial diversity was assessed by terminal restriction fragment length polymorphism ( T-RFLP ) using restriction enzymes Sau96I and AluI , with a greater number of peaks representing greater diversity of bacterial communities . RESULTS Microbial diversity at day 7 was significantly lower in infants with eczema at age 12 months as compared to infants without eczema ( AluI mean number of peaks 13.1 vs. 15.5 , p = 0.003 , 95 % CI for difference in means -3.9 , -0.8 ; Sau96I 14.7 vs. 17.2 , p = 0.03 , 95 % CI -4.9 , -0.3 ) . No differences were observed for atopic compared to non-atopic infants , or infants with two allergic parents compared to those with one or no allergic parent . CONCLUSIONS A more diverse intestinal microbiota in the first week of life is associated with a reduced risk of subsequent eczema in infants at increased risk of allergic disease . Interventions that enhance microbial diversity in early life may provide an effective means for the prevention of eczema in high-risk infants Background Deviations in composition and diversity of intestinal microbiota in infancy have been associated with both the development and recurrence of atopic eczema . Thus , we decided to use a deep and global microarray-based method to characterize the diversity and temporal changes of the intestinal microbiota in infancy and to define specific bacterial signatures associated with eczema . Faecal microbiota at 6 and 18 months of age were analysed from 34 infants ( 15 with eczema and 19 healthy controls ) selected from a prospect i ve follow-up study based on the availability of faecal sample s. The infants were originally r and omized to receive either Lactobacillus rhamnosus GG or placebo . Results Children with eczema harboured a more diverse total microbiota than control subjects as assessed by the Simpson ’s reciprocal diversity index of the microarray profiles . Composition of the microbiota did not differ between study groups at age of 6 months , but was significantly different at age of 18 months as assessed by MCPP ( p=0.01 ) . At this age healthy children harboured 3 -fold greater amount of members of the Bacteroidetes ( p=0.01 ) . Microbiota of children suffering from eczema had increased abundance of the Clostridium clusters IV and XIVa , which are typically abundant in adults . Probiotic Lactobacillus rhamnosus GG supplementation in early infancy was observed to have minor long-term effects on the microbiota composition . Conclusion A diverse and adult-type microbiota in early childhood is associated with eczema and it may contribute to the perpetuation of eczema BACKGROUND Changes in the human microbiome have been suggested as a risk factor for a number of lifestyle-related disorders , such as atopic diseases , possibly through a modifying influence on immune maturation in infancy . OBJECTIVES We aim ed to explore the association between neonatal fecal flora and the development of atopic disorders until age 6 years , hypothesizing that the diversity of the intestinal microbiota influences disease development . METHODS We studied the intestinal microbiota in infants in the Copenhagen Prospect i ve Study on Asthma in Childhood , a clinical study of a birth cohort of 411 high-risk children followed for 6 years by clinical assessment s at 6-month intervals , as well as at acute symptom exacerbations . Bacterial flora was analyzed at 1 and 12 months of age by using molecular techniques based on 16S rRNA PCR combined with denaturing gradient gel electrophoresis , as well as conventional culturing . The main outcome measures were the development of allergic sensitization ( skin test and specific serum IgE ) , allergic rhinitis , peripheral blood eosinophil counts , asthma , and atopic dermatitis during the first 6 years of life . RESULTS We found that bacterial diversity in the early intestinal flora 1 and 12 months after birth was inversely associated with the risk of allergic sensitization ( serum specific IgE P = .003 ; skin prick test P = .017 ) , peripheral blood eosinophils ( P = .034 ) , and allergic rhinitis ( P = .007 ) . There was no association with the development of asthma or atopic dermatitis . CONCLUSIONS Reduced bacterial diversity of the infant 's intestinal flora was associated with increased risk of allergic sensitization , allergic rhinitis , and peripheral blood eosinophilia , but not asthma or atopic dermatitis , in the first 6 years of life . These results support the general hypothesis that an imbalance in the intestinal microbiome is influencing the development of lifestyle-related disorders , such as allergic disease Background The extended ' hygiene hypothesis ' suggests that the initial composition of the infant gut microbiota is a key determinant in the development of atopic disease . Several studies have demonstrated that the microbiota of allergic and non-allergic infants are different even before the development of symptoms , with a critical time window during the first 6 months of life . The aim of the study was to investigate the association between early intestinal colonisation and the development of asthma in the first 3 years of life using DGGE ( denaturing gradient gel electrophoresis ) . Methods In a prospect i ve birth cohort , 110 children were classified according to the API ( Asthma Predictive Index ) . A positive index included wheezing during the first three years of life combined with eczema in the child in the first years of life or with a parental history of asthma . A fecal sample was taken at the age of 3 weeks and analysed with DGGE using universal and genus specific primers . Results The Asthma Predictive Index was positive in 24/110 ( 22 % ) of the children . Using universal V3 primers a b and corresponding to a Clostridum coccoides XIVa species was significantly associated with a positive API . A Bacteroides fragilis subgroup b and was also significantly associated with a positive API . A final DGGE model , including both b and s , allowed correct classification of 73 % ( 80/110 ) of the cases . Conclusion Fecal colonisation at age 3 weeks with either a Bacteroides fragilis subgroup or a Clostridium coccoides subcluster XIVa species is an early indicator of possible asthma later in life . These findings need to be confirmed in a new longitudinal follow-up study BACKGROUND The intestinal microflora is a likely source for the induction of immune deviation in infancy . OBJECTIVE The purpose of this study was to prospect ively relate the intestinal microflora to allergy development in 2 countries differing with respect to the prevalence of atopic diseases . METHODS Newborn infants were followed prospect ively through the first 2 years of life in Estonia ( n = 24 ) and Sweden ( n = 20 ) . By that age , 9 Estonian and 9 Swedish infants had developed atopic dermatitis and /or positive skin prick test results . Stool sample s were obtained at 5 to 6 days and at 1 , 3 , 6 , and 12 months , and 13 groups of aerobic and anaerobic microorganisms were cultivated through use of st and ard methods . RESULTS In comparison with healthy infants , babies who developed allergy were less often colonized with enterococci during the first month of life ( 72 % vs 96 % ; P < .05 ) and with bifidobacteria during the first year of life ( 17 % to 39 % vs 42 % to 69 % ; P < .05 ) . Furthermore , allergic infants had higher counts of clostridia at 3 months ( median value , 10.3 vs 7.2 log(10 ) ; P < .05 ) . The prevalence of colonization with Staphylococcus aureus was also higher at 6 months ( 61 % vs 23 % ; P < .05 ) , whereas the counts of Bacteroides were lower at 12 months ( 9.9 vs 10.6 log(10 ) ; P < .05 ) . CONCLUSION Differences in the composition of the gut flora between infants who will and infants who will not develop allergy are demonstrable before the development of any clinical manifestations of atopy . Because the observations were made in 2 countries with different st and ards of living , we believe that our findings could indicate a role for the intestinal microflora in the development of and protection from allergy Objective . To examine the association between the intestinal flora at the age of three weeks and wheezing during the first year of life in a prospect i ve birth cohort study . Methods . The Asthma and Allergy study is a prospect i ve birth cohort study . A total of 154 children were recruited through maternity clinics . Selection criteria were vaginal delivery at term and uncomplicated perinatal period . Question naires were collected with data on the parents , including demography , smoking , and asthma . Data of the child on demographic factors , respiratory symptoms , and risk factors for asthma were collected at the ages of 3 weeks and 6 and 12 months . A fecal sample was collected at 3 weeks of age . Results . The frequency of wheezing averaged on 11.8 % , 18.4 % , and 23.5 % at the three time points . In univariate analyses , increasing total concentration of anerobic bacteria were associated with increased odds of wheezing . Furthermore , several trends were observed between wheezing and Bifidobacterium and Clostridium . A final model showed a significant association between wheezing during the first year of life and antibiotic use , total concentration of anerobic bacteria , while increasing concentrations of Clostridium were protective of wheezing . Conclusion . This study demonstrated an association between antibiotics , anerobic bacteria , and wheezing during the first year of life . The effect of antibiotics was probably due to reverse causation . Since Clostridium was protective of wheezing , other anerobic bacteria are probably responsible for the increased risk of wheezing , which remains to be demonstrated BACKGROUND Newborn infants in modern maternity hospitals are subject to numerous factors that affect normal intestinal colonization -- for example , cesarean delivery and antimicrobial agents . To study the duration of the effect of external factors on intestinal colonization , two groups of infants with different delivery methods were investigated . METHODS The fecal flora of 64 healthy infants was studied prospect ively . Thirty-four infants were delivered vaginally , and 30 by cesarean birth with antibiotic prophylaxis administered to their mothers before the delivery . The fecal flora was cultured on nonselective and selective media in infants 3 to 5 , 10 , 30 , 60 , and 180 days of age . Gastrointestinal signs were recorded daily by the mothers for 2 months . RESULTS The fecal colonization of infants born by cesarean delivery was delayed . Bifidobacterium-like bacteria and Lactobacillus-like bacteria colonization rates reached the rates of vaginally delivered infants at 1 month and 10 days , respectively . Infants born by cesarean delivery were significantly less often colonized with bacteria of the Bacteroides fragilis group than were vaginally delivered infants : At 6 months the rates were 36 % and 76 % , respectively ( p=0.009 ) . The occurrence of gastrointestinal signs did not differ between the study groups . CONCLUSIONS This study shows for the first time that the primary gut flora in infants born by cesarean delivery may be disturbed for up to 6 months after the birth . The clinical relevance of these changes is unknown , and even longer follow-up is needed to establish how long-lasting these alterations of the primary gut flora can be |
13,738 | 27,565,200 | Results indicated that women with symptoms of PPA are less likely to breastfeed exclusively and more likely to terminate breastfeeding earlier .
Some evidence also suggests that those experiencing PPA are less likely to initiate breastfeeding and more likely to supplement with formula in the hospital .
In those who do breastfeed , PPA reduces self-efficacy , increases breastfeeding difficulties , and may negatively affect breastfeeding behaviors and breast milk composition .
However , in combination with a review linking depression with similar negative infant-feeding sequelae , the findings provide evidence for the effect of negative postpartum mood on breastfeeding . | There is increasing evidence for the effect of postpartum anxiety ( PPA ) on maternal and infant health outcomes .
Despite evidence linking suboptimal infant-feeding outcomes with other indices of maternal mental health , the relationship between PPA and infant feeding has not yet been review ed . | BACKGROUND Although much research has focused on identifying factors that influence breastfeeding initiation and duration , many high-risk factors are nonmodifiable demographic variables . Predisposing factors for low breastfeeding duration rates that are amenable to supportive interventions should be identified . The purpose of this study was to assess the effect of maternal confidence ( breastfeeding self-efficacy ) on breastfeeding duration . METHOD A prospect i ve survey was conducted with 300 women in the last trimester of pregnancy recruited from the antenatal clinic of a large metropolitan hospital in Brisbane , Australia . Telephone interviews were conducted at 1 week and 4 months postpartum to assess infant feeding methods and breastfeeding confidence using the Breastfeeding Self-Efficacy Scale . RESULTS Although 92 percent of participants initiated breastfeeding , by 4 months postpartum almost 40 percent discontinued and only 28.6 percent were breastfeeding exclusively ; the most common reason for discontinuation was insufficient milk supply . Antenatal and 1-week Breastfeeding Self-Efficacy Scale scores were significantly related to breastfeeding outcomes at 1 week and 4 months . Mothers with high breastfeeding self-efficacy were significantly more likely to be breastfeeding , and doing so exclusively , at 1 week and 4 months postpartum than mothers with low breastfeeding self-efficacy . CONCLUSIONS Maternal breastfeeding self-efficacy is a significant predictor of breastfeeding duration and level . Integrating self-efficacy enhancing strategies may improve the quality of healthcare that healthcare professionals deliver and may increase a new mother 's confidence in her ability to breastfeed , and to persevere if she does encounter difficulties Background & Methods To examine the relationship between breastfeeding and maternally-rated infant temperament at age 3 months , 316 infants in the prospect i ve Cambridge Baby Growth Study , UK had infant temperament assessed at age 3 months by mothers using the Revised Infant Behavior Question naire , which produces scores for three main dimensions of temperament derived from 14 subscales . Infant temperament scores were related to mode of infant milk feeding at age 3 months ( breast only ; formula milk only ; or mixed ) with adjustment for infant 's age at assessment and an index of deprivation . Results Infant temperament dimension scores differed across the three infant feeding groups , but appeared to be comparable between exclusive breast-fed and mixed-fed infants . Compared to formula milk-fed infants , exclusive breast-fed and mixed-fed infants were rated as having lower impulsivity and positive responses to stimulation ( adjusted mean [ 95 % CI ] “ Surgency/Extraversion ” in formula-fed vs. mixed-fed vs. breast-fed groups : 4.3 [ 4.2–4.5 ] vs. 4.0 [ 3.8–4.1 ] vs. 4.0 [ 3.9–4.1 ] ; p-heterogeneity = 0.0006 ) , lower ability to regulate their own emotions ( “ Orienting/Regulation ” : 5.1 [ 5.0–5.2 ] , vs. 4.9 [ 4.8–5.1 ] vs. 4.9 [ 4.8–5.0 ] ; p = 0.01 ) , and higher emotional instability ( “ Negative affectivity ” : 2.8 [ 2.6–2.9 ] vs. 3.0 [ 2.8–3.1 ] vs. 3.0 [ 2.9–3.1 ] ; p = 0.03 ) . Conclusions Breast and mixed-fed infants were rated by their mothers as having more challenging temperaments in all three dimensions ; particular subscales included greater distress , less smiling , laughing , and vocalisation , and lower soothability . Increased awareness of the behavioural dynamics of breastfeeding , a better expectation of normal infant temperament and support to cope with difficult infant temperament could potentially help to promote successful breastfeeding OBJECTIVE : Postpartum anxiety screening does not typically occur , despite changes in life roles and responsibility after childbirth . We sought to determine the prevalence of postpartum anxiety during the maternity hospitalization and its associations with maternal and child outcomes . We further aim ed to compare correlates of anxiety with correlates of depression . METHODS : For a r and omized controlled trial of mothers with “ well ” newborns ≥34 weeks ’ gestation comparing 2 post – hospital discharge care models , mothers completed baseline in-person interviews during the postpartum stay and telephone surveys at 2 weeks , 2 months , and 6 months to assess health care use , breastfeeding duration , anxiety , and depression . All participants intended to breastfeed . State anxiety scores ≥40 on the State Trait Anxiety Inventory ( STAI ) and depression scores ≥12 on the Edinburgh Postnatal Depression Survey ( EPDS ) were considered positive . RESULTS : A total of 192 ( 17 % ) of 1123 participating mothers had a positive baseline STAI ; 62 ( 6 % ) had a positive EPDS . Primiparity was associated with a positive STAI ( 20 % vs 15 % , P = .02 ) , but not a positive EPDS ( 4 % vs 7 % , P = .05 ) . Positive STAI scores were associated with cesarean delivery ( 22 % vs 15 % , P = .001 ) , reduced duration of breastfeeding ( P = .003 ) , and increased maternal , but not infant total unplanned health care utilization within 2 weeks of delivery ( P = .001 ) . Positive STAI scores occurred more frequently than positive EPDS scores at each assessment through 6 months postpartum . CONCLUSIONS : Postpartum state anxiety is a common , acute phenomenon during the maternity hospitalization that is associated with increased maternal health care utilization after discharge and reduced breastfeeding duration . State anxiety screening during the postpartum stay could improve these outcomes Several pilot studies have provided evidence that mindfulness-based intervention is beneficial during pregnancy , yet its effects in mothers during the early parenting period are unknown . The purpose of the present pilot study was to examine the effectiveness of a mindfulness-based intervention in breast-feeding mothers . We developed and tested an 8-week mindfulness-based intervention aim ed at improving maternal self-efficacy , mindfulness , self-compassion , satisfaction with life , and subjective happiness , and at reducing psychological distress . A r and omized controlled , between-groups design was used with treatment and control groups ( n = 26 ) and pretest and posttest measures . ANCOVA results indicated that , compared to the control group , mothers in the treatment group scored significantly higher on maternal self-efficacy , some dimensions of mindfulness ( observing , acting with awareness , non-judging , and non-reactivity ) , and self-compassion ( self-kindness , mindfulness , over- identification , and total self-compassion ) . In addition , mothers who received the treatment exhibited significantly less anxiety , stress , and psychological distress . The results supported previous research findings about the benefits of mindfulness-based intervention in women from the perinatal and postpartum periods through the early parenting period . Additional research is needed to vali date our findings in non-breast-feeding mothers and to examine the intervention ’s indirect benefits in terms of family relationships and child development Background Despite high levels of breastfeeding initiation in Australia , only 47 percent of women are breastfeeding ( exclusively or partially ) six months later , with marked differences between social groups . It is important to identify women who are at increased risk of early cessation of breastfeeding . Methods Data from the three arms of a r and omised controlled trial were pooled and analysed as a cohort using logistic regression to identify which factors predicted women continuing to feed any breast milk at six months postpartum . The original trial included 981 primiparous women attending a public , tertiary , women 's hospital in Melbourne , Australia in 1999–2001 . The trial evaluated the effect of two mid-pregnancy educational interventions on breastfeeding initiation and duration . In the 889 women with six month outcomes available , neither intervention increased breastfeeding initiation nor duration compared to st and ard care . Independent variables were included in the predictive model based on the literature and discussion with peers and were each tested individually against the dependent variable ( any breastfeeding at six months ) . Results Thirty-three independent variables of interest were identified , of which 25 qualified for inclusion in the preliminary regression model ; 764 observations had complete data available . Factors remaining in the final model that were positively associated with breastfeeding any breast milk at six months were : a very strong desire to breastfeed ; having been breastfed oneself as a baby ; being born in an Asian country ; and older maternal age . There was an increasing association with increasing age . Factors negatively associated with feeding any breast milk at six months were : a woman having no intention to breastfeed six months or more ; smoking 20 or more cigarettes per day pre-pregnancy ; not attending childbirth education ; maternal obesity ; having self-reported depression in the six months after birth ; and the baby receiving infant formula while in hospital . Conclusion In addition to the factors commonly reported as being associated with breastfeeding in previous work , this study found a negative association between breastfeeding outcomes and giving babies infant formula in hospital , a high maternal body mass index , and self-reported maternal depression or anxiety in the six months after the baby was born . Interventions that seek to increase breastfeeding should consider focusing on women who wish to breastfeed but are at high risk of early discontinuation Background Very low birthweight infants are at risk for deficits in cognitive and language development , as well as attention and behaviour problems . Maternal sensitive behaviour ( i.e. awareness of infant cues and appropriate responsiveness to those cues ) in interaction with her very low birthweight infant is associated with better outcomes in these domains ; however , maternal anxiety interferes with the mother 's ability to interact sensitively with her very low birthweight infant . There is a need for brief , cost-effective and timely interventions that address both maternal psychological distress and interactive behaviour . The Cues and Care trial is a r and omized controlled trial of an intervention design ed to reduce maternal anxiety and promote sensitive interaction in mothers of very low birthweight infants . Methods and design Mothers of singleton infants born at weights below 1500 g are recruited in the neonatal intensive care units of 2 tertiary care hospitals , and are r and omly assigned to the experimental ( Cues ) intervention or to an attention control ( Care ) condition . The Cues intervention teaches mothers to attend to their own physiological , cognitive , and emotional cues that signal anxiety and worry , and to use cognitive-behavioural strategies to reduce distress . Mothers are also taught to underst and infant cues and to respond sensitively to those cues . Mothers in the Care group receive general information about infant care . Both groups have 6 contacts with a trained intervener ; 5 of the 6 sessions take place during the infant 's hospitalization , and the sixth contact occurs after discharge , in the participant mother 's home . The primary outcome is maternal symptoms of anxiety , assessed via self-report question naire immediately post-intervention . Secondary outcomes include maternal sensitive behaviour , maternal symptoms of posttraumatic stress , and infant development at 6 months corrected age . Discussion The Cues and Care trial will provide important information on the efficacy of a brief , skills-based intervention to reduce anxiety and increase sensitivity in mothers of very low birthweight infants . A brief intervention of this nature may be more readily implemented as part of st and ard neonatal intensive care than broad-based , multi-component interventions . By intervening early , we aim to optimize developmental outcomes in these high risk infants . Trial Registration Current Controlled Trials IS RCT N00918472The Cues and Care Trial : A r and omized controlled trial of an intervention to reduce maternal anxiety and improve developmental outcomes in very low birthweight AIM Depressive and anxiety symptoms are common in new mothers . The aim of this study is to explore the link between postpartum psychological adjustment and feeding preferences of the mothers . METHODS Sixty mothers and newborns were enrolled in this prospect i ve , longitudinal study . Maternal depressive symptoms were screened by the Edinburgh Postpartum Depression Scale ( EPDS ) , and maternal anxiety level was assessed by the State-Trait Anxiety Inventory at 1 month postpartum . The Multidimensional Scale of Perceived Social Support was used for the assessment of maternal social support . The Adult Attachment Scale was used to determine the attachment style of the mother . Infants were examined and evaluated at 1 and 4 months of life . RESULTS All mothers started breastfeeding their infants postpartum ; 91 % and 68.1 % continued exclusive breastfeeding at 1 and 4 months , respectively . The first-month median EPDS score of mothers who breastfeed at the fourth month was statistically significantly lower than those who were not breastfeeding ( 6 and 12 , respectively ) ( P = 0001 ) . The first-month median EPDS score of mothers with secure attachment was lower than the median score of mothers with insecure attachment ( 5 and 9 , respectively ) ( P < 0001 ) . Exclusive breastfeeding rate was not statistically different among mothers with secure and insecure attachment styles . The median state and trait anxiety scores and social support scores of mothers were not different between groups according to breastfeeding status . CONCLUSIONS This study has shown an association between higher EPDS scores and breastfeeding cessation by 4 months after delivery BACKGROUND Maternal eating disorders ( ED ) have been shown to increase the risk of feeding difficulties in the offspring . Very few studies , however , have investigated whether the effect of a maternal ED on childhood feeding is a direct effect or whether it can be ascribed to other child or maternal factors . We aim ed to determine the role of maternal anxiety and depression in mediating the risk for feeding difficulties in infants of women with ED . METHODS A prospect i ve study comparing women with lifetime ED ( 441 ) and without any lifetime psychiatric disorder ( 10,461 ) and their infants from the Avon Longitudinal Study of Parents and Children ( ALSPAC ) . We investigated the effect of : maternal anxiety and depression in late pregnancy ( 32 weeks ) and the post-partum ( 8 weeks ) , child temperament and developmental status on infant feeding difficulties at 1 and 6 months . We also investigated the effect of active pregnancy ED symptoms . We tested 3 models and their fit to the data using structured equation modelling : a direct effect model , a fully mediational model and an integrated ( partial meditational ) model . RESULTS The integrated model including a direct effect of maternal lifetime ED on infant feeding and a mediational path via maternal distress ( a latent variable combining anxiety and depression ) fitted the data best . This also applied to maternal pregnancy ED symptoms . Feeding difficulties in turn increased maternal distress over time . CONCLUSIONS Lifetime ED and active pregnancy ED increase the risk for infant feeding difficulties and do so via maternal distress ( i.e. , depression and anxiety ) . This has important implication s for prevention and early intervention in relation to infant feeding difficulties , as well as for future research in the field OBJECTIVE To investigate whether mothers , with no known biological reason to account for elevated breast milk sodium ( BMS ) and associated hypernatremic dehydration ( HND ) in their exclusively breastfed infants , have more adverse psychosocial characteristics compared with controls . METHODS Design is prospect i ve case-control . Mothers of 21 term infants diagnosed as HND with associated high BMS and mothers of 43 healthy , exclusively breastfed term infants , with expected milk sodium levels , were compared on rates of socio-demographic and relationship variables , pregnancy wantedness and planning , maternal attitudes towards breastfeeding , postnatal maternal depression and anxiety . A semi-structured interview , State and Trait Anxiety Inventory and Edinburgh Postnatal Depression Scale were used . RESULTS Reported maternal history of previous psychiatric morbidity ( 57.1 % vs. 18.6 % ; P = 0.003 ) , poor relationship with her own mother ( 36.8 % vs. 9.6 % ; P = 0.026 ) , not finding herself suitable to be a mother ( 28.6 % vs. 4.6 % ; P = 0.012 ) , unplanned pregnancy ( 52.4 % vs. 20.9 % ; P = 0.020 ) and higher state anxiety scores ( mean ( SD ) = 42.2 ( 11.1 ) vs. 35.5 ( 10.5 ) ; P = 0.038 ) in the post-partum period were significantly common in mothers with elevated BMS levels compared with the controls . Univariate analyses revealed that unplanned pregnancy and maternal perception of not being suitable to be mother constitute significant risks with odds ratios 4.2 and 8.2 , respectively . CONCLUSION The present study displays that mothers , with no known biological reason to account for elevated BMS , have more adverse psychosocial characteristics compared with controls ; emphasising the importance of psychosocial and emotional factors during lactation and offering implication s for the establishment of successful lactation through providing additional psychosocial support to vulnerable mothers Objective : To examine the association of breastfeeding with maternal sensitive responsiveness and infant-mother attachment security and disorganization . Methods : We included 675 participants of a prospect i ve cohort study . Question naires about breastfeeding practice s were administered at 2 and 6 months postpartum . At 14 months , maternal sensitive responsiveness was assessed in a 13-minute laboratory procedure using Ainsworth 's sensitivity scales , and attachment quality was assessed with the Strange Situation Procedure . Mothers were genotyped for oxytocin receptor genes OXTR rs53576 and OXTR rs2254298 . Linear regressions and analyses of covariance adjusted for various background variables were conducted . We tested for mediation and moderation by maternal sensitive responsiveness and maternal oxytocin receptor genotype . Results : Continuous analyses showed that longer duration of breastfeeding was associated with more maternal sensitive responsiveness ( B = 0.11 , 95 % confidence interval [ CI ] 0.02 ; 0.20 , p < .05 ) , more attachment security ( B = 0.24 , 95 % CI = 0.02 ; 0.46 , p < .05 ) , and less attachment disorganization ( B = −0.20 , 95 % CI −0.36 ; −0.03 , p < .05 ) . Duration of breastfeeding was not related to the risk of insecure-avoidant or insecure-resistant versus secure attachment classification , but longer duration of breastfeeding predicted a lower risk of disorganized versus secure attachment classification ( n = 151 ; odds ratio [ OR ] = 0.81 , 95 % CI 0.66 to 0.99 , p = .04 ) . Maternal sensitive responsiveness did not mediate the associations , and maternal oxytocin receptor genotype was not a significant moderator . Conclusions : Although duration of breastfeeding was not associated with differences in infant-mother attachment classifications , we found subtle positive associations between duration of breastfeeding and sensitive responsiveness , attachment security , and disorganization OBJECTIVES To pilot test a newly developed breastfeeding self-efficacy intervention . DESIGN Pilot r and omized controlled trial ( RCT ) . SETTING An acute care hospital located in Northwestern Ontario that is the sole provider of maternity care for the city and referral center for the region . PARTICIPANTS One-hundred- and -fifty primiparous women intending to breastfeed their healthy , term , singleton infant . INTERVENTION A st and ardized , individualized nursing intervention protocol was design ed and administered to increase mothers ' breastfeeding self-efficacy . Participants were r and omly allocated to the intervention group or control group using sealed , opaque envelopes . Participants in the intervention group received three individualized , self-efficacy enhancing sessions with the research er : two in-hospital and one by telephone . Participants in the control group received st and ard in-hospital and community care . MAIN OUTCOME MEASURES Feasibility , compliance , and the acceptability of the breastfeeding self-efficacy intervention . Other outcomes assessed were breastfeeding self-efficacy , duration , and exclusivity . RESULTS Findings suggest that the intervention was feasible ; there was a high degree of protocol compliance , and the majority of mothers reported that the intervention was beneficial . Mothers in the intervention group had higher rates of breastfeeding self-efficacy , duration , and exclusivity at 4 and 8 weeks postpartum . However , the differences between groups were not statistically significant . CONCLUSION The pilot RCT provided valuable information in examining the feasibility of the trial design and intervention Two studies examined the effects of breast-feeding on maternal stress and mood . In Experiment 1 , perceived stress in the past month was compared between 28 breast-feeding and 27 bottle-feeding mothers . Breast-feeding mothers reported less perceived stress , after controlling for demographic confounds . In Experiment 2 , mood ratings were assessed in the same 24 mothers both before and then after 1 breast-feeding and 1 bottle-feeding session . Breast-feeding was associated with a decrease in negative mood , and bottle-feeding was associated with a decrease in positive mood from pre- to postfeeding . Results indicated that breast-feeding buffers negative mood . These effects appeared to be attributable to the effects of breast-feeding itself and not solely to individual-differences factors OBJECTIVE To assess the degree to which mothers ' prepartum personality traits predict breastfeeding status at 6 months postpartum . STUDY DESIGN This prospect i ve cohort study is part of the Norwegian Mother and Child Cohort Study , conducted at the Norwegian Institute of Public Health . A total of 27,753 mothers completed assessment of negative affectivity ( NA ) and general self-efficacy ( GSE ) at gestation weeks 17 and 30 and completed a question naire about infant feeding at 6 months postpartum . Feeding status was classified with a cutoff at 6 months in the categories of predominant breastfeeding , mixed breastfeeding , and bottle-feeding . RESULTS After adjusting for maternal smoking , age , education , cesarean section , preterm birth , primiparity , and external daycare , NA increased the odds of mixed breastfeeding ( odds ratio [ OR ] , 1.16 ; 95 % confidence interval [ CI ] , 1.03 to 1.32 ) and bottle feeding ( OR , 1.32 ; 95 % CI , 1.14 to 1.53 ) compared with predominant breastfeeding . GSE decreased the odds of bottle feeding ( OR , 0.90 ; 95 % CI , 0.84 to 0.97 ) but not of mixed breastfeeding ( OR , 0.98 ; 95 % CI , 0.92 to 1.04 ) compared with predominant breastfeeding . The adjusting variables were also predictors of breastfeeding behavior in their own right . CONCLUSIONS Our results show that NA and GSE are important antenatal predictors of breastfeeding status at 6 months postpartum In several studies lactation has been shown to be associated with a hypothalamic-pituitary-adrenal axis hyporesponsiveness to physical and psychological stressors . As it is not known whether the marked blunting of endocrine stress reactivity in women can be ascribed to suckling as a short-term effect or to lactation in general , the acute effects of suckling on the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary system responses to mental stress were investigated in lactating women . Forty-three lactating women were r and omly assigned either to breast-feed or to hold their infants for a 15-min period with the onset 30 min before they were exposed to a brief psychosocial stressor ( Trier Social Stress Test ) . Both breast-feeding and holding the infant yielded significant decreases in ACTH , total plasma cortisol , and salivary free cortisol ( all P < 0.01 ) . There were no significant differences in baseline hormone levels between the groups 1 min before the stress test . In response to stress exposure , ACTH , total plasma cortisol , salivary free cortisol , norepinephrine , and epinephrine were significantly increased in all lactating women ( all P < 0.001 ) . However , total cortisol and free cortisol responses to stress were attenuated in breast-feeding women ( P = 0.001 and P = 0.067 , respectively ) , who also showed significantly decreasing PRL levels during the stress test ( P = 0.005 ) . In addition , there was no change in plasma oxytocin or vasopressin in response to the stressor . Breast-feeding as well as holding led to decreased anxiety ( P < 0.05 ) , whereas , in contrast , stress exposure worsened mood , calmness , and anxiety in the total group ( all P < 0.001 ) . From these data we conclude that lactation in women , in contrast to that in rats , does not result in a general restraint of the hypothalamic-pituitary-adrenal axis response to a psychosocial stressor . Rather , suckling is suggested to exert a short-term suppression of the cortisol response to mental stress BACKGROUND Although anxiety disorders are documented in the literature for new mothers ( but less so for fathers ) , rates of postpartum caseness tend to include only those with depression when diagnostic interviews or self-report measures vali date d on such interviews are used . This methodology therefore underestimates the true percentage of women and men who experience significant psychological difficulties postpartum . This has implication s for assessment , treatment and screening for postnatal mood disorders . METHOD Two studies were conducted on a total of 408 women and 356 men expecting their first child . They were recruited antenatally , and interviewed at 6 weeks postpartum using the Diagnostic Interview Schedule . DSM-IV criteria were applied to determine the presence since birth of depression ( major or minor ) , panic disorder , acute adjustment disorder with anxiety ( meeting the criteria for generalised anxiety disorder except for the duration criterion ) , and phobia . RESULTS The inclusion of diagnostic assessment for panic disorder and acute adjustment disorder with anxiety increased the rates of caseness by between 57 and 100 % for mothers , and 31 - 130 % for fathers , over the rates for major or minor depression . Inclusion of assessment for phobia further increased the rates of disorder in both sample s. Couple concordance rates were between 6.6 and 11.1 % , with no significant difference between rates for depressive or depressive and anxious caseness . For women , a previous history of an anxiety disorder appears to be a greater risk factor for a postnatal mood disorder ( i.e. depression or anxiety ) than a history of a depressive disorder . CONCLUSIONS These results clearly show the need to assess for both depression and anxiety in new and expectant parents , and we believe the term ' postnatal mood disorder ' ( PMD ) , rather than postnatal depression , more accurately reflects significant adjustment difficulties in new parents |
13,739 | 30,010,119 | Conclusion : Systematic and comprehensive assessment of studies of 18FDG-PET for prediction of conversion from MCI to AD dementia reveals many studies have method ological limitations according to Cochrane diagnostic test accuracy gold st and ards , and shows accuracy remains highly variable , including in the most recent studies . | Background : A previous Cochrane systematic review concluded there is insufficient evidence to support the routine use of 18F-FDG PET in clinical practice in people with mild cognitive impairment ( MCI ) .
Objectives : To up date the evidence and reassess the accuracy of 18F-FDG-PET for detecting people with MCI at baseline who would clinical ly convert to Alzheimer ’s disease ( AD ) dementia at follow-up . | [11C]Pittsburgh compound B ( [11C]PIB ) and [18F]‐2‐fluoro‐2‐deoxy‐D‐glucose ( [18F]FDG ) PET measure fibrillar amyloid‐β load and glucose metabolism , respectively . We evaluated the impact of these tracers on the diagnostic process in a memory clinic population BACKGROUND Subjects with a mild cognitive impairment ( MCI ) have a memory impairment beyond that expected for age and education yet are not demented . These subjects are becoming the focus of many prediction studies and early intervention trials . OBJECTIVE To characterize clinical ly subjects with MCI cross-sectionally and longitudinally . DESIGN A prospect i ve , longitudinal inception cohort . SETTING General community clinic . PARTICIPANTS A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease ( AD ) , all from a community setting as part of the Mayo Clinic Alzheimer 's Disease Center/Alzheimer 's Disease Patient Registry , Rochester , Minn. MAIN OUTCOME MEASURES The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination , Wechsler Adult Intelligence Scale-Revised , Wechsler Memory Scale-Revised , Dementia Rating Scale , Free and Cued Selective Reminding Test , and Auditory Verbal Learning Test . Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders , Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer 's Disease and Related Disorders Association criteria , respectively . RESULTS The primary distinction between control subjects and subjects with MCI was in the area of memory , while other cognitive functions were comparable . However , when the subjects with MCI were compared with the patients with very mild AD , memory performance was similar , but patients with AD were more impaired in other cognitive domains as well . Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD . CONCLUSIONS Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD . They appear to constitute a clinical entity that can be characterized for treatment interventions Purpose [11C]PIB and [18F]FDDNP are PET tracers for in vivo detection of the neuropathology underlying Alzheimer ’s disease ( AD ) . [18F]FDG is a glucose analogue and its uptake reflects metabolic activity . The purpose of this study was to examine longitudinal changes in these tracers in patients with AD or mild cognitive impairment ( MCI ) and in healthy controls . Methods Longitudinal , paired , dynamic [11C]PIB and [18F]FDDNP ( 90 min each ) and static [18F]FDG ( 15 min ) PET scans were obtained in 11 controls , 12 MCI patients and 8 AD patients . The mean interval between baseline and follow-up was 2.5 years ( range 2.0–4.0 years ) . Parametric [11C]PIB and [18F]FDDNP images of binding potential ( BPND ) and [18F]FDG st and ardized uptake value ratio ( SUVr ) images were generated . Results A significant increase in global cortical [11C]PIB BPND was found in MCI patients , but no changes were observed in AD patients or controls . Subsequent regional analysis revealed that this increase in [11C]PIB BPND in MCI patients was most prominent in the lateral temporal lobe ( p < 0.05 ) . For [18F]FDDNP , no changes in global BPND were found . [18F]FDG uptake was reduced at follow-up in the AD group only , especially in frontal , parietal and lateral temporal lobes ( all p < 0.01 ) . Changes in global [11C]PIB binding ( ρ = −0.42 , p < 0.05 ) and posterior cingulate [18F]FDG uptake ( ρ = 0.54 , p < 0.01 ) were correlated with changes in Mini-Mental-State Examination score over time across groups , whilst changes in [18F]FDDNP binding ( ρ = −0.18 , p = 0.35 ) were not . Conclusion [11C]PIB and [18F]FDG track molecular changes in different stages of AD . We found increased amyloid load in MCI patients and progressive metabolic impairment in AD patients . [18F]FDDNP seems to be less useful for examining disease progression Objective : To investigate the 10-year risk of dementia in subjects with mild cognitive impairment ( MCI ) ages 40 to 85 years . Methods : We selected subjects from a memory clinic if they met one of the following definitions of MCI : cognitive complaints ( n = 181 ) , aging-associated cognitive decline ( AACD ) ( n = 163 ) , mild functional impairment ( n = 86 ) , or amnestic MCI ( n = 64 ) . Subjects were reassessed after 2 , 5 , and 10 years . The risk of dementia was calculated with Kaplan-Meier statistics . Analyses were conducted in the entire sample and in subgroups of subjects aged 40 to 54 years , 55 to 69 years , and 70 to 85 years . Results : The 10-year risk of dementia was 0.27 ( 95 % CI 0.20 to 0.34 ) in subjects with cognitive complaints , 0.28 ( 95 % CI 0.21 to 0.35 ) in subjects with AACD , 0.44 ( 95 % CI 0.32 to 0.56 ) in subjects with mild functional impairment , and 0.48 ( 95 % CI 0.35 to 0.61 ) in subjects with amnestic MCI . Ninety-one percent of the demented subjects had probable AD . The risk of dementia increased with increasing age for all MCI definitions ( p < 0.001 ) . Depending on the MCI definition used , the risk for dementia ranged from 0 to 0.06 in subjects aged 40 to 54 years , from 0.37 to 0.52 in subjects aged 55 to 69 years , and from 0.77 to 1.0 in subjects aged 70 to 85 years . Conclusions : The majority of subjects with MCI do not progress to dementia at the long term . Age strongly influences the dementia risk . MCI often represents the predementia stage of a neurodegenerative disorder in elderly subjects but rarely in younger subjects CONTEXT Small single-center studies have shown that cerebrospinal fluid ( CSF ) biomarkers may be useful to identify incipient Alzheimer disease ( AD ) in patients with mild cognitive impairment ( MCI ) , but large-scale multicenter studies have not been conducted . OBJECTIVE To determine the diagnostic accuracy of CSF beta-amyloid(1 - 42 ) ( Abeta42 ) , total tau protein ( T-tau ) , and tau phosphorylated at position threonine 181 ( P-tau ) for predicting incipient AD in patients with MCI . DESIGN , SETTING , AND PARTICIPANTS The study had 2 parts : a cross-sectional study involving patients with AD and controls to identify cut points , followed by a prospect i ve cohort study involving patients with MCI , conducted 1990 - 2007 . A total of 750 individuals with MCI , 529 with AD , and 304 controls were recruited by 12 centers in Europe and the United States . Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia . MAIN OUTCOME MEASURES Sensitivity , specificity , positive and negative likelihood ratios ( LRs ) of CSF Abeta42 , T-tau , and P-tau for identifying incipient AD . RESULTS During follow-up , 271 participants with MCI were diagnosed with AD and 59 with other dementias . The Abeta42 assay in particular had considerable intersite variability . Patients who developed AD had lower median Abeta42 ( 356 ; range , 96 - 1075 ng/L ) and higher P-tau ( 81 ; range , 15 - 183 ng/L ) and T-tau ( 582 ; range , 83 - 2174 ng/L ) levels than MCI patients who did not develop AD during follow-up ( 579 ; range , 121 - 1420 ng/L for Abeta42 ; 53 ; range , 15 - 163 ng/L for P-tau ; and 294 ; range , 31 - 2483 ng/L for T-tau , P < .001 ) . The area under the receiver operating characteristic curve was 0.78 ( 95 % confidence interval [ CI ] , 0.75 - 0.82 ) for Abeta42 , 0.76 ( 95 % CI , 0.72 - 0.80 ) for P-tau , and 0.79 ( 95 % CI , 0.76 - 0.83 ) for T-tau . Cut-offs with sensitivity set to 85 % were defined in the AD and control groups and tested in the MCI group , where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83 % ( 95 % CI , 78%-88 % ) , specificity 72 % ( 95 % CI , 68%-76 % ) , positive LR , 3.0 ( 95 % CI , 2.5 - 3.4 ) , and negative LR , 0.24 ( 95 % CI , 0.21 - 0.28 ) . The positive predictive value was 62 % and the negative predictive value was 88 % . CONCLUSIONS This multicenter study found that CSF Abeta42 , T-tau , and P-tau identify incipient AD with good accuracy , but less accurately than reported from single-center studies . Intersite assay variability highlights a need for st and ardization of analytical techniques and clinical procedures Abstract OBJECTIVES To determine the 2-year outcome from 16 different current classifications of mild cognitive impairment ( MCI ) in a population -based sample . DESIGN Prospect i ve cohort study : baseline and 2-year follow-up phases . SETTING Large-scale multicenter study , United Kingdom . PARTICIPANTS : Thirteen thous and four individuals aged 65 and older from the Medical Research Council Cognitive Function and Ageing Study . From this , a sub sample of 2,640 individuals was selected and completed a more-detailed cognitive assessment . Individuals who underwent further assessment were asked to complete annual or 2-year follow-ups . MEASUREMENTS Information on sociodemographic status , general health , cognitive impairment and functional ability were collected using a structured interview . Individuals were classified according to 16 different definitions of MCI . These were applied retrospectively . RESULTS The dominant outcome across definitions was an impairment that was not classifiable or reversion to normality . Progression to dementia was variable and generally poor . Overall progression was highest in classifications in which impairment extended to memory and nonmemory domains . Predictability was age dependent in some but not all classifications . CONCLUSION Current classifications of MCI have variable outcomes in population -based sample s. Progression to dementia is relatively rare and is dependent on age and definition . Selection criteria developed for the clinic are based on a " high risk " approach that leads to exclusion of a large percentage of the impaired population who are neither normal nor demented and for whom no intervention options are currently available . A refined definition of this construct is urgently needed if MCI is to be used to predict dementia in population -based studies UNLABELLED Patients with mild cognitive impairment ( MCI ) represent a risk population for progressing to dementia of the Alzheimer type ( DAT ) . However , clinical criteria do not ensure reliable individual prognosis in these patients . The objective of this longitudinal , prospect i ve study was to examine the value of (18)F-FDG PET of cerebral glucose metabolism and of genetic susceptibility , as defined by an APOEepsilon4-positive genotype , with regard to the early diagnosis of DAT in patients with MCI . METHODS In 30 patients with the diagnosis of MCI ( 16 female , 14 male ; age , 70 + /- 8 y ) , baseline and follow-up examinations ( mean observation period , 16 mo ) were performed . In all patients , the APOE genotype was assessed and cerebral glucose metabolism was evaluated at baseline using cranial (18)F-FDG PET . Individual PET data were screened for findings suggestive of Alzheimer 's disease ( AD ) , with the help of an automated computer program . After stereotactical normalization of the PET images , this program performs an observer-independent statistical comparison with an age-matched reference data base ( n = 22 ) . RESULTS In 43 % of all MCI subjects , a PET scan suggestive of AD pathology according to our predefined criteria was observed at baseline ( PET+ ) ; 57 % of all MCI patients were carriers of the APOE epsilon4 allele ( e4 + ) . In 40 % of all patients , progression of symptoms within the observation period justified the clinical diagnosis of probable DAT at the time of follow-up reevaluation . Statistical evaluation revealed the best results for PET with regard to early diagnosis of DAT in MCI patients ( sensitivity , 92 % ; specificity , 89 % ) . Classification according to the APOE genotype was significantly less successful ( sensitivity , 75 % ; specificity , 56 % ) . However , a combination of both diagnostic tests allowed early diagnosis with either very high specificity ( PET+ AND e4 + : sensitivity , 67 % ; specificity , 100 % ) or very high sensitivity ( PET+ OR e4 + : sensitivity , 100 % ; specificity , 44 % ) . CONCLUSION (18)F-FDG PET of cerebral glucose metabolism is a valuable diagnostic tool for the prediction of clinical outcome in individual MCI patients . Results are superior to the exclusive assessment of the APOE genotype . A combination of both functional imaging and genotyping may allow an early high-risk or low-risk stratification of patients with either very high sensitivity or very high specificity . This may be valuable , for example , for patient selection in scientific studies BACKGROUND 18F-FDG-PET is defined as a biomarker of neuronal injury according to the revised National Institute on Aging – Alzheimer ’s Association criteria . OBJECTIVE The objective of this multicenter prospect i ve cohort study was to examine the value of 18F-FDG-PET in predicting the development of Alzheimer ’s disease ( AD ) in patients with mild cognitive impairment ( MCI ) . METHODS In total , 114 patients with MCI at 9 participating institutions underwent clinical and neuropsychological examinations , MRI , and 18F-FDG-PET at baseline . The cases were visually classified into predefined dementia patterns by three experts . Anautomated analysis for 18F-FDG-PET was also performed to calculate the PET score . Subjects were followed periodically for 3 years , and progression to dementia was evaluated . RESULTS In 47 % of the patients with MCI , progression of symptoms justified the clinical diagnosis of “ probable AD ” . The PET visual interpretation predicted conversion to AD during 3-year follow-up with an overall diagnostic accuracy of 68 % . Overall diagnostic accuracy of the PET score was better than that of PET visual interpretation at all follow-up intervals , and the optimized PET score threshold revealed the best performance at the 2-year follow-up interval with an overall diagnostic accuracy of 83%,a sensitivity of 70 % , and a specificity of 90 % . Multivariate logistic regression analysis identified the PET score as the most significant predictive factor distinguishing AD converters from non-converters . CONCLUSION The PET score is the most statistically significant predictive factor for conversion from MCI to AD , and the diagnostic performance of the PET score is more promising for rapid converters over 2 years |
13,740 | 28,214,633 | Findings indicated small to moderate effect sizes on reduction of ED risk factors or symptoms which occurred up to three-year post-intervention .
Cognitive behavioural therapy ( CBT ) interventions had the largest effect size ( -0.40 , 95 % CI -0.55 to -0.26 ) on dieting outcome at 9-month follow-up while the healthy weight intervention reduced ED risk factors and body mass index .
No indicated prevention interventions were found to be effective in reducing ED risk factors .
CONCLUSIONS There are a number of promising preventive interventions for ED risk factors including CD , CBT and ML .
Whether these actually lower ED incidence is , however , uncertain . | OBJECTIVE To systematic ally review and quantify the effectiveness of Eating Disorder ( ED ) prevention interventions . | OBJECTIVE Because universal psychoeducational eating disorder prevention programs have had little success , we developed and evaluated two interventions for high-risk population s : a healthy weight control intervention and a dissonance-based intervention . METHOD Adolescent girls ( N = 148 ) with body image concerns were r and omized to one of these interventions or to a waitlist control group . Participants completed baseline , termination , and 1 , 3 , and 6-month follow-up surveys . RESULTS Participants in both interventions reported decreased thin-ideal internalization , negative affect , and bulimic symptoms at termination and follow-up relative to controls . However , no effects were observed for body dissatisfaction or dieting and effects diminished over time . DISCUSSION Results provide evidence that both interventions effectively reduce bulimic pathology and risk factors for eating disturbances This study evaluated a targeted intervention design ed to alleviate body image and eating problems in adolescent girls that was delivered over the internet so as to increase access to the program . The program consisted of six , 90-minute weekly small group , synchronous on-line sessions and was facilitated by a therapist and manual . Participants were 73 girls ( mean age=14.4 years , SD=1.48 ) who self-identified as having body image or eating problems and were r and omly assigned to an intervention group ( n=36 ) ( assessed at baseline , post-intervention and at 2- and 6-months follow-up ) or a delayed treatment control group ( n=37 ) ( assessed at baseline and 6–7 weeks later ) . Clinical ly significant improvements in body dissatisfaction , disordered eating , and depression were observed at post-intervention and maintained at follow-up . Internet delivery was enthusiastically endorsed . The program offers a promising approach to improve body image and eating problems that also addresses geographic access problems Although it is widely accepted that dieting increases the risk for bulimic pathology , this hypothesis has not been tested in a r and omized experiment . Accordingly , the authors conducted an experimental test of the dietary restraint model by r and omly assigning nonobese women ( N = 82 ) to either a 6-week , low-calorie diet or a waitlist control condition . The diet intervention result ed in significant weight loss , confirming that dieting was successfully manipulated . Contrary to the restraint model , dieting result ed in significant decreases in bulimic symptoms relative to the control condition . Results converge with past findings from r and omized obesity prevention and treatment trials and provide evidence that dieting does not promote bulimic pathology ; rather , effective decreases in caloric intake appear to reduce bulimic symptoms Project GRAD ( Graduate Ready for Activity Daily ) was a r and omized controlled study to teach university seniors behavioral skills necessary for increasing and /or maintaining physical activity habits in preparation for the transition to working adult roles after graduation . This study examines the secondary effects of this intervention on body image concerns among college-aged men and women . Three hundred thirty-eight undergraduates ( 54 % female , M age = 24 years , SD = 1.95 ; M Body Mass Index = 24.26 , SD = 4.0 ) were studied . The sample was 61 % Anglo , 16 % Latino , 16 % Asian/Pacific Isl and er , 4 % African American , and 3 % Native American/Other . Body image concerns were assessed at pre- and posttreatment using 2 subscales of the Eating Disorder Inventory : Drive for Thinness and Body Dissatisfaction . Because the latter concentrates on body parts typically associated with female concerns ( e.g. , thighs , hips , buttocks ) , a parallel scale was developed to target body parts that may be of more concern to men ( e.g. , legs , shoulders , arms , stomach ) . Results indicated that compared to the control group , women in the intervention showed a significant increase in drive for thinness without any changes in body dissatisfaction . For men , there were no significant changes in drive for thinness or body dissatisfaction . These results suggest that physical activity interventions may have some negative consequences of increasing concerns about thinness in women . This negative effect occurred despite intervention content design ed to prevent concern over eating , dieting , and the importance of weight . Health promotion studies should include assessment s of potential negative side effects BACKGROUND Body image dissatisfaction during adolescence is common but not benign . School-based interventions have the potential for wide reach , but scalability of previous programmes is limited by a reliance on external facilitators . AIMS To assess the acceptability , feasibility and efficacy of a teacher-delivered body image intervention . METHOD A pilot clustered r and omised controlled trial in which 16 classes of adolescent girls were allocated to a 6-session body image programme ( n = 261 ) , or usual curriculum control ( n = 187 ) ( registration : IS RCT N42594993 ) . RESULTS Students in the intervention group had significantly improved body esteem and self-esteem and reduced thin-ideal internalisation . Effects for body esteem and thin-ideal internalisation were maintained for 3 months . There were no group differences for eating pathology , peer factors or depression . Acceptability , feasibility and efficacy varied between schools . CONCLUSIONS Teacher-delivered body image lessons have promise but further work is needed to increase efficacy and make interventions suitable across a range of schools This study assessed the impact of a school-based program aim ed at preventing disordered eating . The program was based on the media-literacy approach and has interactive format . The program was assessed under strong method ological conditions . Seven schools with 263 Spanish adolescent girls in the area of Barcelona , were r and omly assigned to either the complete prevention program condition , the partial program condition or the non-treatment control condition , and assessed at pre , post and 6-month follow-up . The program was effective in generating positive changes at follow-up . The effects sizes ( ES(d ) = 0.29 to ES(d ) = 0.38 ) were greater , on average , than that obtained up to now in selective-universal programs , and similar or greater than that achieved by targeted prevention programs . The results indicate a greater and relevant effect size of the intervention in those participants who completed the inter-session interactive activities ( ES(d ) = 0.29 to ES(d ) = 0.45 ) although the differences were not significant . These results suggest the importance of monitoring adherence to the activities in all programs defined as " interactive " . The implication s and limitations of this study are discussed OBJECTIVE Although several prospect i ve studies have identified factors that increase risk for eating disorders , little is known about when these risk factors emerge and escalate , or when they begin to predict future eating disorder onset . The objective of this report was to address these key research gaps . METHOD Data were examined from a prospect i ve study of 496 community female adolescents ( M = 13.5 , SD = 0.7 at baseline ) who completed eight annual assessment s of potential risk factors and eating disorders from preadolescence to young adulthood . RESULTS Three variables exhibited positive linear increases : Perceived pressure to be thin , thin-ideal internalization , and body dissatisfaction ; three were best characterized as quadratic effects : dieting ( essentially little change ) ; negative affectivity ( overall decrease ) , and BMI ( overall increase ) . Elevated body dissatisfaction at ages 13 , 14 , 15 , and 16 predicted DSM-5 eating disorders onset in the 4-year period after each assessment , but the predictive effects of other risk factors were largely confined to age 14 ; BMI did not predict eating disorders at any age . DISCUSSION The results imply that these risk factors are present by early adolescence , although eating disorders tend to emerge in late adolescence and early adulthood . These findings emphasize the need for efficacious eating disorder prevention programs for early adolescent girls , perhaps targeting 14-year olds , when risk factors seem to be most predictive . In early adolescence , it might be fruitful to target girls with body dissatisfaction , as this was the most consistent predictor of early eating disorder onset in this study OBJECTIVE To assess the impact of an obesity prevention intervention on use of self-induced vomiting/laxatives ( purging ) and diet pills to control weight in girls in early adolescence . DESIGN We matched and r and omly assigned 10 middle schools to an intervention or a control condition in a r and omized controlled trial . Longitudinal multivariable analyses using generalized estimating equations were conducted with data from 480 girls to examine the effects of the intervention on the risk of reporting a new case of purging or diet pill use to control weight at follow-up 21 months later , while controlling for ethnicity and school matched pairs . Girls who reported purging or using diet pills at baseline were excluded from analyses . SETTING Middle schools . PARTICIPANTS Four hundred eighty girls in early adolescence aged 10 to 14 years ( mean age , 11.5 years ) . INTERVENTION The Planet Health obesity prevention program was implemented during 2 school years and was design ed to promote healthful nutrition and physical activity and to reduce television viewing . OUTCOME Reduced risk of using self-induced vomiting/laxatives or diet pills to control weight in the past 30 days . RESULTS After the intervention , we found 14 ( 6.2 % ) of 226 girls in control schools and 7 ( 2.8 % ) of 254 girls in intervention schools reported purging or using diet pills to control their weight ( P = .003 ) . In a multivariable generalized estimating equation model , girls in intervention schools were less than half as likely to report purging or using diet pills at follow-up compared with girls in control schools ( odds ratio , 0.41 ; 95 % confidence interval , 0.22 - 0.75 ) . CONCLUSION These findings provide promising evidence that school-based interventions may effectively integrate prevention of both obesity and disordered weight-control behaviors This two-group experimental study evaluated the effectiveness of a cognitive-behavioral body image intervention , adapted from an effective clinical intervention , with normal college females . Participants included non clinical , freshman college women who were assigned r and omly to either the experimental intervention or the control group ( brief educational session ) . Participants were assessed prior to the intervention and again 1 month later on dieting behavior , body image , fear of fat , and anxiety concerning physical appearance . Although it was hypothesized that each of these variables would be lower in the experimental group , none of these results , except for a trend for decreased dieting , were found . Overall these results of slightly reduced dieting behavior are consistent with other research targeting primary and secondary prevention . This intervention 's failure to impact body image and eating behaviors of college students illustrates the continuing challenge of eating disorders prevention CONTEXT Eating disorders , an important health problem among college-age women , may be preventable , given that modifiable risk factors for eating disorders have been identified and interventions have been evaluated to reduce these risk factors . OBJECTIVE To determine if an Internet-based psychosocial intervention can prevent the onset of eating disorders ( EDs ) in young women at risk for developing EDs . SETTING San Diego and the San Francisco Bay Area in California . PARTICIPANTS College-age women with high weight and shape concerns were recruited via campus e-mails , posters , and mass media . Six hundred thirty-seven eligible participants were identified , of whom 157 were excluded , for a total sample of 480 . Recruitment occurred between November 13 , 2000 , and October 10 , 2003 . Intervention A r and omized controlled trial of an 8-week , Internet-based cognitive-behavioral intervention ( Student Bodies ) that included a moderated online discussion group . Participants were studied for up to 3 years . MAIN OUTCOME MEASURES The main outcome measure was time to onset of a sub clinical or clinical ED . Secondary measures included change in scores on the Weight Concerns Scale , Global Eating Disorder Examination Question naire , and Eating Disorder Inventory drive for thinness and bulimia subscales and depressed mood . Moderators of outcome were examined . RESULTS There was a significant reduction in Weight Concerns Scale scores in the Student Bodies intervention group compared with the control group at postintervention ( P < .001 ) , 1 year ( P < .001 ) , and 2 years ( P < .001 ) . The slope for reducing Weight Concerns Scale score was significantly greater in the treatment compared with the control group ( P = .02 ) . Over the course of follow-up , 43 participants developed sub clinical or clinical EDs . While there was no overall significant difference in onset of EDs between the intervention and control groups , the intervention significantly reduced the onset of EDs in 2 subgroups identified through moderator analyses : ( 1 ) participants with an elevated body mass index ( BMI ) ( > or = 25 , calculated as weight in kilograms divided by height in meters squared ) at baseline and ( 2 ) at 1 site , participants with baseline compensatory behaviors ( eg , self-induced vomiting , laxative use , diuretic use , diet pill use , driven exercise ) . No intervention participant with an elevated baseline BMI developed an ED , while the rates of onset of ED in the comparable BMI control group ( based on survival analysis ) were 4.7 % at 1 year and 11.9 % at 2 years . In the subgroup with a BMI of 25 or higher , the cumulative survival incidence was significantly lower at 2 years for the intervention compared with the control group ( 95 % confidence interval , 0 % for intervention group ; 2.7 % to 21.1 % for control group ) . For the San Francisco Bay Area site sample with baseline compensatory behaviors , 4 % of participants in the intervention group developed EDs at 1 year and 14.4 % , by 2 years . Rates for the comparable control group were 16 % and 30.4 % , respectively . CONCLUSIONS Among college-age women with high weight and shape concerns , an 8-week , Internet-based cognitive-behavioral intervention can significantly reduce weight and shape concerns for up to 2 years and decrease risk for the onset of EDs , at least in some high-risk groups . To our knowledge , this is the first study to show that EDs can be prevented in high-risk groups Body-image dissatisfaction is a problem that affects a substantial minority ofwomen and cuts across various diagnostic groups . College women with a significant level ofbody-image dissatisfaction were r and omly assigned to either a cognitive-behavioral treatment ( CBT ) program ( n = 15 ) or to a waiting-list control group ( n = 16 ) . The CBT program consisted of six structured , individual sessions that applied cognitive-behavioral procedures to the problem of negative body image . At pretest , posttest , and 7-week foUow-up , multiple aspects of body image and other areas of psychosocial functioning were assessed . Relative to the control condition , the CBT program successfully improved affective body image , weakened maladaptive body-image cognitions , and enhanced social self-esteem and feelings about physical fitness and sexuality . Treatment effects were largely maintained at followup . After posttest , the control group received a 3-week treatment with immediate effects that generally replicated those obtained in the 6-wer program BACKGROUND A r and omized controlled trial of three school-based programs and a no-intervention control group was conducted to evaluate their efficacy in reducing eating disorder and obesity risk factors . METHOD A total of 1316 grade 7 and 8 girls and boys ( mean age = 13.21 years ) across three Australian states were r and omly allocated to : Media Smart ; Life Smart ; the Helping , Encouraging , Listening and Protecting Peers ( HELPP ) initiative ; or control ( usual school class ) . Risk factors were measured at baseline , post-program ( 5 weeks later ) , and at the 6- and 12-month follow-ups . RESULTS Media Smart girls had half the rate of onset of clinical ly significant concerns about shape and weight than control girls at the 12-month follow-up . Media Smart and HELPP girls reported significantly lower weight and shape concern than Life Smart girls at the 12-month follow-up . Media Smart and control girls scored significantly lower than HELPP girls on eating concerns and perceived pressure at the 6-month follow-up . Media Smart and HELPP boys experienced significant benefit on media internalization compared with control boys and these were sustained at the 12-month follow-up in Media Smart boys . A group × time effect found that Media Smart participants reported more physical activity than control and HELPP participants at the 6-month follow-up , while a main effect for group found Media Smart participants reported less screen time than controls . CONCLUSIONS Media Smart was the only program to show benefit on both disordered eating and obesity risk factors . Whilst further investigations are indicated , this study suggests that this program is a promising approach to reducing risk factors for both problems PURPOSE To examine the effect of a 1-yr school-based intervention program to prevent the development of new cases of eating disorders ( ED ) and symptoms associated with ED among adolescent female and male elite athletes . METHODS All 16 Norwegian Elite Sport High Schools were included ( intervention group [ n = 9 ] and control group [ n = 7 ] ) . In total , 465 ( 93.8 % ) first-year student athletes were followed during high school ( 2008 - 2011 , three school years ) . The athletes completed the Eating Disorder Inventory 2 and questions related to ED before ( pretest ) , immediately after ( posttest 1 ) , and 9 months after the intervention ( posttest 2 ) . Clinical interviews ( Eating Disorder Examination ) were conducted after the pretest ( all with symptoms [ n = 115 , 97 % ] and a r and om sample without symptoms [ n = 116 , 97 % ] ) , and at posttest 2 , all athletes were interviewed ( n = 463 , 99.6 % ) . RESULTS Among females , there were no new cases of ED in the intervention schools , while 13 % at the control schools had developed and fulfilled the DSM-IV criteria for ED not otherwise specified ( n = 7 ) or bulimia nervosa ( n = 1 ) , P = 0.001 . The risk of reporting symptoms was lower in the intervention than in the control schools at posttest 1 ( odds ratio [ OR ] = 0.45 , 95 % confidence interval [ CI ] = 0.23 - 0.89 ) . This effect was attenuated by posttest 2 ( OR = 0.57 , 95 % CI = 0.29 - 1.09 ) . The intervention showed a relative risk reduction for current dieting ( OR = 0.10 , 95 % CI = 0.02 - 0.54 ) and three or more weight loss attempts ( OR = 0.47 , 95 % CI = 0.25 - 0.90 ) . Among males , there was one new case of ED at posttest 2 ( control school ) and no difference in the risk of reporting symptoms between groups at posttest 1 or 2 . CONCLUSION A 1-yr intervention program can prevent new cases of ED and symptoms associated with ED in adolescent female elite athletes OBJECTIVE This study compared the efficacy of a media literacy program and a self-esteem program design ed to reduce general and specific risk factors for eating disorders . METHOD Four classes of 86 grade 8 students ( 53 boys and 33 girls ) , mean age of 13 years , were r and omly assigned to either a control condition or one of the two intervention conditions . Assessment of general and specific risk factors was carried out at baseline , postintervention and 3-month follow-up . RESULTS At postintervention the media literacy group had lower mean scores on weight concern than the control group ( p = 0.007 ) but the self-esteem group did not . There were some differences on self-esteem measures at the 3-month follow-up . DISCUSSION Media literacy programs combined with an interactive , student-centered framework may potentially be a safe and effective way of reducing risk factors for eating disorders . The impact of teaching style needs to be further evaluated in prevention research OBJECTIVE Given the overlap among depressive symptoms , disordered eating , and overweight , identifying shared risk factors for these conditions may inform public health interventions . This study aim ed to examine cross-sectional and prospect i ve relationships among these 3 conditions , and identify potential shared eating-related and psychosocial variable risk factors ( i.e. , body dissatisfaction , dieting , teasing experiences ) . METHOD A population -based sample ( n = 1,902 ) self-reported depressive symptoms , disordered eating ( binge eating , extreme weight control behaviors ) , weight status , and several putative risk factors ( body satisfaction , dieting frequency , weight-related teasing ) at 5-year intervals spanning early/middle adolescence , middle adolescence/early young adulthood , and early/middle young adulthood . RESULTS There was moderate overlap among depressive symptoms , disordered eating , and overweight at each time point , and moderate stability in each condition over time . Body dissatisfaction and dieting were the most potent shared risk factors for later depressive symptoms , disordered eating , and overweight among males and females ( ps < .05 ) . CONCLUSIONS Depressive symptoms , disordered eating , and overweight share several risk factors , including dieting and body dissatisfaction , which may be effective targets for interventions aim ing to simultaneously prevent these 3 conditions BACKGROUND Women reporting initial eating disorder ( ED ) symptoms are at highest risk for the development of an eating disorder . Preventive interventions should , therefore , be specifically tailored for this subgroup . AIMS To adapt and evaluate the effects of the Internet-based prevention program " Student Bodies ™ " for women with symptoms of disordered eating and /or subthreshold eating disorder ( ED ) syndromes . METHOD 126 women , reporting subthreshold ED symptoms ( high weight and shape concerns and below threshold bingeing , purging , chronic dieting or several of these symptoms ) were r and omly assigned to a Student Bodies ™ + ( SB+ ) intervention or a wait-list control group and assessed at pre-intervention , post-intervention , and 6-month follow-up . " Student Bodies ™ " was adapted to be suitable for subthreshold EDs . Main outcome measures were attitudes and symptoms of disordered eating . Pre-follow-up data were analyzed by ANCOVAS with mixed effects . RESULTS At 6-month follow-up , compared to participants in the control group , participants in the intervention group showed significantly greater improvements on ED-related attitudes . Intervention participants also showed 67 % ( 95 % CI = 20 - 87 % ) greater reductions in combined rates of subjective and objective binges , and 86 % ( 95 % CI = 63 - 95 % ) greater reduction in purging episodes . Also , the rates of participants abstinent from all symptoms of disordered eating ( restrictive eating , binge eating and any compensatory behavior ) were significantly higher in the intervention group ( 45.1 % vs. 26.9 % ) . Post-hoc subgroup analyses revealed that for participants with binge eating the effect on EDE-Q scores was larger than in the pure restricting subgroup . CONCLUSION The adapted " SB+ " program represents an effective intervention for women with subthreshold EDs of the binge eating subtype Adolescent girls with body dissatisfaction ( N = 481 , SD = 1.4 ) were r and omized to a dissonance-based thin-ideal internalization reduction program , healthy weight control program , expressive writing control condition , or assessment -only control condition . Dissonance participants showed significantly greater decreases in thin-ideal internalization , body dissatisfaction , negative affect , eating disorder symptoms , and psychosocial impairment and lower risk for eating pathology onset through 2- to 3-year follow-up than did assessment -only controls . Dissonance participants showed greater decreases in thin-ideal internalization , body dissatisfaction , and psychosocial impairment than did expressive writing controls . Healthy weight participants showed greater decreases in thin-ideal internalization , body dissatisfaction , negative affect , eating disorder symptoms , and psychosocial impairment ; less increases in weight ; and lower risk for eating pathology and obesity onset through 2- to 3-year follow-up than did assessment -only controls . Healthy weight participants showed greater decreases in thin-ideal internalization and weight than did expressive writing controls . Dissonance participants showed a 60 % reduction in risk for eating pathology onset , and healthy weight participants showed a 61 % reduction in risk for eating pathology onset and a 55 % reduction in risk for obesity onset relative to assessment -only controls through 3-year follow-up , implying that the effects are clinical ly important and enduring OBJECTIVE Efficacy trials found that a dissonance-based eating disorder prevention program in which female high school and college students with body image concerns critique the thin ideal reduced eating disorder risk factors , eating disorder symptoms , and future eating disorder onset . The present effectiveness trial tested whether this program produces effects through long-term follow-up when high school clinicians recruit students and deliver the intervention under real-world conditions . METHOD Female high school students with body image concerns ( N = 306 ; M age = 15.7 years , SD = 1.1 ) were r and omized to the dissonance intervention or an educational brochure control condition and completed assessment s through 3-year follow-up . RESULTS Dissonance participants showed significantly greater decreases in body dissatisfaction at 2-year follow-up and eating disorder symptoms at 3-year follow-up than controls ; effects on other risk factors , risk for eating disorder onset , and other outcomes ( e.g. , body mass ) were marginal or nonsignificant . CONCLUSIONS Although it was encouraging that some key effects persisted over long-term follow-up , effects were on average smaller in this effectiveness trial than previous efficacy trials , which could be due to ( a ) facilitator selection , training , and supervision ; ( b ) the lower risk status of participants ; or ( c ) the use of a control condition that produces some effects OBJECTIVE Although several eating disorder prevention programs reduce eating disorder risk factors and symptoms for female high school and college students , few efficacious prevention programs exist for female middle school students , despite the fact that body image and eating disturbances often emerge then . Two pilot trials evaluated a new dissonance-based eating disorder prevention program for middle school girls with body image concerns . METHOD Female middle school students with body dissatisfaction from two sites [ Study 1 : N = 81 , M age = 12.1 , st and ard deviation ( SD ) = 0.9 ; Study 2 : N = 52 , M age = 12.5 , SD = 0.8 ] were r and omized to a dissonance intervention ( MS Body Project ) or educational brochure control ; Study 2 included a 3-month follow-up . RESULTS Intervention participants showed significant post-test reductions in only one of the six variables with both Studies 1 and 2 ( i.e. , pressure to be thin and negative affect , respectively ) , though post-test effect sizes suggested medium reductions in eating disorder risk factors and symptoms ( Study 1 : M d = .40 ; Study 2 : M d = .65 ) ; reductions at 3-month follow-up in Study 2 were not evident ( M d = .19 ) . CONCLUSIONS Results suggest that this new middle school version of the Body Project is producing medium magnitude reductions in eating disorder risk factors at post-test but that effects are showing limited persistence . Continued refinement and evaluation of this intervention appears warranted to develop more effective prevention programs for this age group Because no single report has examined risk factors that predict future onset each type of eating disorder and core symptom dimensions that crosscut disorders , we addressed these aims to advance knowledge regarding risk factor specificity . Data from 3 prevention trials that targeted young women with body dissatisfaction ( N = 1,272 ; Mage = 18.5 , SD = 4.2 ) and collected annual diagnostic interview data over 3-year follow-up were combined to identify predictors of subthreshold/threshold anorexia nervosa ( AN ) , bulimia nervosa ( BN ) , binge eating disorder ( BED ) , and purging disorder ( PD ) . Negative affect and functional impairment predicted onset of all eating disorders . Thin-ideal internalization , body dissatisfaction , dieting , overeating , and mental health care predicted onset of subthreshold/threshold BN , BED , and PD ; positive thinness expectations , denial of cost of pursuing the thin ideal , and fasting predicted onset of 2 of these 3 disorders . Similar risk factors predicted core eating disorder symptom onset . Low BMI and dieting specifically predicted onset of subthreshold/threshold AN or low BMI . Only a subset of factors showed unique predictive effects in multivariate models , likely due to moderate correlations between the risk factors ( M r = .14 ) . Results provide support for the theory that pursuit of the thin ideal and the result ing body dissatisfaction , dieting , and unhealthy weight control behaviors increase risk for binge/purge spectrum eating disorders , but suggest that youth who are inherently lean , rather than purpose ly pursuing the thin ideal , are at risk for AN . Impaired interpersonal functioning and negative affect are transdiagnostic risk factors , suggesting these factors should be targeted in prevention programs The aim of this study was to replicate and extend results of a previous trial that investigated the effectiveness of 2 peer-led eating disorders prevention interventions in reducing eating disorder risk factors in undergraduate women ( C. B. Becker , L. M. Smith , & A. C. Ciao , 2006 ) . To extend findings from the previous study by allowing for investigation of differential response , the authors r and omly assigned a larger sample of both higher and lower risk sorority members ( N = 188 ; age M = 18.64 years , range = 18 - 21 ; 20 % minority ) to either a cognitive dissonance ( CD ) or a media advocacy ( MA ) intervention under naturalistic conditions . Interventions were delivered by trained sorority peer leaders and consisted of two 2-hr group sessions . Participants completed question naires that assessed eating disorder risk factors at pretreatment , posttreatment , 7-week follow-up , and 8-month follow-up . Results indicate that both interventions reduced thin-ideal internalization , body dissatisfaction , dietary restraint , and bulimic pathology at 8 months , although higher and lower risk participants responded somewhat differently . Both CD and MA generally appeared effective for higher risk participants ; only CD , however , appeared to benefit lower risk participants . Results further support the viability of using peer leaders in dissonance-based prevention OBJECTIVE The present preliminary trials tested whether undergraduate peer leaders can effectively deliver a dissonance-based eating disorder prevention program , which could facilitate broad dissemination of this efficacious intervention . METHOD In Study 1 , female undergraduates ( N=171 ) were r and omized to peer-led groups , clinician-led groups , or an educational brochure control condition . In Study 2 , which improved a design limitation of Study 1 by using completely parallel outcome measures across conditions , female undergraduates ( N=148 ) were r and omized to either immediate peer-led groups or a waitlist control condition . RESULTS In Study 1 , participants in peer- and clinician-led groups showed significantly greater pre-post reductions in risk factors and eating disorder symptoms than controls ( M d=.64 and .98 respectively ) , though clinician- versus peer-led groups had higher attendance and competence ratings , and produced stronger effects at posttest ( M d=.32 ) and at 1-year follow-up ( M d=.26 ) . In Study 2 , participants in peer-led groups showed greater pre-post reductions in all outcomes than waitlist controls ( M d=.75 ) . CONCLUSIONS Results provide novel evidence that dissonance-based eating disorder prevention groups led by undergraduate peers are feasible and produce greater reductions in eating disorder risk factors and symptoms than minimal-intervention control conditions , but indicate that effects are smaller for peer- versus clinician-led groups In this trial , adolescent girls with body dissatisfaction ( N = 481 , M age = 17 years ) were r and omized to an eating disorder prevention program involving dissonance-inducing activities that reduce thin-ideal internalization , a prevention program promoting healthy weight management , an expressive writing control condition , or an assessment -only control condition . Dissonance participants showed significantly greater reductions in eating disorder risk factors and bulimic symptoms than healthy weight , expressive writing , and assessment -only participants , and healthy weight participants showed significantly greater reductions in risk factors and symptoms than expressive writing and assessment -only participants from pretest to posttest . Although these effects faded over 6-month and 12-month follow-ups , dissonance and healthy weight participants showed significantly lower binge eating and obesity onset and reduced service utilization through 12-month follow-up , suggesting that both interventions have public health potential OBJECTIVE Evaluate a selective prevention program targeting both eating disorder symptoms and unhealthy weight gain in young women . METHOD Female college students at high-risk for these outcomes by virtue of body image concerns ( N = 398 ; M age = 18.4 years , SD = 0.6 ) were r and omized to the Healthy Weight group-based 4-hr prevention program , which promotes gradual lasting healthy improvements to dietary intake and physical activity , or an educational brochure control condition . RESULTS Compared to controls , intervention participants showed significantly greater reductions in body dissatisfaction and eating disorder symptoms , and greater increases in physical activity , at posttest and significantly greater reductions in body mass index ( BMI ) and self-reported dieting at 6-month follow-up . Moderator analyses revealed significantly greater reductions in eating disorder symptoms for those with initially elevated symptoms and pressure to be thin and significantly greater reductions in BMI for those with initially elevated eating disorder symptoms . CONCLUSIONS Results indicate that this intervention reduced both eating disorder symptoms and unhealthy weight gain , but suggest it should be improved to produce stronger and more persistent effects , and that it may be useful to target young women with both body image and eating disturbances OBJECTIVE To evaluate a community-based intervention aim ed at the primary prevention of disordered eating among preadolescent girls . DESIGN Girl Scout troop members were r and omized into control and intervention groups . Program feasibility and effect at postintervention and 3-month follow-up were evaluated . SUBJECTS/ SETTING 226 girls ( mean age = 10.6 years , st and ard deviation = 0.7 ) from 24 Girl Scout troops . INTERVENTION Six 90-minute sessions focusing on media literacy and advocacy skills . MAIN OUTCOME MEASURES Evaluation focused on program satisfaction and short-term effect on dieting behaviors , body image attitudes , and media knowledge , attitudes , and habits . STATISTICAL ANALYSES Performed t tests , chi 2 tests , and analyses of covariance including troop as a r and om source of variation . RESULTS At baseline , 29 % of the girls were trying to lose weight . The program had a notable positive influence on media-related attitudes and behaviors including internalization of sociocultural ideals , self-efficacy to impact weight-related social norms , and print media habits . A modest program effect on body-related knowledge and attitudes was apparent at post-intervention ( i.e. , on body size acceptance , puberty knowledge , and perceived weight status ) but not at follow-up . Significant changes were not noted for dieting behaviors , but they were in the hypothesized direction . Satisfaction with the program was high among girls , parents , and leaders . APPLICATIONS/ CONCLUSIONS It is feasible to use community youth setting s , such as the Girl Scouts , to implement interventions to prevent disordered eating behaviors . The program led to positive trends in outcome variables ; however , longer and more intensive interventions are needed for lasting changes in body image and dieting behaviors OBJECTIVE Evaluate the effects of a prevention program targeting both eating disorders and obesity at 1- and 2-year follow-ups . METHOD Female college students at risk for these outcomes because of body image concerns ( N = 398 ) were r and omized to the Healthy Weight 2 group-based 4-hr prevention program , which promotes lasting healthy improvements to dietary intake and physical activity and nutrition science health behavior change principles , or an educational brochure control condition . RESULTS Intervention participants showed significantly less body dissatisfaction and eating disorder symptoms and lower eating disorder onset through 2-year follow-up versus controls , but the former 2 effects were small . There were no main effects for body mass index ( BMI ) , depressive symptoms , dieting , caloric intake , physical activity , or obesity onset . Moderator analyses revealed stronger eating disorder symptom effects for youths with initially elevated symptoms and lower pressure to be thin , stronger BMI effects for youths with initially elevated symptoms and BMI scores , and weaker eating disorder symptom effects for youths with initially elevated pressure to be thin . CONCLUSIONS The 60 % reduction in eating disorder onset over the 2-year follow-up was clinical ly significant and a novel effect for a prevention program , but the main effects on continuous outcomes were small , suggesting that adding nutrition science principles weakened the intervention efficacy . Effects on both eating disorder symptoms and BMI were greater for those with elevated eating disorder symptoms and BMI at pretest , implying that it might be useful to target these individuals in future trials OBJECTIVE Excessive weight or shape concerns and dieting are among the most important and well-established risk factors for the development of symptoms of disordered eating or full-syndrome eating disorders . Prevention programs should therefore target these factors in order to reduce the likelihood of developing an eating disorder . The aims of this study were to determine the short-term and maintenance effects of an internet-based prevention program for eating disorders . METHOD One hundred female students at two German universities were r and omly assigned to either an 8-week intervention or a waiting-list control condition and assessed at preintervention , postintervention , and 3-month follow-up . RESULTS Compared with the control group , the intervention produced significant and sustained effects for high-risk women . CONCLUSION Internet-based prevention is effective and can be successfully adapted to a different culture OBJECTIVE To determine the effect of a school-based intervention to promote healthful nutrition and physical activity on disordered weight-control behaviors ( self-induced vomiting or use of laxatives or diet pills to control weight ) in early adolescent girls and boys . DESIGN Using a group-r and omized , controlled-trial design , we r and omly assigned middle schools to an intervention or control condition . Multivariate logistic regression analyses were used to assess the effect of the intervention on the odds of reporting a new case of disordered weight-control behaviors at follow-up , adjusting for sex , school-level prevalence of disordered weight-control behaviors at baseline , and school clusters . Students reporting these behaviors at baseline were excluded from the analyses . SETTING Thirteen middle schools . PARTICIPANTS At baseline , 749 girls and 702 boys in grade s 6 and 7 . Intervention The 5 - 2 - 1 Go ! intervention ( Planet Health obesity prevention curriculum plus School Health Index for Physical Activity and Healthy Eating : A Self- Assessment and Planning Guide , Middle/High School Version ) was implemented during 2 school years , from November 2002 through May 2004 . Main Outcome Measure Self-reported disordered weight-control behaviors in last 30 days at follow-up . RESULTS At follow-up in girls , 3.6 % ( 15 of 422 ) in control schools compared with 1.2 % ( 4 of 327 ) in intervention schools reported engaging in disordered weight-control behaviors ( P = .04 ) . Multivariate analyses indicated that the odds of these behaviors in girls in intervention schools were reduced by two thirds compared with girls in control schools ( odds ratio , 0.33 ; 95 % confidence interval , 0.11 - 0.97 ) . No intervention effect was observed in boys . CONCLUSIONS Results add compelling support for the effectiveness of an interdisciplinary , school-based obesity prevention intervention to prevent disordered weight-control behaviors in early adolescent girls Subsequent to an epidemiological study on eating behaviour in adolescents , a prospect i ve study was carried out to examine the effect of health promotion lessons on disturbed eating behaviour . From the original sample ( t1 , n=1944 ) , a subgroup of 314 students of both sexes , 14–19 years of age , was selected . Participants came from a total of 20 classes in which a high percentage of students exhibited disturbed eating behaviour . Ten classes were then r and omly selected to receive health promotion lessons ( intervention group , high‐risk ; IGHR ) , while the other 10 classes served as controls ( control group , high‐risk ; CGHR ) . The Eating Attitudes Test ( EAT‐26 ) , the Giessen Physical Complaint List for Children and Adolescents ( GSCL‐C ) and the Self‐Report Symptom Check‐List ( SCL‐90‐R ) were administered shortly before ( t2 ) and 3 months after ( t3 ) the interventions . The three health promotion lessons dealt with issues concerning beauty ideals , gender differences in psychosexual maturation and body awareness , healthy eating behaviour , physiology of nutrition , early symptoms of eating disorders and therapeutic approaches . The data analyses revealed an improvement on all three symptom scales for both groups between t2 and t3 , but there were no significant differences between the IGHR and CGHR groups . When data from high‐scoring female participants only were analysed ( HRf‐IGHR and HRf‐CGHR ) , the multivariate analysis revealed a significant interaction between time and group ( 15.2 % of variance explained ) . Our experiences in implementing health promotion lessons that conveyed knowledge about eating disorders and addressed physical and psychological issues in a more general way indicated that these interventions can be carried out in schools , and may contribute to increases in physical and psychological well‐being in a high‐risk population of adolescents OBJECTIVE An efficacy trial found that a dissonance-based prevention program reduced risk factors , eating disorder symptoms , and future eating disorder onset , but smaller effects emerged when high school clinicians recruited students and delivered the program under real-world conditions in an effectiveness trial . The current report describes results at 2- and 3-year follow-up from an effectiveness trial that tested whether a new enhanced dissonance version of this program produced larger effects when college clinicians recruit students and deliver the intervention using improved train and supervision procedures . METHOD Young women from eight universities ( N = 408 , M age = 21.6 , SD = 5.64 ) were r and omized to the prevention program or an educational brochure control condition . RESULTS Dissonance participants showed greater decreases in risk factors , eating disorder symptoms , and psychosocial impairment by 3-year follow-up than controls , but not healthcare utilization , BMI , or eating disorder onset . CONCLUSIONS This novel multisite effectiveness trial found that the enhanced dissonance intervention and improved training and supervision procedures produced an average effect size at 3-year follow-up that was 290 % and 160 % larger than effects observed in the high school effectiveness trial and efficacy trial respectively . Yet , the lack of eating disorder onset effects may imply that factors beyond pursuit of the thin ideal now contribute to eating disorder onset Food , Mood , and Attitude ( FMA ) is a CD-ROM prevention program developed to decrease risk for eating disorders in college women . Female 1st-year students ( N = 240 ) were r and omly assigned to the intervention ( FMA ) or control group . Equal numbers of students at risk and of low risk for developing an eating disorder were assigned to each condition . Participants in the FMA condition improved on all measures relative to controls . Significant 3-way interactions ( Time x Condition x Risk Status ) were found on measures of internalization of sociocultural attitudes about thinness , shape concerns , and weight concerns , indicating that at-risk participants in the intervention group improved to a greater extent than did low-risk participants . At follow-up , significantly fewer women in the FMA group reported overeating and excessive exercise relative to controls OBJECTIVE This study evaluated an eating disorder intervention multimedia program modeled after self-help eating disorder treatment programs . It was hypothesized that women who completed the program would increase their body satisfaction and decrease their preoccupation with weight and frequency of disordered eating behaviors . METHOD Participants were 57 undergraduate females r and omly assigned to either the intervention or control group . Psychological functioning was assessed at baseline , at 3 months postintervention , and at 3 months follow-up . RESULTS Intervention group subjects significantly improved their scores on all psychological measures over time . When compared to the control group , however , only the intervention group 's improvements on the Body Shape Question naire were statistically significant . DISCUSSION This study has demonstrated that minimally effective eating disorder intervention programs can be delivered . A revised program that eliminates interface problems and increases the structure of the intervention is likely to be even better received and more effective The purpose of this experiment was to provide an empirical comparison of two dissonance-based eating disorder prevention paradigms and a no-treatment control condition . Asymptomatic and symptomatic participants ( N = 155 ) were r and omly assigned to one of three experimental conditions : high level dissonance , low level dissonance , or no-treatment control . Group × symptomatic status interactions , main effects , and pairwise comparisons were examined to assess differences in eating disorder attitudes and behaviors at postintervention and 4-week follow-up . Participants in the high level condition displayed fewer eating disorder attitudes and behaviors compared to participants in the low level condition at postintervention . Eating disorder attitudes and behaviors were not significantly lower among participants in either intervention condition compared to no-treatment control participants Because depressive and bulimic pathologies often co-occur among adolescent girls , a preventive program focusing on both disturbances would have clinical utility . Thus , we developed a cognitive-behavioral intervention targeting body dissatisfaction , an established risk factor for both conditions . A r and omized prevention trial with late adolescent girls suggested that the intervention reduced body dissatisfaction , negative affect , depressive symptoms , and bulimic symptoms , but not dieting . Effects persisted through 3-month follow-up , but most faded by 6-month follow-up . Intervention effects on negative affect , depressive symptoms , and bulimic symptoms appeared to be mediated by change in body dissatisfaction . Participant age , ethnicity , and body mass did not moderate intervention effects . Results suggest that an intervention that improves body satisfaction might reduce depressive and bulimic symptoms but imply that greater emphasis on preventing future symptoms might be necessary for persistent effects Computer-based delivery of health-related psychoeducational programming is increasingly popular . In the present study , 72 non-symptomatic undergraduate women were r and omized to an Internet-based prevention program for eating disorders with or without accompanying discussion groups , or a control group . Sixty-one of the women ( 84 % ) completed the Student Bodies program , and were assessed at short and eight – nine month follow-up . Participation in the program result ed in better outcomes across all groups compared to controls , and women in the unmoderated discussion group appeared to have the most reduction in risk . Benefits of the program continued at follow-up . Decrease in risk also was associated with time spent using the Internet-based program . The present study suggests that the use of Student Bodies may reduce risk of eating and body image concerns over the long term , and that moderation of discussion groups may not be essential for successful outcomes . Further research on larger sample s will help determine the degree to which discussion groups or the Student Bodies program alone are effective OBJECTIVE The aim of this study was to compare the outcomes following an eight-session , small group , therapist-led , intervention for body dissatisfaction , and disordered eating in adult women , delivered either in face-to-face or synchronous , internet mode . METHOD Community women with high body dissatisfaction and internet access were r and omly assigned to either face-to-face delivery ( N = 42 ) , internet delivery ( N = 37 ) , or delayed treatment control ( N = 37 ) . All groups were assessed at baseline and 8 - 9 weeks later . The intervention groups were reassessed at 6-months follow-up . RESULTS Both intervention groups showed large improvements in body dissatisfaction compared with the delayed treatment control and these improvements were maintained at follow-up . However , posttreatment improvements were greater in the face-to-face than internet intervention . CONCLUSION In adult women , it is desirable to deliver the body image intervention in a face-to-face mode , but the internet mode is effective and has the potential to increase access to therapy BACKGROUND Weight-related problems are prevalent in adolescent girls . PURPOSE To evaluate New Moves , a school-based program aim ed at preventing weight-related problems in adolescent girls . DESIGN School-based group-r and omized controlled design . SETTING / PARTICIPANTS 356 girls ( mean age=15.8±1.2 years ) from six intervention and six control high schools . More than 75 % of the girls were racial/ethnic minorities and 46 % were overweight or obese . Data were collected in 2007 - 2009 and analyzed in 2009 - 2010 . INTERVENTION An all-girls physical education class , supplemented with nutrition and self-empowerment components , individual sessions using motivational interviewing , lunch meetings , and parent outreach . MAIN OUTCOME MEASURES Percentage body fat , BMI , physical activity , sedentary activity , dietary intake , eating patterns , unhealthy weight control behaviors , and body/self-image . RESULTS New Moves did not lead to significant changes in the girls ' percentage body fat or BMI but improvements were seen for sedentary activity , eating patterns , unhealthy weight control behaviors , and body/self-image . For example , in comparison to control girls , at 9-month follow-up , intervention girls decreased their sedentary behaviors by approximately one 30-minute block a day ( p=0.050 ) ; girls increased their portion control behaviors ( p=0.014 ) ; the percentage of girls using unhealthy weight control behaviors decreased by 13.7 % ( p=0.021 ) ; and improvements were seen in body image ( p=0.045 ) and self-worth ( p=0.031 ) . Additionally , intervention girls reported more support by friends , teachers , and families for healthy eating and physical activity . CONCLUSIONS New Moves provides a model for addressing the broad spectrum of weight-related problems among adolescent girls . Further work is needed to enhance the effectiveness of interventions to improve weight status of youth |
13,741 | 16,388,044 | It is not clear why telephone consultations are briefer , i.e. if it is due to loss of physical examination time , discussion of fewer problems , less health promotion , less social speech or if it is achieved at the expense of patient-centredness or holistic care .
In a recent pilot study of out-of-hours telephone consultations ( Heaney D , personal communication 2005 ) clinical quality , while difficult to measure reliably , appeared worryingly poor .
While most patients have access to telephones , the most disadvantaged may only have access to expensive mobile devices .
In addition , some minority groups such as those who are hard of hearing ( 43 % of those over 70 years11 ) and those who do not use English as a first language may be disadvantaged by systems that insist on the telephone being the first point of contact .
Currently , telephone consulting appears to be rather indiscriminately used for many very different problems , presentations and patient groups despite scant information on quality of care , patient acceptability and impact on workload .
Particularly as this form of consultation appears to be increasingly used and in new ways it is important to establish for which types of consultation and problems and for which patients it is most appropriate . | Improving access to healthcare is a major priority for both patients and the UK National Health Service (NHS).1 Increasingly and internationally , many traditional services once transacted face to face ( e.g. banking and shopping ) are transacted by telephone and electronically .
Starting in the USA this trend has been mirrored in healthcare where in many countries the telephone has now often become the first point of contact .
There is a dearth of studies exploring the content of telephone consultations in relation to face-to-face consulting and measures of quality have largely been restricted to patient satisfaction outcomes either by question naire or qualitative interviews that are insensitive to clinical quality issues . | The introduction , more than half a century ago , of properly r and omised trials in which the treatment allocation was rigorously concealed was a watershed in the evaluation of treatment effects.1 But this major advance did not come out of the blue : as was highlighted at a recent conference in Oxford ( Beating biases in therapeutic research : historical perspectives , www.wuhmo.ox.ac.uk/docs/BeatingBiases.html ) , attempts to combat bias in therapeutic evaluation had in fact been made during the preceding few centuries.2–4 In the 18th century , the traditional practice of cl aim ing therapeutic achievement on the basis of pathophysiological theories and anecdotal “ successes ” started to be challenged by medical non-conformists who wrote careful , prospect i ve , analytical accounts of medical treatments , some of which included comparison with a control group.4 These “ arithmetic observationists and experimentalists”4 recognised the need 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 BACKGROUND Only about a third of people with asthma attend an annual review . Clinicians need to identify cost-effective ways to improve access and ensure regular review . AIM To compare the cost-effectiveness of nurse-led telephone with face-to-face asthma review s. DESIGN OF STUDY Cost-effectiveness analysis based on a 3-month r and omised controlled trial . SETTING Four general practice s in Engl and . METHOD Adults due an asthma review were r and omised to telephone or face-to-face consultations . Trial nurses recorded proportion review ed , duration of consultation , and abortive calls/missed appointments . Data on use of healthcare re sources were extracted from GP records . Cost-effectiveness was assessed from the health service perspective ; sensitivity analyses were based on proportion review ed and duration of consultation . RESULTS A total of 278 people with asthma were r and omised to surgery ( n = 141 ) or telephone ( n = 137 ) review . Onehundred- and -one ( 74 % ) of those with asthma in the telephone group were review ed versus 68 ( 48 % ) in the surgery group ( P < 0.001 ) . Telephone consultations were significantly shorter ( mean duration telephone = 11.19 minutes [ st and ard deviation { SD } = 4.79 ] versus surgery = 21.87 minutes [ SD = 6.85 ] , P < 0.001 ) . Total respiratory healthcare costs per patient over 3 months were similar ( telephone = pounds sterling 64.49 [ SD = 73.33 ] versus surgery = pounds sterling 59.48 [ SD = 66.02 ] , P = 0.55 ) . Total costs of providing 101 telephone versus 68 face-to-face asthma review s were also similar ( telephone = pounds sterling 725.84 versus surgery = pounds sterling 755.70 ) , but mean cost per consultation achieved was lower in the telephone arm ( telephone = pounds sterling 7.19 [ SD = 2.49 ] versus surgery = pounds sterling 11.11 [ SD = 3.50 ] ; mean difference = - pounds sterling 3.92 [ 95 % confidence interval = - pounds sterling 4.84 to pounds sterling 3.01 ] , P < 0.001 ) . CONCLUSIONS Telephone consultations enable a greater proportion of asthma patients to be review ed at no additional cost to the health service . This mode of delivering care improves access and reduces cost per consultation achieved 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 As part of a larger study of the effect of foot shape on functioning , 47 Royal Australian Air Force recruits with flexible flat feet who were embarking on a 10-week basic training course took part in a r and omized controlled trial of orthotic therapy . In particular , recruits were assigned at r and om to an untreated group or a group that received Australian Orthotics Laboratory , three-quarter-length , flexible , shoe inserts . The groups were assessed at baseline and week 8 . Outcome measures included pain , injury , foot health , and quality of life . The untreated group ( n = 22 ) had a greater proportion of heavier recruits than did the treated group ( n = 25 ) . There were no significant differences in outcome measures at baseline . Only one-half of the group assigned to orthotic therapy wore the orthotics most or all of the time . At the end of the trial , although the results were not statistically significant , those who were provided with orthotics and wore them had the least lower limb pain and the best general foot health and quality of life . Notably , none of the recruits who wore their orthotics most or all of the time sustained a training injury 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 |
13,742 | 25,495,416 | The choice of control interventions showed great variability .
Therapy of PM is a prerequisite for the prevention of peri-implantitis | AIM To systematic ally assess the efficacy of patient-administered mechanical and /or chemical plaque control protocol s in the management of peri-implant mucositis ( PM ) . | OBJECTIVE To monitor clinical , microbiological and host-derived alterations occurring around teeth and titanium implants during the development of experimental gingivitis/mucositis and their respective healing sequence in humans . MATERIAL AND METHODS Fifteen subjects with healthy or treated periodontal conditions and restored with dental implants underwent an experimental 3-week period of undisturbed plaque accumulation in the m and ible . Subsequently , a 3-week period with optimal plaque control was instituted . At Days 0 , 7 , 14 , 21 , 28 , 35 and 42 , the presence/absence of plaque deposits around teeth and implants was assessed , ( plaque index [ PlI ] ) and the gingival/mucosal conditions were evaluated ( gingival index[GI ] ) . Subgingival/submucosal plaque sample s and gingival/mucosal crevicular fluid ( CF ) sample s were collected from two pre-determined sites around each experimental unit . CF sample s were analyzed for matrix-metalloproteinase-8 ( MMP-8 ) and interleukin-1beta ( IL-1β ) . Microbial sample s were analyzed using DNA-DNA hybridization for 40 species . RESULTS During 3 weeks of plaque accumulation , the median PlI and GI increased significantly at implants and teeth . Implant sites yielded a greater increase in the median GI compared with tooth sites . Over the 6-week experimental period , the CF levels of MMP-8 were statistically significantly higher at implants compared with teeth ( P<0.05 ) . The CF IL-1β levels did not differ statistically significantly between teeth and implants ( P>0.05 ) . No differences in the total DNA counts between implant and tooth sites were found at any time points . No differences in the detection frequency were found for putative periodontal pathogens between implant and tooth sites . CONCLUSION Peri-implant soft tissues developed a stronger inflammatory response to experimental plaque accumulation when compared with that of their gingival counterparts . Experimental gingivitis and peri-implant mucositis were reversible at the biomarker level . Clinical ly , however , 3 weeks of resumed plaque control did not yield pre-experimental levels of gingival and peri-implant mucosal health indicating that longer healing periods are needed AIM To determine the incidence of peri-implantitis in individuals with mucositis in a 5-year follow-up study . MATERIAL AND METHODS A sample of 212 partially edentulous individuals , rehabilitated with dental implants , underwent periodontal and peri-implant clinical examinations in 2005 ( baseline ) . Five years later , 80 individuals who had been diagnosed with mucositis in the baseline examination were re-examined . These individuals were divided into two groups : one group with preventive maintenance during the study period ( GTP ; n = 39 ) , and another group without preventive maintenance ( GNTP ; n = 41 ) . The following parameters were clinical ly evaluated : plaque index , bleeding on periodontal and peri-implant probing , periodontal and peri-implant probing depth , suppuration and peri-implant bone loss . The influence of biological and behavioural risk variables associated with the occurrence of peri-implantitis was analysed using univariate and multivariate logistic regression analyses . RESULTS The incidence of peri-implantitis in the global sample was 31.2 % ( GNTP = 43.9 % and GTP = 18.0 % ) . CONCLUSION The absence of preventive maintenance in individuals with pre-existing peri-implant mucositis was associated with a high incidence of peri-implantitis . Clinical parameters , such as bleeding on peri-implant probing , periodontal probing depth and the presence of periodontitis were associated with a higher risk of developing peri-implantitis PURPOSE To evaluate the effect of irrigation with 0.06 % chlorhexidine ( PerioGard ) ( CHX ) using a powered oral irrigator ( Water Pik ) with a special subgingival irrigating tip ( Pik Pocket Subgingival Tip ) compared to rinsing with 0.12 % chlorhexidine gluconate once daily . MATERIAL S AND METHODS Following a prophylaxis , patients were r and omly assigned to an irrigation or a rinse group . The following clinical parameters were measured at baseline and at the 3-month end of the study : Modified Gingival Index ( MGI ) , Plaque Index ( PI ) , Bleeding Index ( BI ) , and Calculus Index ( CI ) . Also , a Stain Index ( SI ) was measured at 3 months . RESULTS Patients irrigating with diluted CHX showed a statistically significant reduction ( P < 0.05 ) from their baseline in the MGI , PI , BI , and CI scores at 3 months . In the rinse group both MGI and BI showed statistically significant reduction from their baseline ( P < 0.05 ) at 3 months . The rinse group showed a nonsignificant ( P > 0.05 ) increase from baseline in CI and a nonsignificant decrease in PI . Intergroup comparisons showed that CHX irrigation produced statistically significantly greater reductions than CHX rinsing in the PI , MGI , and SI . The irrigation group also showed a greater reduction in BI and CI than the rinsing group but these differences were not statistically significant ( P = 0.12 ) . The results of this study suggest that use of diluted 0.06 % CHX when used in a powered irrigator may be a valuable adjunct to oral health in patients with implants OBJECTIVES To evaluate clinical ly and radiographically immediate implants 5 years after insertion and to compare them with delayed-placed implants in the same subjects . MATERIAL AND METHODS Twenty-two consecutive patients that needed at least two implants for replacing hopeless teeth , one immediately upon extraction and the other in a delayed fashion ( at least 4 months post- extraction ) were selected in this prospect i ve cohort study . Post- extraction immediate implants ( II ) and delayed implants ( DI ) groups were defined . One and 5 years after implant loading , clinical and radiographical outcome variables were recorded and analysed both at site and at implant level . Intra-group and inter-group comparisons were performed . RESULTS The intergroup comparison did not show significant differences for plaque index , bleeding on probing and suppuration . These parameters worsen in both groups along the study . This trend was stronger for the plaque index in the group II , which increased from 15.6 % at 1 year to 25.9 % at 5 years ( P < 0.04 ) . One year after loading , the sites with probing depth ≥5 mm were higher for the group II compared to DI ( 2.5 % vs. 0 % ; P = 0.049 ) . At the end of the study , no significant statistical differences were found . Radiographically , bone crestal changes did not yield significant differences . During the follow-up period , 25 % of the implants ( 26.4 % in group II and 23.5 % in DI ) showed biological complications : mucositis ( 20 % ) and /or periimplantitis ( 5.8 % ) . No differences between groups were found . CONCLUSIONS Within the same patients , the implants placed with the immediate protocol demonstrated a higher tendency to crestal bone loss and to peri-implantitis , although these differences were not statistically significant AIM Supportive therapy to maintain dental implants is increasingly important . This study examined the effect of a 0.3 % triclosan/2 % copolymer dentifrice on oral biofilms and gingival inflammation ( GI ) on dental implants and peri-implant tissues . MATERIAL S AND METHODS One hundred and twenty adults with a dental implant and contra-lateral tooth were enrolled in this 6 month , double-blind , two-treatment , parallel group study . Sixty subjects were r and omly assigned to a triclosan/copolymer dentifrice test group and 60 subjects to a fluoride dentifrice control group and instructed to brush twice daily for 6 months . At baseline , 3 , and 6 months , a calibrated dentist assessed dental plaque , GI and collected supragingival dental plaque for microbiological analysis . RESULTS Subjects in the triclosan/copolymer group demonstrated significantly lower levels of dental plaque , gingivitis , and bleeding on probing at 3 and 6 months at both the implant and contra-lateral tooth compared with the fluoride group ( p<0.05 ) . There were significantly fewer Gram-negative anaerobes in the triclosan/copolymer group ( p<0.05 ) including > 90 % reductions in Aggregatibacter actinomycetemcomitans , Campylobacter rectus , Eubacterium saburreum , Fusobacterium nucleatum , Porphyromonas gingivalis , Prevotella melaninogenica , Solobacterium moorei , and Tannerella forsythia . CONCLUSIONS Twice daily use of a triclosan/copolymer dentifrice may enhance dental implant maintenance by reducing dental plaque and GI PURPOSE The aim of the present study was to investigate plaque levels following sonic-powered and manual toothbrushing in subjects with dental implants . MATERIAL S AND METHODS This study included 36 male and 47 female partially edentulous patients ( age range 45 - 78 years , mean age 59.8 years ) that were r and omly assigned to one of two treatment groups : the sonic toothbrush group ( n = 42 ; Philips Sonicare FlexCare ® toothbrush ) or the manual toothbrush group ( n = 41 ; Oral-B P40 ® ) . Clinical , microbiological and immunological examinations were performed blinded at baseline and after 3 , 6 , 9 and 12 months . Microbiological analyses were performed by real-time polymerase chain reaction . Immunological analyses ( prostagl and in E2 ) were performed by chromatography-electrospray spectrometry . RESULTS The plaque index difference between baseline and 12 months at implants showed no significant difference between sonic or manual toothbrushing in a two-sided Mann-Whitney test ( W = 773.5 , P = 0.426 , 95 % CI -0.64 to 0.20 ) . At the end of the study , there were no significant changes in plaque index , bleeding on probing , gingival index , pocket probing depth , gingival recession , clinical attachment level or the microbiological and immunological outcomes at implants or teeth in either group . CONCLUSIONS This study uncovered no significant difference between sonic and manual toothbrushing for plaque reduction at implants and teeth . Both toothbrushes maintain healthy peri-implant soft tissue PURPOSE This double-blind r and omized controlled trial assessed the effect of subgingival ozone ( O3 , gaseous ozone , HealOzone MK II , KaVo ) and /or hydrogen peroxide ( H2O2 ) on the development of peri-implant mucositis . MATERIAL S AND METHODS Twenty subjects ( mean age , 60 ± 7.7 years ) with 80 implants ( 4 implants each ) were recruited . First , a 2-week pretrial phase took place to achieve healthy gingiva . Subsequently , partial gum shields were constructed for the experimental area ( around the 4 implants ) ; subjects were asked to refrain from brushing in that area by wearing the gum shield . The following treatments were r and omly applied ( for 60 seconds ) to implant sites on days 0 , 7 , and 14 : ( 1 ) air ( O2 ) and saline ( 0.9 % NaCl ) ( control group ) , ( 2 ) O2 and H2O2 ( 3 % ) , ( 3 ) O3 and saline , and ( 4 ) O3 and H2O2 . Plaque , gingival , and bleeding indices were recorded on days 0 , 7 , 14 , and 21 . RESULTS Significant differences were seen among the treatments ( P < .01 ) in plaque ( F = 16.68 ) , modified gingival ( F = 7.86 ) , and bleeding ( F = 18.42 ) indices . O3 + saline and O3 + H2O2 produced optimum gingival health scores and were equally effective and the most effective in controlling bleeding ( mean score = 0.05 ) , while O2 + saline was the least effective ( mean score = 0.56 ) . CONCLUSION Ozone showed great potential for management of peri-implant mucositis OBJECTIVE The aim of this prospect i ve study was to assess the outcomes of an implant maintenance protocol for implants supporting a full-arch rehabilitation . MATERIAL S AND METHODS Sixty-one patients ( 28 women and 33 men ) treated with immediately loaded full-arch rehabilitation , both m and ibular and maxillary , supported by a combination of two tilted and two axial implants , were included in the study . Patients were scheduled for follow-up visits every 6 months for + 2 years , then yearly up to 4 years . Each patient received professional oral hygiene treatment and detailed oral hygiene instructions . During each visit , modified plaque index , bleeding index and probing depth were assessed . The presence of peri-implant tissue inflammation was also evaluated . RESULTS Mean observation time , considering both m and ible and maxilla , was 18.3 months ranging from 6 months to 5 years . Both plaque and bleeding indexes frequency decreased over time . Probing depth was stable ( 2.46 ± 0.5 mm at 4 years ) . Only three implants were lost due to peri-implantitis ( 1.4 % at 12 months ) , whereas the incidence of peri-implant mucositis was less than 10 % in each considered period . CONCLUSIONS The adoption of a systematic hygienic protocol is effective in keeping low the incidence of peri-implant mucositis as well as in controlling plaque accumulation and clinical attachment loss The aim of the present study was to compare the cleansing properties of mechanical supportive care for dental implants with the use of an etching gel . Sixteen patients underwent a 5-month clinical trial with monthly recalls . These patients , wearing maxillary complete dentures and m and ibular overdentures supported by a bar device on 4 implants , were treated in a split-mouth study design . Test and control therapy were r and omly assigned to left and right sides of the m and ible . At the test side , 35 % phosphoric etching gel ( pH 1 ) was applied in the peri-implant sulcus . After 1 minute , the sulcus was thoroughly rinsed with a water spray for approximately 15 seconds per implants . Control therapy consisted of supra- and subgingival debridement using carbon fiber curettes and a rubber cup . Plaque , calculus , probing pocket depth , and modified Gingival Index were determined before each treatment . Microbiologic evaluation was performed at baseline , 1 month later , and 5 months later , just before and immediately after each treatment . Per treatment and per assessment , the mean scores of all clinical parameters were calculated for each patient . The number of colony-forming units was used as the primary efficacy variable in the analysis of microbiologic data . At baseline , no differences between test and control sites were observed for any of the clinical parameters . The mean Gingival Index and the mean probing pocket depth were reduced over the 5-month period . The mean reduction in Gingival Index at the test sites proved to be significantly larger at the control sites ( P = .03 ) . Both treatment modalities result ed in an instant reduction of the number of colony-forming units , where the reduction by chemical cleaning was larger ( P < .05 ) . This short-term study employing a high recall frequency indicates that local application of 35 % phosphoric acid gel can be as effective as conventional mechanical supportive therapy AIM The aim of this study was to compare the clinical effectiveness of a powered toothbrush ( Braun Oral-B Plaque Remover 3-D ) and a manual soft toothbrush ( Oral-B Squish-grip brush ) for the control of supragingival plaque and soft tissue inflammation around implants supporting m and ibular overdentures . MATERIAL AND METHODS The study sample involved 40 edentulous subjects , aged 55 - 80 years , having 2 unsplinted m and ibular implants supporting a complete removable overdenture opposed by a maxillary complete denture . In this single-blinded , r and omised , cross-over clinical trial , two 6-week experimental phases were separated by a 2-week wash-out period . 2 weeks prior to each experimental phase ( pre-entry visits ) , implant abutments were polished to remove all plaque and a st and ardised instruction in the use of the toothbrush was given . Modified plaque and bleeding indices were recorded at the start and end of each experimental period . Mean index scores at each phase were analysed using paired t-test , and the mean number of sites showing a change in plaque or mucositis were compared using the Mann-Whitney U-test . Combined data from 2 different implant systems were considered after controlling for implant type . RESULTS Only minor changes in plaque and bleeding scores were observed following the two test periods . There were no statistically significant differences between the manual and powered toothbrushes . CONCLUSION Manual and powered brushes were found to be of comparable efficacy with regard to improvement in peri-implant bleeding and plaque indices OBJECTIVE The objective of the present clinical study was to assess the effect of the use of a dentifrice containing triclosan on peri-implant mucositis in subjects that had been restored with dental implants . METHODS The trial was design ed as a double-blind , r and omized , two-treatment , parallel-group clinical study . Sixty male and female subjects , aged 30 - 70 years , were recruited . All subjects had lost teeth due to periodontal disease , and had been restored with a minimum of two implants at least one year prior to the start of the trial . Subjects were r and omly assigned to two treatment groups . The subjects in the test group ( Test ) brushed their teeth and implant-supported restorations with a dentifrice containing triclosan , while the control subjects brushed with a sodium fluoride dentifrice . Only subjects with a minimum of one implant site showing clinical signs of peri-implant mucositis , i.e. , bleeding after probing , were enrolled in the study . Clinical examinations were performed at baseline , and after three and six months . The following parameters were scored : Probing pocket depth ( PPD ) , bleeding on probing ( BoP ) , and plaque . The change from baseline within each treatment group at three months and six months was evaluated for all parameters using ANOVA and ANCOVA . RESULTS Subjects with peri-implant mucositis who used a dentifrice containing 0.3 % triclosan , as an adjunct to mechanical tooth brushing , exhibited significantly fewer clinical signs of inflammation than subjects who used a regular fluoride dentifrice at six months . The BoP scores were reduced from 53.8 % to 29.1 % in the Test group , whereas in the same interval there was an increase from 52.3 % to 58.8 % in the Control group . Furthermore , the individual mean PPD , as well as the frequency of sites with 5 mm and > or = 6 mm deep pockets , were reduced significantly more in the Test than in the Control group . CONCLUSION The regular use of a dentifrice containing triclosan may reduce the clinical signs of inflammation in the mucosa adjacent to dental implants BACKGROUND Although most patients with implants have lost their natural teeth because of poor oral hygiene , limited data exist to guide practitioners in their recommendations of home-care regimens for their patients ' endosseous dental implants and maintenance of peri-implant soft-tissue health . The authors conducted a study to compare the home-care effectiveness of a counter-rotational powered tooth-brush with that of conventional home-care regimens . METHODS Before starting the six-year study , the authors trained 85 clinical investigators at 32 dental research centers across the United States in gathering periodontal data . Data for 2,966 implants were entered into a central ized data base . Outcomes were derived from 24-month observations of a subset of the implants studied . RESULTS Repeated- measures analysis of the toothbrushing methods used on 2,966 implants showed that the counter-rotational powered toothbrush removed plaque significantly better than manual methods ( P < .0001 Wald statistic ) from all implant surfaces and at all recall intervals up to 24 months . Similar results were demonstrated for the gingival index . CONCLUSIONS The counter-rotational powered brush appears to be well-suited for home-care regimens aim ed at maintaining optimal peri-implant soft-tissue health in patients with dental implants . CLINICAL IMPLICATION S The importance of maintaining the health of the peri-implant tissues is well-recognized by the dental profession . The counter-rotational powered toothbrush is an effective tool in meeting the oral hygiene challenges associated with implant prosthesis maintenance BACKGROUND Glycine powder air-polishing ( GPAP ) has the potential to effectively erase biofilms and may improve the treatment efficacy of peri-implant mucositis . This pilot clinical trial evaluated the effect of GPAP as an adjunct in treating peri-implant mucositis . MATERIAL S AND METHODS Twenty-four subjects having at least one implant with peri-implant mucositis were r and omly assigned to test ( 12 subjects with 17 implants ) and control ( 12 subjects with 16 implants ) groups . Following baseline assessment , all subjects received oral hygiene instruction and non-surgical debridement . In the test group , the sites with probing depth ( PD ) ≥4 mm were additionally treated by GPAP for 5 sec. Clinical parameters were measured at 1-week , 1-month , and 3-month recall visits . RESULTS At the 3-month visit , the mean reductions in PD at site level were 0.93 ± 0.93 mm and 0.91 ± 0.98 mm in the test and control groups , respectively ( P < 0.05 ) , and no significant difference existed between two groups . Mean bleeding score was also significantly reduced in both groups after the intervention . No complications or discomfort were reported during the study . CONCLUSIONS This pilot clinical trial suggests that non-surgical mechanical debridement may effectively control peri-implant mucositis , and adjunctive GPAP treatment seems to have a limited beneficial effect as compared with mechanical debridement alone . However , further clinical trials with a large sample size are needed to confirm this preliminary observation |
13,743 | 24,890,702 | We did not observe any significant association between overall or progression-free survival , neither when considering all colorectal cancer patients nor for subgroup analyses ( metastatic , anti-EGFR [ epidermal growth factor receptor ] treatment , or KRAS wild type ) .
We have found no clear evidence to support an association between the KRAS-LCS6 genotype and overall or progression-free survival among colorectal cancer patients , even after conducting subgroup analyses by stage and anti-EGFR treatment status . | There is a small but growing body of literature regarding the predictive utility of a Let-7 microRNA-binding-site polymorphism in the 3'-untranslated region ( UTR ) of KRAS ( KRAS-LCS6 ) for colorectal cancer outcome , although the results are conflicting .
We performed a review and meta- analysis in an attempt to better clarify this relationship . | BACKGROUND Treatment with cetuximab , a monoclonal antibody directed against the epidermal growth factor receptor , improves overall and progression-free survival and preserves the quality of life in patients with colorectal cancer that has not responded to chemotherapy . The mutation status of the K-ras gene in the tumor may affect the response to cetuximab and have treatment-independent prognostic value . METHODS We analyzed tumor sample s , obtained from 394 of 572 patients ( 68.9 % ) with colorectal cancer who were r and omly assigned to receive cetuximab plus best supportive care or best supportive care alone , to look for activating mutations in exon 2 of the K-ras gene . We assessed whether the mutation status of the K-ras gene was associated with survival in the cetuximab and supportive-care groups . RESULTS Of the tumors evaluated for K-ras mutations , 42.3 % had at least one mutation in exon 2 of the gene . The effectiveness of cetuximab was significantly associated with K-ras mutation status ( P=0.01 and P<0.001 for the interaction of K-ras mutation status with overall survival and progression-free survival , respectively ) . In patients with wild-type K-ras tumors , treatment with cetuximab as compared with supportive care alone significantly improved overall survival ( median , 9.5 vs. 4.8 months ; hazard ratio for death , 0.55 ; 95 % confidence interval [ CI ] , 0.41 to 0.74 ; P<0.001 ) and progression-free survival ( median , 3.7 months vs. 1.9 months ; hazard ratio for progression or death , 0.40 ; 95 % CI , 0.30 to 0.54 ; P<0.001 ) . Among patients with mutated K-ras tumors , there was no significant difference between those who were treated with cetuximab and those who received supportive care alone with respect to overall survival ( hazard ratio , 0.98 ; P=0.89 ) or progression-free survival ( hazard ratio , 0.99 ; P=0.96 ) . In the group of patients receiving best supportive care alone , the mutation status of the K-ras gene was not significantly associated with overall survival ( hazard ratio for death , 1.01 ; P=0.97 ) . CONCLUSIONS Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab , whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab . The mutation status of the K-ras gene had no influence on survival among patients treated with best supportive care alone . ( Clinical Trials.gov number , NCT00079066 . Support for prospect i ve registration of protocol s for systematic review s has been gathering momentum . The PRISMA statement , a guideline for reporting systematic review s and meta-analyses of studies that evaluate health-care interventions , advocates registration . Well-conducted systematic review s are accepted as the best- quality evidence to inform policy and practice , and the dramatic upward trend in the number of systematic review s published annually ( fi gure ) is set to continue . However , there is currently no single facility for identifying this type of research in advance of the appearance of the results of the review . There is concern about and evidence of publication and selective outcome -reporting biases associated with systematic review s. An open registry of review s captured at the protocol stage would facilitate good practice in systematic review s by providing transparency of the review process and outcomes . Discrepancies between the methods of the published review and those planned in the registered protocol could be more readily identifi ed . Registration might also encourage full publication of the review ’s fi ndings and transparency in changes to methods that could bias fi ndings . In both the prevention and revelation of potential bias , registration should improve quality and increase confi dence that policy or practice informed by the fi ndings of systematic review s are indeed drawing on best- quality evidence . A registry of protocol s of systematic review s could assist those planning new review s and updating existing ones . Easy access to information about ongoing review s should help to optimise the use of fi nite re sources by enabling funding and commissioning agencies to avoid unnecessary duplication and encourage collaboration . A comprehensive registry could also create opportunities for method ological and other research , both within and across disciplines . Existing access to systematic - review protocol s is limited to the outputs of individual organisations , such as the Cochrane and Campbell Collaborations and the Joanna Briggs Institute . The National Public Health Service for Wales is piloting an All Wales Systematic Review s Register , but , up to now , there has been no central ised comprehensive registry of systematic - review protocol s. We are developing an international facility to register the details of ongoing systematic review s in health and social care . Our registry is being established with the existing platform and infrastructure that supports the Data base of Abstract s of Review s of Eff ects ( DARE ) , the NHS Economic Evaluations Data base ( NHS EED ) and the Health Technology Assessment ( HTA ) data base produced by the Centre for Review s and Dissemination . The initial scope of the registry will be limited to systematic review s of the eff ectiveness of health interventions . However , the longterm aim is for the registry to include details of all ongoing systematic review s with a health-related outcome in the broadest sense . Ultimately , inclusion will encompass systematic review s of health-care interventions , and review s of the social determinants of health , of service delivery , and of risk factors and genetic associations . Our web-based registry will off er free public access , be electronically search able , and open to all prospect i ve registrants . Registration will require the provision of a minimum data set , the completeness of which will be checked automatically before registration . After acceptance , the registry ’s entry and protocol for the review , if available , will be loaded on the data base as a permanent entry and a unique identifi cation number issued . An audit trail for any amendments to the information will be available within the record . Links to result ing publications will be added . These provisions ensure that the registry will match the relevant criteria required of clinical trials registries |
13,744 | 27,820,152 | BMI provides the most useful population -level measure of overweight and obesity as it is the same for both sexes and for all ages worldwide .
Measures of central obesity such as the waist : hip ratio and waist circumference can provide more robust indices of overall obesity-related health risk than BMI alone .
Overweight and obese children are likely to stay obese into adulthood and are more likely to develop non-communicable diseases like diabetes and cardiovascular diseases at a younger age .
In addition to a higher risk of obesity and non-communicable diseases later in life , affected children experience adverse outcomes such as breathing difficulties , increased risk of fractures , hypertension , and early markers of cardiovascular disease , different forms of cancers , insulin resistance , and psychological effects .
Childhood obesity is associated with a higher chance of obesity , premature death , and disability in adulthood .
If a child is overweight before eight years of age , obesity in adulthood is likely to be more severe .
Child and adolescent obesity is also associated with increased risk of emotional problems .
Teens with weight problems tend to have much lower self-esteem and are less popular with their peers .
Depression , anxiety , and obsessive compulsive disorder can also occur as a result of childhood obesity .
Reducing the incidence of obesity in childhood can help children grow into adults with normal body weights and the tools necessary to sustain a health weight .
Haerens , et al. explains the importance of school-based programs in dealing with the serious problem of childhood obesity and overweight .
The school setting is known as having a powerful influence on student 's eating and physical activities .
Programs that may have a more positive impact are those that help increase physical activity and promote healthy foods in youth .
Previous studies looking at the implementation of diet and exercise programs in schools were effective in changing food habits and increasing physical activity ; however , few of these studies showed a reduction in body weight .
The Planet Health study , conducted over a period of two years , focused on healthy life style and showed a reduction in obesity in girls but not in boys .
The program was found to be a potential low cost method to positively impact public health and health behaviours . | REVIEW OBJECTIVE The objective of this review is to synthesis e the best available evidence on the effectiveness of web-based programs on the reduction of childhood obesity in school age children .
BACKGROUND Childhood obesity is one of the most serious public health challenges of the 21st century .
The problem is global and is steadily affecting many low- and middle-income countries , particularly in urban setting s.[1 ] The prevalence has increased at an alarming rate globally.[2 ] The International Association for the Study of Obesity ; estimates that up to 200 million school aged children are either overweight or obese , of those 40 - 50 million are classified as obese .
Obesity has negative health impact in childhood , as well as in the long term .
Overweight and obesity are defined as abnormal or excessive fat accumulation that may impair health .
Body mass index ( BMI ) is a simple index of weight-for-height that is commonly used to classify overweight and obesity .
It is defined as a person 's weight in kilograms divided by the square of his/her height in meters ( kg/m ) .
The incidence of obesity has more than doubled since 1980 .
Overweight and obesity now ranks as the fifth leading global risk for mortality .
Sixty-five percent of the world 's population lives in countries where childhood overweight and obesity kills more people than being underweight .
In addition , 44 % of the diabetes burden , 23 % of the ischemic heart disease burden , and between 7 % and 41 % of certain cancer burdens are attributable to overweight and obesity .
Childhood obesity continues to be a significant health problem in the United States .
There has been a rapid rise in obesity among the school-age population despite efforts made by Healthy People 2010 in promoting weight management and physical activity .
These on-going efforts have been extended to be part of the goals for Healthy People 2020 .
In addition to the diseases associated with obesity , the economic consequences of obesity are enormous for families , health care systems , and the global economy .
Direct medical costs include preventative , diagnostic , and treatment services related to overweight and associated co-morbidities .
European nations spend 2 - 8 % of their health care budgets on obesity , equating to 0.6 % of their gross domestic product .
In the United States , estimates based on 2008 data indicated that overweight and obesity account for $ 147 billion in total medical expenditure .
This shows an increase from the $ 117 billion spent in the year 2000.While indirect costs of overweight and obesity on society can be significantly higher , they are often overlooked .
These costs stem from childhood obesity continuing on to obesity in adulthood , which can then results in income lost from decreased productivity , reduced opportunities and restricted activity , illness , absenteeism , and premature death .
In addition , there are high costs associated with the numerous infrastructure changes that societies must make to cope with obese people such as reinforced beds , operating tables and wheel chairs ; enlarged turnstiles and seats in in public gathering spaces ; and modifications to transportation safety st and ards .
Obesity is reaching p and emic proportions across much of the world , and its consequences are set to impose unparalleled health , financial and social burdens on global society unless effective actions are taken to reverse the trend .
The United States Department of Health and Human Services report of 2009 indicates that school aged children spend an average of 7 hours and 11 minutes per day watching television , using a computer , and playing video games .
Using these technology devices as educational tools could have significant impact by increasing knowledge about healthy choices .
Web-based technology has become part of our children 's life in the last decade providing the foundation to a large number of daily activities .
The use of web-based technology may be one method to provide a more personalised intervention to reduce obesity in school-aged children . | OBJECTIVE To assess the process variables involved in a weight loss program for African-American adolescent girls . Several process variables have been identified as affecting success in in vivo weight loss programs for adults and children , including program adherence , self-efficacy , and social support . The current study sought to broaden the underst and ing of these process variables as they pertain to an intervention program that is presented using the Internet . It was hypothesized that variables such as program adherence , dietary self-efficacy , psychological factors , and family environment factors would mediate the effect of the experimental condition on weight loss . RESEARCH METHODS AND PROCEDURES Participants were 57 adolescent African-American girls who joined the program with one obese parent ; family pairs were r and omized to either a behavioral or control condition in an Internet-based weight loss program . Outcome data ( weight loss ) are reported for the first 6 months of the intervention . RESULTS Results partially supported the hypotheses . For weight loss among adolescents , parent variables pertaining to life and family satisfaction were the strongest mediating variables . For parental weight loss , changes in dietary practice s over the course of 6 months were the strongest mediators . DISCUSSION The identification of factors that enhance or impede weight loss for adolescents is an important step in improving weight loss programs for this group . The current findings suggest that family/parental variables exert a strong influence on weight loss efforts for adolescents and should be considered in developing future programs OBJECTIVES Motivating adolescents to adopt proper nutrition and physical activity behaviors is important in this nation 's fight to prevent obesity and chronic diseases . This study was conducted to determine which health education delivery method would elicit a greater behavior change . METHOD The intervention was conducted in three schools ( control , computer-based , and traditional education ) . RESULTS Students who received the computer-based intervention showed increased knowledge ( p<0.001 ) , physical activity ( p=0.001 ) , self-efficacy ( p<0.001 ) , and social support ( p<0.001 ) , and decreased meals skipped ( p<0.001 ) . CONCLUSION The computer-based group showed more positive behavior changes . However , future programs may be enhanced by including group discussion and individual feedback Background Childhood obesity has reached epidemic proportions in developed countries . Sedentary screen-based activities such as video gaming are thought to displace active behaviors and are independently associated with obesity . Active video games , where players physically interact with images onscreen , may have utility as a novel intervention to increase physical activity and improve body composition in children . The aim of the Electronic Games to Aid Motivation to Exercise ( eGAME ) study is to determine the effects of an active video game intervention over 6 months on : body mass index ( BMI ) , percent body fat , waist circumference , cardio-respiratory fitness , and physical activity levels in overweight children . Methods / Design Three hundred and thirty participants aged 10–14 years will be r and omized to receive either an active video game up grade package or to a control group ( no intervention ) . Discussion An overview of the eGAME study is presented , providing an example of a large , pragmatic r and omized controlled trial in a community setting . Reflection is offered on key issues encountered during the course of the study . In particular , investigation into the feasibility of the proposed intervention , as well as robust testing of proposed study procedures is a critical step prior to implementation of a large-scale trial . Trial registration Australian New Zeal and Clinical Trials Registry PURPOSE To examine the feasibility and efficacy of a theory-driven and family-based program delivered online to promote healthy lifestyles and weights in Chinese American adolescents . METHODS A r and omized controlled study of a web-based intervention was developed and conducted in 54 Chinese American adolescents ( ages , 12 - 15 years ) and their families . Data on anthropometry , blood pressure , dietary intake , physical activity , and knowledge and self-efficacy regarding physical activity and nutrition were collected at baseline and 2 , 6 , and 8 months after the baseline assessment . Data were analyzed using linear mixed modeling . RESULTS The intervention result ed in significant decreases in waist-to-hip ratio and diastolic blood pressure and increases in vegetable and fruit intake , level of physical activity , and knowledge about physical activity and nutrition . CONCLUSION This web-based behavior program for Chinese American adolescents and their families seems feasible and effective in the short-term . Long-term effects remain to be determined . This type of program can be adapted for other minority ethnic groups who are at high-risk for overweight and obesity and have limited access to programs that promote healthy lifestyles PURPOSE To compare the effectiveness of two school-based internet obesity prevention programs for diverse adolescents on body mass index ( BMI ) , health behaviors , and self-efficacy , and to explore moderators of program efficacy . It was hypothesized that the addition of coping skills training to a health education and behavioral support program would further enhance health outcomes . METHODS A r and omized clinical trial with cluster r and omization by class and repeated measures with follow-up at 3 and 6 months was conducted ( n = 384 ) . BMI was assessed by use of st and ard procedures . Sedentary behavior , physical activity , nutrition behavior , self-efficacy , and satisfaction were assessed with self-report measures . Data analysis consisted of mixed model analyses with autoregressive covariance structure for repeated data by use of intent-to-treat procedures . RESULTS The mean age of students was 15.31 years ( ±0.69 ) , with a mean BMI of 24.69 ( ±5.58 ) . The majority were girls ( 62 % ) and of diverse race/ethnicity ( 65 % non-white ) . There were no significant differences between groups on any outcomes and no change in BMI over time . There were significant improvements in health behaviors ( sedentary behavior , moderate and vigorous physical activity , healthy eating , fruit and vegetable intake , sugar beverages , and junk food intake ) and self-efficacy . Gender and lesson completion moderated select health outcomes . There was excellent participation and high satisfaction with the programs . CONCLUSIONS School-based internet obesity prevention programs are appealing to adolescents and improve health behaviors . The differential effect of coping skills training may require longer follow-up OBJECTIVE To evaluate the impact of a school-based health behavior intervention known as Planet Health on obesity among boys and girls in grade s 6 to 8 . DESIGN R and omized , controlled field trial with 5 intervention and 5 control schools . Outcomes were assessed using preintervention ( fall 1995 ) and follow-up measures ( spring 1997 ) , including prevalence , incidence , and remission of obesity . PARTICIPANTS A group of 1295 ethnically diverse grade 6 and 7 students from public schools in 4 Massachusetts communities . INTERVENTION Students participated in a school-based interdisciplinary intervention over 2 school years . Planet Health sessions were included within existing curricula using classroom teachers in 4 major subjects and physical education . Sessions focused on decreasing television viewing , decreasing consumption of high-fat foods , increasing fruit and vegetable intake , and increasing moderate and vigorous physical activity . MAIN OUTCOME MEASURES Obesity was defined as a composite indicator based on both a body mass index and a triceps skinfold value greater than or equal to age- and sex-specific 85th percentiles . Because schools were r and omized , rather than students , the generalized estimating equation method was used to adjust for individual-level covariates under cluster r and omization . RESULTS The prevalence of obesity among girls in intervention schools was reduced compared with controls , controlling for baseline obesity ( odds ratio , 0.47 ; 95 % confidence interval , 0.24 - 0.93 ; P = .03 ) , with no differences found among boys . There was greater remission of obesity among intervention girls vs. control girls ( odds ratio , 2.16 ; 95 % confidence interval , 1.07 - 4.35 ; P = .04 ) . The intervention reduced television hours among both girls and boys , and increased fruit and vegetable consumption and result ed in a smaller increment in total energy intake among girls . Reductions in television viewing predicted obesity change and mediated the intervention effect . Among girls , each hour of reduction in television viewing predicted reduced obesity prevalence ( odds ratio , 0.85 ; 95 % confidence interval , 0.75 - 0.97 ; P = .02 ) . CONCLUSION Planet Health decreased obesity among female students , indicating a promising school-based approach to reducing obesity among youth OBJECTIVE A r and omized controlled trial tested the efficacy of an internet-based lifestyle behavior modification program for African-American girls over a 2-year period of intervention . RESEARCH METHODS AND PROCEDURES Fifty-seven overweight ( mean BMI percentile , 98.3 ) African-American girls ( mean age , 13.2 years ) were r and omly assigned to an interactive behavioral internet program or an internet health education program , the control condition . Overweight parents were also participants in the study . Forty adolescent-parent dyads ( 70 % ) completed the 2-year trial . Outcome data including BMI , body weight , body composition , and weight loss behaviors were collected at baseline and at 6-month intervals . A computer server tracked use of the web sites . RESULTS An intention-to-treat statistical approach was used , with the last observation carried forward . In comparison with the control condition , adolescents in the behavioral program lost more mean body fat ( BF ) ( -1.12 + /- 0.47 % vs. 0.43 + /- 0.47 % BF , p < 0.05 ) , and parents in the behavioral program lost significantly more mean body weight ( -2.43 + /- 0.66 vs. -0.35 + /- 0.64 kg , p < 0.05 ) during the first 6 months . This weight loss was regained over the next 18 months . After 2 years , differences in fat for adolescents ( -0.08 + /- 0.71 % vs. 0.84 + /- 0.72 % BF ) and weight for parents ( -1.1 + /- 0.91 vs. -0.60 + /- 0.89 kg ) did not differ between the behavioral and control programs . DISCUSSION An internet-based weight management program for African-American adolescent girls and their parents result ed in weight loss during the first 6 months but did not yield long-term loss due to reduced use of the web site over time OBJECTIVE . This study examined the efficacy of an Internet-facilitated intervention for weight maintenance and binge eating in adolescents . METHODS . A total of 105 adolescent male and female high school students at risk for overweight ( mean age : 15.1 ± 1.0 years ) were r and omly assigned to a 16-week online intervention , StudentBodies2-BED ( n = 52 ) , or the wait-list control group ( n = 53 ) . RESULTS . Participants in the StudentBodies2-BED group had significantly lower BMI z scores and BMI from baseline assessment to follow-up assessment , compared with the wait-list control group . In addition , significant reductions in objective binge episodes and subjective binge episodes from baseline assessment to posttreatment assessment and from baseline assessment to follow-up assessment were observed among StudentBodies2-BED participants . The StudentBodies2-BED group also reported significantly reduced weight and shape concerns from posttreatment assessment to follow-up assessment and from baseline assessment to follow-up assessment . Participants in the StudentBodies2-BED group who engaged in objective overeating or binge eating episodes at baseline assessment experienced a significantly greater reduction in BMI at follow-up assessment , compared with the wait-list control group . CONCLUSIONS . Results suggest that an Internet-facilitated intervention is moderately effective in short-term weight loss and weight maintenance and yields a large reduction in binge eating . This study also demonstrates that weight management and reduction of eating disorder psychopathological features can be achieved simultaneously by using an easily disseminated , Internet-facilitated program Background : Because physical inactivity poses serious health risks , interventions are urgently needed to reverse the increasingly sedentary lifestyles of adolescent girls . Objective : The aim of this study was to determine the feasibility of " Girls on the Move , " an individually tailored computerized physical activity ( PA ) program plus nurse counseling intervention , in increasing PA . Methods : A pretest-posttest control group design was used with 77 racially diverse sedentary girls in Grade s 6 , 7 , and 8 from two middle schools . Each of the instructional grade s was r and omly assigned to either an intervention or control condition . After completing computerized question naires , each girl in the control group received a h and out listing the PA recommendations . To encourage PA , each girl in the intervention group received computerized , individually tailored feedback messages based on her responses to the question naires , individual counseling from the school 's pediatric nurse practitioner ( PNP ) , and telephone calls and mailings from a trained research assistant . At 12 weeks , girls in both groups responded to the question naires . Results : No differences in self-reported PA emerged between the intervention and control groups at Weeks 1 ( baseline ) and 12 ( postintervention ) . Repeated measures ANOVA showed a significant interaction between group and time for social support for PA , F(1 , 69 ) = 5.73 , p = .019 , indicating that the intervention group had significantly greater social support across time than did the control group . From baseline to postintervention , social support increased for the intervention group but decreased for the control group . Discussion : Reasons for the lack of significant differences between the groups on the PA measures were cited . Important information that could inform subsequent studies that test interventions to increase youth PA was acquired from conducting this study . Future efforts to increase PA participation might include this approach for enhancing social support for PA An interactive , open-access website was launched as an overweight intervention for teens and preteens , and was generally unsuccessful . An underst and ing was needed of the reasons for weight loss failures versus successes in youth using the site . Bulletin board posts , chat room transcripts , and poll responses were prospect ively gathered and qualitatively and quantitatively analyzed over a ten-year period . Many respondents , ages 8 to 21 , exhibited DSM-IV substance dependence ( addiction ) criteria when describing their relationship with highly pleasurable foods . Further research is needed on possible addiction to highly pleasurable foods in youth . Incorporating substance dependence methods may improve the success rate in combating the childhood obesity epidemic BACKGROUND This study reports on effectiveness trial outcomes of Health in Motion , a computer tailored multiple behavior intervention for adolescents . METHODS Using school as level of assignment , students ( n=1800 ) from eight high schools in four states ( RI , TN , MA , and NY ) were stratified and r and omly assigned to no treatment or a multi-media intervention for physical activity , fruit and vegetable consumption , and limited TV viewing between 2006 and 2007 . RESULTS Intervention effects on continuous outcomes , on movement to action and maintenance stages , and on stability within action and maintenance stages were evaluated using r and om effects modeling . Effects were most pronounced for fruit and vegetable consumption and for total risks across all time points and for each behavior immediately post intervention . Co-variation of behavior change occurred within the treatment group , where individuals progressing to action or maintenance for one behavior were 1.4 - 4.2 times more likely to make similar progress on another behavior . CONCLUSION Health in Motion is an innovative , multiple behavior obesity prevention intervention relevant for all adolescents that relies solely on interactive technology to deliver tailored feedback . The outcomes of the effectiveness trial demonstrate both an ability to initiate behavior change across multiple energy balance behaviors simultaneously and feasibility for ease of dissemination BACKGROUND Our objective was to evaluate the effects of environmental , policy , and social marketing interventions on physical activity and fat intake of middle school students on campus . DESIGN Twenty-four middle schools were r and omly assigned to intervention or control conditions . Baseline measures were collected in spring 1997 , and interventions were conducted during the 1997 - 1998 and 1998 - 1999 school years SETTING /PARTICIPATION : The schools had mean enrollments of 1109 , with 44.5 % nonwhite students . Over 2 years , physical activity interventions were design ed to increase physical activity in physical education classes and throughout the school day . Nutrition interventions were design ed to provide and market low-fat foods at all school food sources , including cafeteria breakfasts and lunches , a la carte sources , school stores , and bag lunches . School staff and students were engaged in policy change efforts , but there was no classroom health education . MAIN OUTCOMES MEASURES Primary outcomes were measured by direct observation and existing records . RESULTS R and omized regression models ( N = 24 schools ) revealed a significant intervention effect for physical activity for the total group ( p < 0.009 ) and boys ( p < 0.001 ) , but not girls ( p < 0.40 ) . The intervention was not effective for total fat ( p < 0.91 ) or saturated fat ( p < 0.79 ) . Survey data indicated that the interventions reduced reported body mass index for boys ( p < 0.05 ) . CONCLUSIONS Environmental and policy interventions were effective in increasing physical activity at school among boys but not girls . The interventions were not effective in reducing fat intake at school . School environmental and policy interventions have the potential to improve health behavior of the student population , but barriers to full implementation need to be better understood and overcome OBJECTIVE To evaluate the effects of a 2-year middle school physical activity and healthy food intervention , including an environmental and computer-tailored component on BMI and BMI z-score in boys and girls . RESEARCH METHODS AND PROCEDURES A r and om sample of 15 schools with seventh and eighth grade rs was r and omly assigned to three conditions : an intervention with parental support group , an intervention-alone group , and a control group . Weight and height were measured at the beginning and end of each school year to assess BMI and BMI z-score . A physical activity and healthy food program was implemented over 2 school years . RESULTS In girls , BMI and BMI z-score increased significantly less in the intervention with parental support group compared with the control group ( p < 0.05 ) or the intervention-alone group ( p = 0.05 ) . In boys , no significant positive intervention effects were found . DISCUSSION This was the first study evaluating the effectiveness of an intervention combining environmental changes with personal computer-tailored feedback on BMI and BMI z-score in middle school children . After 2 school years , BMI and BMI z-score changed in a more positive direction in girls as a result of the intervention with parental support OBJECTIVE The Girls health Enrichment Multisite Studies ( GEMS ) Fun , Food , and Fitness Project ( FFFP ) was design ed to prevent obesity among 8-year-old African-American girls . DESIGN Twelve-week , two-arm parallel group r and omized controlled pilot study . SETTING Summer day camp and homes in Houston , Texas . PARTICIPANTS Thirty-five girls and their parents or caregivers were r and omly assigned to treatment ( N=19 ) or control groups ( N=16 ) . INTERVENTION Girls in the intervention group attended a special 4-week summer day camp , followed by a special 8-week home Internet intervention for the girls and their parents . Control group girls attended a different 4-week summer day camp , followed by a monthly home Internet intervention , neither of which components included the GEMS-FFFP enhancements . MAIN OUTCOME MEASURES Body mass index ( BMI ) , consumption of fruit , 100 % fruit juice , and vegetables ( FJV ) , physical activity . RESULTS After adjusting for baseline BMI , there were no significant differences in BMI between treatment and control group girls , either at the end of the 4-week summer day camp , or after the full 12-week intervention . By the end of the summer camp , the subgroup of treatment group girls heavier at baseline exhibited a trend ( P<.08 ) toward lower BMI , compared to their heavier counterparts in the control group . Overall results at the end of the 12-week program demonstrated substantial , although not significant , differences between treatment and control groups in the hypothesized directions . On average , less than half the treatment sample logged onto the Website , which limited intervention dose . CONCLUSIONS Summer day camp appears to offer promise for initiating health behavior change . Effective methods must be developed and tested to enhance log-on rates among healthy children and their parents before Internet programs can achieve their potential OBJECTIVE To investigate the feasibility and impact of the Food-O-Meter , an Internet-based computer-tailored nutrition intervention in adolescents . DESIGN Participants in the intervention condition received the computer-tailored advice at baseline and at 1 month , those in the control condition received st and ardised advice . Effects were evaluated at 1 month ( n 621 ) and at 3 months ( n 558 ) using multi-level modelling . SETTING Secondary schools in six European cities . Adolescents accessed the intervention in the school computer room under the supervision of teachers . SUBJECTS Classes with students aged 12 - 17 years in the schools participating in the HELENA ( Healthy Lifestyle in Europe by Nutrition in Adolescence ) cross-sectional study were r and omised into intervention and control schools . RESULTS In most participating centres the intervention was feasible and generally well appreciated , especially by girls . Technical problems and lack of motivation of the teachers hindered implementation in some centres . Overweight adolescents had higher scores for reading and using the advice than normal weight adolescents . After 1 month adolescents receiving the st and ardised advice reported an increase in fat intake , while fat intake in the intervention condition was stable ( F = 4·82 , P < 0·05 ) . After 3 months , there was a trend in the total group for an intervention effect of the tailored advice on fat intake ( F = 2·80 , P < 0·10 ) . In the overweight group there was a clear positive effect ( F = 5·76 , P < 0·05 ) . CONCLUSIONS The Food-O-Meter should be developed further . The results were modest but clear for percentage energy from fat , specifically in the overweight group . Adaptations based on new research are needed to enhance the reliability and effectiveness of the intervention OBJECTIVE To evaluate the short- and long-term results of FATaintPHAT , a Web-based computer-tailored intervention aim ing to increase physical activity , decrease sedentary behavior , and promote healthy eating to contribute to the prevention of excessive weight gain among adolescents . DESIGN Cluster r and omized trial with an intervention group and a no-intervention control group . SETTING Twenty schools in the Netherl and s. PARTICIPANTS A total of 883 students ( aged 12 - 13 years ) . INTERVENTION The FATaintPHAT ( VETisnietVET in Dutch ) Web-based computer-tailored intervention . OUTCOME MEASURES Self-reported behaviors ( diet , physical activity , sedentary behavior ) and pedometer counts were measured at baseline and at 4-month and 2-year follow-up ; body mass index ( BMI ) , waist circumference , and fitness were measured at baseline and at 2-year follow-up . Descriptive and multilevel regression analyses were conducted among the total study population and among students not meeting behavioral recommendations at baseline ( students at risk ) . RESULTS The complete case analyses showed that FATaintPHAT had no effect on BMI and waist circumference . However , the intervention was associated with lower odds ( 0.54 ) of drinking more than 400 mL of sugar-sweetened beverages per day and with lower snack intake ( β = -0.81 snacks/d ) and higher vegetable intake ( β = 19.3 g/d ) but also with a lower step count ( β = -10 856 steps/wk ) at 4-month follow-up . In addition , among students at risk , FATaintPHAT had a positive effect on fruit consumption ( β = 0.39 g/d ) at 4-month follow-up and on step count ( β = 14 228 steps/wk ) at 2-year follow-up but an inverse effect on the odds of sports participation ( odds ratio , 0.45 ) at 4-month follow-up . No effects were found for sedentary behavior . CONCLUSION The FATaintPHAT intervention was associated with positive short-term effects on diet but with no effects or unfavorable effects on physical activity and sedentary behavior PURPOSE To compare the effectiveness of a Web-based physical activity ( PA ) intervention with identical content delivered in a printed workbook among a sample of adolescent girls . METHODS Participants consisted of 319 girls with home Internet access enrolled in four middle schools within one school district . A r and omized trial design was used to compare changes in PA self-efficacy and intentions after two weeks of exposure to either a Web- or print-based intervention delivered to their home . Self-reported physical activity was assessed as a secondary outcome . Analysis of covariance was conducted to determine changes between the intervention groups while controlling for baseline levels of PA constructs . RESULTS Both Web and print groups had significant changes in physical activity self-efficacy ( Web : t[155 ] = 2.58 , p = .01 ; print : t[156 ] = 3.11 , p = .002 ) and intentions ( Web : t[157 ] = 2.27 , p = .02 ; print : t[159 ] = 6.32 , p < or = .001 ) . The print group demonstrated significantly greater increases in intentions compared with the Web group ( F [ 1,315 ] = 13.53 , p < or = .001 ) . Self-reported physical activity increased significantly in the print group only ( t[159 ] = 3.21 , p = .002 ) . CONCLUSIONS It can not be assumed that new media technologies are superior to traditional media such as print for health communication to adolescents . These results suggest that a printed workbook was more effective than an identical website for increasing physical activity intentions and behavior among a sample of middle school girls Objective : This r and omized controlled trial tested the efficacy of an internetbased lifestyle behavior modification program for weight management in African-American girls . Design : African-American girls were r and omly assigned to an interactive behavioral internet program or an internet health education program , the control condition . The behavioral intervention included internet counseling and was highly interactive . The control intervention was a passive ( non-interactive ) educational program . Parents were also participants in the study . Participants in both treatment groups met in face-to-face sessions on four occasions over the first 12 weeks of a 6-month intervention . Subjects : The study enrolled 57 African-American adolescent girls ( ages 11 to 15 years ) who were overweight or obese and had at least one biological parent who was obese [ body mass index ( BMI ) > 30 kg/m2 ] . Of the 57 participants , 50 ( 88 % ) completed the 6-month trial . Measurements : Outcome data , including BMI , body weight , body composition , dietary intake , and weight loss behaviors were collected at baseline and 6-months later . A computer server tracked utilization of the websites . Participation in the program was measured by number of “ hits ” on the website . Results : Compared to the control condition , adolescents in the behavioral treatment lost more body fat ( group difference = 1.6 % body fat ) and parents lost significantly more body weight ( group difference = 2.1 kg ) . Utilization of the behavioral website by adolescents and parents was associated with positive outcome . Dietary fat intake was lowered for adolescents and parents in the behavioral treatment group . Conclusion : An internet-based behavioral intervention was superior to internet-based health education and yielded decreased body fat for adolescent girls and decreased body weight for parents PURPOSE To evaluate the effects of a middle school physical activity intervention , new in combining an environmental and computer tailored component ; and to evaluate the effects of parental involvement . METHODS A clustered r and omized controlled design was used . A r and om sample of 15 schools with 7th and 8th grade rs was r and omly assigned to one of three conditions : ( a ) intervention with parental support , ( b ) intervention alone , and ( c ) control group . The intervention was new in combining environmental strategies with computer-tailored feedback to increase levels of moderate to vigorous physical activity . The intervention was implemented by the school staff . Physical activity was measured through a question naire in the total sample and with accelerometers in a sub sample of adolescents . RESULTS The intervention with parental support led to an increase in self-reported school-related physical activity of , on average , 6.4 minutes per day ( p < or = .05 , d = .40 ) . Physical activity of light intensity measured with accelerometers decreased with , on average , 36 minutes per day as a result of the intervention with parental support ( p < or = .05 , d = .54 ) . Physical activity of moderate to vigorous intensity measured with accelerometers significantly increased with on average 4 minutes per day in the intervention group with parental support , while it decreased with almost 7 minutes per day in the control group ( p < or = .05 , d = .46 ) . CONCLUSIONS The physical activity intervention , implemented by the school staff , result ed in enhanced physical activity behaviors in both middle school boys and girls . The combination of environmental approaches with computer-tailored interventions seemed promising The rising tide of obesity erodes the health of youths and many times results in adult obesity . The purpose of this investigation was to examine the effectiveness of an eight-session health promotion/transtheoretical model Internet/video-delivered intervention to increase physical activity and reduce dietary fat among low-income , culturally diverse , seventh- grade students . Those who completed more than half the sessions increased exercise , t ( 103 ) = -1.99 , p = .05 , and decreased the percentage of dietary fat , t ( 87 ) = 2.73 , p = .008 . Responses to the intervention by stage of change , race , and income are examined BACKGROUND This study reports the results of a 9-week intervention on the physical activity levels of adolescent males . METHODS Participants were 473 10- to 14-year-old Houston Boy Scouts ( 42 troops ) with troops r and omly assigned to intervention or control conditions . Data were collected in spring ( 16 troops ) and fall ( 26 troop ) waves during 2003 . Intervention participants received a 9-week troop and Internet program to increase physical activity skills , self-efficacy and goal - setting . Physical activity was assessed at baseline , end of the intervention ( Post#1 ) and post-6 months ( Post#2 ) by accelerometer . Minutes of sedentary , light and moderate to vigorous physical activity were calculated . Repeated measure analyses were performed to test differences in physical activity over time between groups with participants nested in troops . RESULTS A three-way interaction ( group * time * wave ) that approached significance ( P = 0.051 ) indicated a 12-min reduction in sedentary behavior among spring intervention participants . A significant three-way interaction ( P = 0.011 ) ( group * time * wave ) indicated a 12-min increase in light intensity activity among the spring intervention group . CONCLUSION Participation in the Fit for Life badge program result ed in a trend towards a small decrease in sedentary behavior and increased light intensity physical activity among spring participants only . There was no effect on moderate to vigorous physical activity This paper reports the final 24-month outcomes of a r and omized controlled trial evaluating the effect of additional therapeutic contact ( ATC ) as an adjunct to a community-based weight-management program for overweight and obese 13–16-year-olds . ATC involved telephone coaching or short-message-service and /or email communication once per fortnight . Adolescents were r and omized to receive the Loozit group program — a two-phase behavioral lifestyle intervention with ( n=73 ) , or without ( n=78 ) , ATC in Phase 2 . Adolescents/parents separately attended seven weekly group sessions ( Phase 1 ) , followed by quarterly adolescent sessions ( Phase 2 ) . Assessor-blinded , 24-month changes in anthropometry and metabolic health included primary outcomes body mass index ( BMI ) z-score and waist : height ratio ( WHtR ) . Secondary outcomes were self-reported psychosocial and lifestyle changes . By 24 months , 17 adolescents had formally withdrawn . Relative to the Loozit program alone , ATC largely had no impact on outcomes . Secondary pre-post assessment of the Loozit group program showed mean ( 95 % CI ) reductions in BMI z-score ( −0.13 ( −0.20 , −0.06 ) ) and WHtR ( −0.02 ( −0.03 , −0.01 ) ) in both arms , with several metabolic and psychosocial improvements . Adjunctive ATC did not provide further benefits to the Loozit group program . We recommend that further work is needed to optimize technological support for adolescents in weight-loss maintenance . Australian New Zeal and Clinical Trials Registry Number ACTRNO12606000175572 OBJECTIVE To investigate the differences in effects of a computer tailored physical activity advice as compared to generic information in adolescents . METHODS Students ( mean age , 14.6+/-1.2 ) out of 90 classes from six different Flemish schools were r and omly assigned to the tailored intervention ( n=563 ) or the generic non-tailored intervention ( n=608 ) condition . Both interventions included information on public health recommendations and tips on becoming more active . Participants in both groups received their assessment and feedback at baseline , at 4 weeks and at 3 months during school hours . Physical activity levels were determined using an adolescent adaptation of the International Physical Activity Question naire ( IPAQ ) . RESULTS After 4 weeks , almost all physical activity scores increased over time in both the generic and the tailored intervention group . No differences between groups were found ( all F < or = 0.07 ) . After 3 months , the generic intervention was more effective for increasing ' walking in leisure time ' among students not complying with recommendations . For all other physical activity scores , no differences between groups were found ( all F < or = 2.3 ) . CONCLUSIONS In contrast to the expectations , changes in physical activity scores did not differ between the tailored and the non-tailored intervention group . For most of the physical activity scores increases were found in both groups |
13,745 | 23,984,074 | The results did not show the relation between the six-minute walk distance and adverse events after CABG .
The predictive power of the distance walked for death in HF patients undergoing cardiac surgery was not found .
It is not yet proved if the change in the six-minute walk distance is associated with prognosis . | Background .
The prognostic value of cardiopulmonary exercise testing ( CPET ) is known , but the predictive value of 6MWT in patients with heart failure ( HF ) and patients undergoing coronary artery bypass grafting ( CABG ) is not established yet .
Objective .
We conducted a systematic review exploring the prognostic value of 6MWT in HF patients undergoing cardiac surgery .
The aim was to find out whether the change in the distance walked during follow-up visits was associated with prognosis . | Background — Frailty is an emerging concept in medicine yet to be explored as a risk factor in cardiac surgery . Where elderly patients are increasingly referred for cardiac surgery , the prevalence of a frail group among these is also on the rise . We assessed frailty as a risk factor for adverse outcomes after cardiac surgery . Methods and Results — Functional measures of frailty and clinical data were collected prospect ively for all cardiac surgery patients at a single center . Frailty was defined as any impairment in activities of daily living ( Katz index ) , ambulation , or a documented history of dementia . Of 3826 patients , 157 ( 4.1 % ) were frail . Frail patients were older , were more likely to be female , and had risk factors for adverse surgical outcomes . By logistic regression , frailty was an independent predictor of in-hospital mortality ( odds ratio 1.8 , 95 % CI 1.1 to 3.0 ) , as well as institutional discharge ( odds ratio 6.3 , 95 % CI 4.2 to 9.4 ) . Frailty was an independent predictor of reduced midterm survival ( hazard ratio 1.5 , 95 % CI 1.1 to 2.2 ) . Conclusions — Frailty is a risk for postoperative complications and an independent predictor of in-hospital mortality , institutional discharge , and reduced midterm survival . Frailty screening improves risk assessment in cardiac surgery patients and may identify a subgroup of patients who may benefit from innovative processes of care OBJECTIVES The purpose of this study was to test the value of gait speed , a clinical marker for frailty , to improve the prediction of mortality and major morbidity in elderly patients undergoing cardiac surgery . BACKGROUND It is increasingly difficult to predict the elderly patient 's risk posed by cardiac surgery because existing risk assessment tools are incomplete . METHODS A multicenter prospect i ve cohort of elderly patients undergoing cardiac surgery was assembled at 4 tertiary care hospitals between 2008 and 2009 . Patients were eligible if they were 70 years of age or older and were scheduled for coronary artery bypass and /or valve replacement or repair . The primary predictor was slow gait speed , defined as a time taken to walk 5 m of ≥ 6 s. The primary end point was a composite of in-hospital post-operative mortality or major morbidity . RESULTS The cohort consisted of 131 patients with a mean age of 75.8 ± 4.4 years ; 34 % were female patients . Sixty patients ( 46 % ) were classified as slow walkers before cardiac surgery . Slow walkers were more likely to be female ( 43 % vs. 25 % , p = 0.03 ) and diabetic ( 50 % vs. 28 % , p = 0.01 ) . Thirty patients ( 23 % ) experienced the primary composite end point of mortality or major morbidity after cardiac surgery . Slow gait speed was an independent predictor of the composite end point after adjusting for the Society of Thoracic Surgeons risk score ( odds ratio : 3.05 ; 95 % confidence interval : 1.23 to 7.54 ) . CONCLUSIONS Gait speed is a simple and effective test that may identify a subset of vulnerable elderly patients at incrementally higher risk of mortality and major morbidity after cardiac surgery BACKGROUND AND PURPOSE The interpretation of patient scores on clinical tests of physical mobility is limited by a lack of data describing the range of performance among people without disabilities . The purpose of this study was to provide data for 4 common clinical tests in a sample of community-dwelling older adults . SUBJECTS Ninety-six community-dwelling elderly people ( 61 - 89 years of age ) with independent functioning performed 4 clinical tests . METHODS Data were collected on the Six-Minute Walk Test ( 6MW ) , Berg Balance Scale ( BBS ) , and Timed Up & Go Test ( TUG ) and during comfortable- and fast-speed walking ( CGS and FGS ) . Intraclass correlation coefficients ( ICCs ) were used to determine the test-retest reliability for the 6MW , TUG , CGS , and FGS measurements . Data were analyzed by gender and age ( 60 - 69 , 70 - 79 , and 80 - 89 years ) cohorts , similar to previous studies . Means , st and ard deviations , and 95 % confidence intervals for each measurement were calculated for each cohort . RESULTS The 6MW , TUG , CGS , and FGS measurements showed high test-retest reliability ( ICC [2,1]=.95-.97 ) . Mean test scores showed a trend of age-related declines for the 6MW , BBS , TUG , CGS , and FGS for both male and female subjects . DISCUSSION AND CONCLUSION Preliminary descriptive data suggest that physical therapists should use age-related data when interpreting patient data obtained for the 6MW , BBS , TUG , CGS and FGS . Further data on these clinical tests with larger sample sizes are needed to serve as a reference for patient comparisons Gremeaux V , Deley G , Duclay J , Antoine D , Hannequin A , Casillas JM : The 200-m fast-walk test compared with the 6-min walk test and the maximal cardiopulmonary test : A pilot study . Objective : The 200-m fast-walk test has been proposed as a high- intensity performance test in healthy , elderly subjects . Adaptation of low-risk coronary artery disease patients during this test were compared with those in a 6-min walk test and a maximal cardiopulmonary exercise test . Design : Thirty patients with stable coronary artery disease ( 51.9 ± 8.7 yrs ) , referred to the cardiac rehabilitation department , performed a cardiopulmonary exercise test , then a 200-m fast-walk test and a 6-min walk test in a r and om order , before and after the training period ( 6 wks , 3 days per week ) . Heart rate was monitored during each test . Peak workload of cardiopulmonary exercise test , distance walked on the 6-min walk test , and time to perform the 200-m fast-walk test were measured . A sub sample of ten patients performed the exercise test with gas exchange measurements , with ventilatory threshold determination . Results : All subjects completed walk tests without complaint or incidents . Compared with the cardiopulmonary exercise test , the cardiac relative intensity was higher during the 200-m fast-walk test than during the 6-min walk test , both before ( 89.6 % vs. 78.1 % of cardiopulmonary exercise test maximal heart rate ; P < 0.05 ) and after ( 83.8 % vs. 74.3 % ; P < 0.05 ) training . Among the sub sample of ten patients , the 200-m fast-walk test heart rate was significantly higher than the ventilatory threshold heart rate , which did not differ from the 6-min walk test heart rate . The 200-m fast-walk test time significantly decreased after training ( −9.1 % , P < 0.01 ) . Conclusion : In patients with coronary artery disease at low risk , the 200-m fast-walk test explores higher levels of cardiorespiratory capacity than the 6-min walk test . Thus , this could be a useful field test in complement to the cardiopulmonary exercise test to assess functional capacity improvement and up date training targets regularly during the course of high-intensity rehabilitation programs in this population OBJECTIVE To estimate the minimal clinical ly important difference ( MCID ) for the 6-minute walk test ( 6MWT ) and the 200-m fast-walk test ( FWT ) in patients with coronary artery disease ( CAD ) during a cardiac rehabilitation program . DESIGN Prospect i ve study using distribution- and anchor-based methods . SETTING Out patients from a cardiac rehabilitation unit . PARTICIPANTS Stable patients with CAD ( N=81 ; 77 men ; mean±SD age , 58.1±8.7y ) enrolled 31±12.1 days after an acute coronary syndrome ( ACS ) . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES 6MWT and 200-m FWT results before and after an 8-week cardiac rehabilitation program and at the 6th and 12th sessions . Patients and physiotherapists who supervised the training were asked to provide a global rating of perceived change in walking ability while blinded to changes in walk test performances . RESULTS Mean change in 6MWT distance ( 6MWD ) in patients who reported no change was -6.5 m versus 23.3 m in those who believed their performance had improved ( P<.001 ) . This result was consistent with the MCID determined by using the distribution method ( 23 m ) . Considering a 25-m cutoff , positive and negative predictive values were 0.9 and .63 , respectively . Conversely , there was no difference in 200-m FWT performance between these 2 groups ( 0.1 vs -1.4s , respectively ) . There was poor agreement with the physiotherapist 's perceived change . CONCLUSIONS The MCID for 6MWD in patients with CAD after ACS was 25 m . This result will help physicians interpret 6MWD change and help research ers estimate sample sizes in further studies using 6MWD as an endpoint BACKGROUND Our purpose was to evaluate the reliability , validity , and responsiveness of the 6-minute walk test ( 6MWT ) in patients with heart failure ( HF ) enrolled in the R and omized Evaluation of Strategies for Left Ventricular Dysfunction ( RESOLVD ) pilot study . METHODS A total of 768 patients was enrolled in a multicenter r and omized clinical trial evaluating the effect of c and esartan , enalapril , and metoprolol on left ventricular ejection fraction ( LVEF ) , 6MWT distance , neurohormones , and quality of life . The 6MWT was performed once at screening and twice at baseline , 18 weeks , and 43 weeks by a st and ardized method . RESULTS Test-retest reliability at baseline ( intraclass correlation coefficient [ ICC ] = 0.90 ) , 18 weeks ( ICC = 0.88 ) , and 43 weeks ( ICC = 0.91 ) was very good . Baseline 6MWT distance was weakly inversely correlated to the quality -of-life cumulative score ( r = -0.26 , P = .0001 ) and moderately inversely correlated to the New York Heart Association functional classification ( NYHA-FC ) ( r = -0.43 , P = .001 ) . In the RESOLVD study , the 6MWT was not responsive to change when effect sizes and st and ardized response means were used . Disease-specific quality of life was responsive to change in patients treated with c and esartan and enalapril and NYHA-FC was responsive to change in the c and esartan and enalapril combination and for enalapril alone with small effect sizes . The 6MWT , NYHA-FC , and quality of life were not responsive to change during the metoprolol or placebo phase . CONCLUSIONS The 6MWT is highly reproducible in patients with symptoms of HF . It is somewhat correlated to NYHA-FC and quality of life . Overall , quality of life was most responsive to change , whereas 6MWT and NYHA-FC were comparable but less responsive to change in the RESOLVD study 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 The Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure trial tested the hypothesis that continuous positive airway pressure ( CPAP ) would improve the survival rate without heart transplantation of patients who have central sleep apnea and heart failure . METHODS After medical therapy was optimized , 258 patients who had heart failure ( mean age [ + /-SD ] , 63+/-10 years ; ejection fraction , 24.5+/-7.7 percent ) and central sleep apnea ( number of episodes of apnea and hypopnea per hour of sleep , 40+/-16 ) were r and omly assigned to receive CPAP ( 128 patients ) or no CPAP ( 130 patients ) and were followed for a mean of two years . During follow-up , sleep studies were conducted and measurements of the ejection fraction , exercise capacity , quality of life , and neurohormones were obtained . RESULTS Three months after undergoing r and omization , the CPAP group , as compared with the control group , had greater reductions in the frequency of episodes of apnea and hypopnea ( -21+/-16 vs. -2+/-18 per hour , P<0.001 ) and in norepinephrine levels ( -1.03+/-1.84 vs. 0.02+/-0.99 nmol per liter , P=0.009 ) , and greater increases in the mean nocturnal oxygen saturation ( 1.6+/-2.8 percent vs. 0.4+/-2.5 percent , P<0.001 ) , ejection fraction ( 2.2+/-5.4 percent vs. 0.4+/-5.3 percent , P=0.02 ) , and the distance walked in six minutes ( 20.0+/-55 vs. -0.8+/-64.8 m , P=0.016 ) . There were no differences between the control group and the CPAP group in the number of hospitalizations , quality of life , or atrial natriuretic peptide levels . An early divergence in survival rates without heart transplantation favored the control group , but after 18 months the divergence favored the CPAP group , yet the overall event rates ( death and heart transplantation ) did not differ ( 32 vs. 32 events , respectively ; P=0.54 ) . CONCLUSIONS Although CPAP attenuated central sleep apnea , improved nocturnal oxygenation , increased the ejection fraction , lowered norepinephrine levels , and increased the distance walked in six minutes , it did not affect survival . Our data do not support the use of CPAP to extend life in patients who have central sleep apnea and heart failure AIMS The 6-min walk test may serve as a more simple clinical tool to assess functional capacity in congestive heart failure than determination of peak oxygen uptake by cardiopulmonary exercise testing . The purpose of the study was to prospect ively examine whether the distance ambulated during a 6-min walk test ( i ) correlates with peak oxygen uptake , ( ii ) allows peak oxygen uptake to be predicted , and ( iii ) provides prognostic information similar to peak oxygen uptake in patients with dilated cardiomyopathy and left ventricular ejection fraction < or = 35 % . METHODS AND RESULTS In 113 patients ( age : 54+/-12 years , NYHA : 2.2+/-0.8 ) with dilated cardiomyopathy ( left ventricular ejection fraction 19+/-7 % ) a 6-min walk test and cardiopulmonary exercise testing were performed . The 6-min walk test and peak oxygen uptake were closely correlated at the initial visit ( r=0.68 , n=113 ) , as well as after 263+/-114 ( r=0.71 , n=28 ) and 381+/-170 days ( r=0.74 , n=14 ) . During serial exercise testing the 6-min walk test allowed peak oxygen uptake to be reliably predicted ( r=0.76 between calculated and real peak oxygen uptake ) . After 528+/-234 days , 42 patients were hospitalized due to worsening heart failure and /or died from cardiovascular causes . Compared to clinical ly stable patients , these 42 patients walked a shorter distance ( 423+/-104 vs 501+/-95 m , P<0.001 ) and had a lower peak oxygen uptake ( 12.7+/-4.0 vs 17.4 + 5.6 ml x min(-1 ) x kg(-1 ) , P<0.001 ) . By univariate analysis the 6-min walk test outperformed other prognostic parameters such as left ventricular ejection fraction , cardiac index and plasma norepinephrine concentration and conferred a prognostic power similar to peak oxygen uptake . This predictive value could be further improved in a multivariate model , by combining the 6-min walk test with independent variables , such as left ventricular ejection fraction or cardiac index . CONCLUSION The 6-min walk test correlated with peak oxygen uptake when tested serially over the course of the disease . Although both tests define two distinct domains of functional capacity , the 6-min walk test provides prognostic information very similar to peak oxygen uptake in congestive heart failure patients with dilated cardiomyopathy BACKGROUND Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies , but its clinical effects have not been evaluated in large , multicenter trials . METHODS AND RESULTS We enrolled 278 patients with moderate to severe heart failure ( 6-minute walk distance , 150 to 450 m ) and a left ventricular ejection fraction < or = 0.35 at 31 centers . After an open-label , run-in period , each patient was r and omly assigned ( double-blind ) to either placebo ( n = 145 ) or carvedilol ( n = 133 ; target dose , 25 to 50 mg BID ) for 6 months , while background therapy with digoxin , diuretics , and an ACE inhibitor remained constant . Compared with placebo , patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration , as evaluated by changes in the NYHA functional class ( P = .014 ) or by a global assessment of progress judged either by the patient ( P = .002 ) or by the physician ( P < .001 ) . In addition , treatment with carvedilol was associated with a significant increase in ejection fraction ( P < .001 ) and a significant decrease in the combined risk of morbidity and mortality ( P = .029 ) . In contrast , carvedilol therapy had little effect on indirect measures of patient benefit , including changes in exercise tolerance or quality -of-life scores . The effects of the drug were similar in patients with ischemic heart disease or idiopathic dilated cardiomyopathy as the cause of heart failure . CONCLUSIONS These findings indicate that , in addition to its favorable effects on survival , carvedilol produces important clinical benefits in patients with moderate to severe heart failure treated with digoxin , diuretics , and an ACE inhibitor BACKGROUND Previous studies have suggested that cardiac resynchronization achieved through atrial-synchronized biventricular pacing produces clinical benefits in patients with heart failure who have an intraventricular conduction delay . We conducted a double-blind trial to evaluate this therapeutic approach . METHODS Four hundred fifty-three patients with moderate-to-severe symptoms of heart failure associated with an ejection fraction of 35 percent or less and a QRS interval of 130 msec or more were r and omly assigned to a cardiac-resynchronization group ( 228 patients ) or to a control group ( 225 patients ) for six months , while conventional therapy for heart failure was maintained . The primary end points were the New York Heart Association functional class , quality of life , and the distance walked in six minutes . RESULTS As compared with the control group , patients assigned to cardiac resynchronization experienced an improvement in the distance walked in six minutes ( + 39 vs. + 10 m , P=0.005 ) , functional class ( P<0.001 ) , quality of life ( -18.0 vs. -9.0 points , P= 0.001 ) , time on the treadmill during exercise testing ( + 81 vs. + 19 sec , P=0.001 ) , and ejection fraction ( + 4.6 percent vs. -0.2 percent , P<0.001 ) . In addition , fewer patients in the group assigned to cardiac resynchronization than control patients required hospitalization ( 8 percent vs. 15 percent ) or intravenous medications ( 7 percent vs. 15 percent ) for the treatment of heart failure ( P<0.05 for both comparisons ) . Implantation of the device was unsuccessful in 8 percent of patients and was complicated by refractory hypotension , bradycardia , or asystole in four patients ( two of whom died ) and by perforation of the coronary sinus requiring pericardiocentesis in two others . CONCLUSIONS Cardiac resynchronization results in significant clinical improvement in patients who have moderate-to-severe heart failure and an intraventricular conduction delay Aims : The authors investigated the additive prognostic value of the 6-minute walk test ( 6MWT ) to Euroscore in patients with severe aortic stenosis undergoing aortic valve replacement ( AVR ) Methods and results : 208 patients with severe AS underwent the 6MWT before AVR , as part of a r and omised trial ( ASSERT ) comparing stented and stentless aortic valves . Clinical follow-up was available for 200 patients up to 12 months . The rate of death , myocardial infa rct ion ( MI ) or stroke ( time to first event ) was 13 % ( n = 14 ) in patients walking < 300 metres compared to 4 % ( n = 4 ) in those who walked ⩾300 metres ( p = 0.017 ) . When rate of death , MI or stroke by Euroscore risk was stratified by 6-minute walking distance , the 6MWT added prognostic information . In a Cox regression analysis 6MWT distance was the only variable retained as an independent predictor of the composite outcome of death , MI or stroke at 12 months ( HR 0.28 95 % CI 0.09 to 0.85 , p = 0.025 ) . Conclusions : The 6MWT is safe and feasible to carry out in patients with severe aortic stenosis before AVR , and provides potentially important functional and prognostic information to clinical assessment and the Euroscore risk score |
13,746 | 25,775,190 | Our systematic review of the last 4 years of treatment emphasizes known treatment strategies already in practice , but also identifies new therapeutic approaches with additional biologic agents and hematopoietic stem cell transplantation | PURPOSE OF REVIEW To review pharmacologic and nonpharmacologic therapies in the treatment of systemic sclerosis ( SSc ) from 2011 to 2014 through a systematic review .
SUMMARY SSc is an orphan autoimmune disorder with significant morbidity and mortality .
Although there has been significant progress over the years in therapeutic options for SSc , the mainstays of treatment are organ-based and primarily symptom management . | The majority of patients with systemic sclerosis ( SSc ) have gastrointestinal ( GI ) tract involvement , but therapies using prokinetic agents are usually unsatisfactory . Ghrelin stimulates gastric motility in healthy human volunteers . In this study , we investigated whether ghrelin could improve gastric emptying in patients with gastrointestinal symptoms due to SSc . The study was performed in a r and omized , double-blind , placebo-controlled crossover fashion on two occasions . Ten SSc patients with GI tract involvement received an infusion of either ghrelin ( 5.0 μg/kg ) or saline , and gastric emptying rate was evaluated by ¹³C-acetic acid breath test . Gastric emptying was significantly accelerated by ghrelin infusion in patients with SSc ( ghrelin vs. saline : 43.3 ± 11.4 min vs. 53.4 ± 5.4 min , P=0.03 ) . No serious adverse effects were observed . Our results suggest that ghrelin might represent a new therapeutic approach for GI tract involvement in patients with SSc OBJECTIVES This paper aims to investigate the efficacy of intravenous immunoglobulin ( IVIG ) for skin sclerosis in diffuse cutaneous systemic sclerosis ( dcSSc ) by a r and omised , double-blind , placebo-controlled , multicentre trial ( DBT ) with subsequent long-term observational and readministration studies . METHODS In DBT , IVIG ( 400mg/kg/day for 5 consecutive days : a single course ) or placebo ( P ) was intravenously administered to 63 dcSSc patients of 17 medical institutions in Japan , and changes in the modified Rodnan skin thickness score ( MRSS ) 12 weeks after administration or at discontinuation were compared as a primary endpoint . Patients with a 5-point or more improvement in the MRSS were continuously observed ( long-term observational study ) , whereas IVIG was administered to those with less than a 5-point improvement ( readministration study ) . RESULTS In DBT , changes in the MRSS ( mean±SD ) were -3.3±4.2 and -4.2±4.6 in IVIG and P groups , respectively , and were not significantly different . Non-responder patients were subsequently subjected to the readministration study , and the change in the MRSS ( LS-mean±SEM ) at 60 weeks after the first administration was -8.3±1.0 in the IVIG → IVIG ( GG ) group treated with two courses of IVIG administration and -4.1±1.1 in the P → IVIG ( PG ) group treated with a single course of IVIG administration . The GG group represented a significant improvement in the MRSS against the PG group ( p=0.0040 ) . CONCLUSIONS Although the primary endpoint was not achieved in DBT , repeated administration of IVIG for two courses may be effective for skin sclerosis in dcSSc . Further investigation by the administration of plural courses will be necessary Objective To assess the safety and effectiveness of imatinib mesylate in the treatment of diffuse cutaneous systemic sclerosis ( dcSSc ) . Methods In this phase IIa , open-label , single-arm clinical trial , 30 patients with dcSSc were treated with imatinib 400 mg daily . Patients were monitored monthly for safety assessment s. Modified Rodnan skin scores ( MRSS ) were assessed every 3 months . Pulmonary function testing , chest radiography , echocardiography and skin biopsies were performed at baseline and after 12 months of treatment . Results Twenty-four patients completed 12 months of therapy . 171 adverse events ( AE ) with possible relation to imatinib were identified ; 97.6 % were grade 1 or 2 . Twenty-four serious AE were identified , two of which were attributed to study medication . MRSS decreased by 6.6 points or 22.4 % at 12 months ( p=0.001 ) . This change was evident starting at the 6-month time point ( Δ=−4.5 ; p<0.001 ) and was seen in patients with both early and late-stage disease . Forced vital capacity ( FVC ) improved by 6.4 % predicted ( p=0.008 ) , and the diffusion capacity remained stable . The improvement in FVC was significantly greater in patients without interstitial lung disease . Health-related quality of life measures improved or remained stable . Blinded dermatopathological analysis confirmed a significant decrease in skin thickness and improvement in skin morphology . Conclusions Treatment with imatinib was tolerated by most patients in this cohort . Although AE were common , most were mild to moderate . In this open-label experience , improvements in skin thickening and FVC were observed . Further investigation of tyrosine kinase inhibition for dcSSc in a double-blind r and omised placebo controlled trial is warranted . Clinical Trials.gov , Objective . A prospect i ve observational study of mycophenolate mofetil ( MMF ) treatment in patients with diffuse progressive cutaneous systemic sclerosis ( SSc ) of recent onset . Methods . Twenty-five previously untreated consecutive patients with recent-onset ( < 24 mo ) diffuse progressive cutaneous SSc received MMF as the only disease-modifying therapy . Modified Rodnan skin score ( mRSS ) and affected body surface area ( BSA ) were compared from initiation of MMF to study end . Pulmonary function tests performed at the same institution before therapy and at study end were available in 15 patients . Histopathology and real-time PCR assessment of fibrosis-related gene expression were performed before and after treatment in skin biopsies from 3 patients . Results . At 18.2 ± 8.73 months of MMF therapy ( median 2000 mg/day ) the mRSS decreased from 24.56 ± 8.62 to 14.52 ± 10.9 ( p = 0.0004 ) and the affected BSA from 36 % ± 16 % to 14 % ± 13.3 % ( p = 0.00001 ) . Pulmonary function tests remained stable from initiation of MMF to the end of the study . Skin histopathology showed a remarkable reduction in accumulation of fibrotic tissue . Real-time PCR of skin biopsies demonstrated a marked decrease in expression of fibrosis-related genes . Conclusion . Patients with diffuse progressive cutaneous SSc of recent onset treated with MMF experienced marked improvement in skin involvement and stabilization of pulmonary function . Skin biopsies from 3 patients demonstrated histopathological improvement and decreased expression of fibrosis-related genes The association of cyclophosphamide ( CYC ) and prednisone ( PRED ) for the treatment of lung fibrosis in systemic sclerosis ( SSc ) was only evaluated in uncontrolled studies , although in idiopathic interstitial lung disease ( ILD ) this association seems to be beneficial in patients with non-specific interstitial pneumonia ( NSIP ) . Objectives : To treat SSc-ILD in a prospect i ve open-label controlled study based on lung pattern during 12 months of treatment . Methods : A 3-year analysis was also performed . Twenty-four consecutive patients with SSc and ILD were su bmi tted to an open lung biopsy . Eighteen patients ( NSIP ) were r and omized in two groups : CYC versus CYC + PRED during 12 months . Lung function tests ( diffusion lung capacity of monoxide carbone corrected for hemoglobin concentration ( DLCO-Hb ) , forced vital capacity ( FVC ) , total lung capacity ) and Modified Rodnan Skin Score ( MRSS ) were performed before , after one of treatment and after 3 years from the end of the treatment . Results : Pulmonary function tests were similar in both groups on baseline . After 1 year of treatment , FVC% was comparable between CYC groups ( p = 0.72 ) and in CYC + PRED ( p = 0.40 ) . Three years after the end of treatment , FVC% values ( p = 0.39 in group CYC and p = 0.61 in CYC + PRED and p = 0.22 in CYC + PRED ) and DLCO-Hb ( p = 0.54 in CYC and p = 0.28 in CYC + PRED ) were similar compared to 1 year of treatment . We observed a reduction of the MRSS in the CYC + PRED group after 1 year of treatment ( p = 0.02 ) ; although after 3 years , MRSS values remained stable in both groups . Conclusions : CYC was effective to stabilize lung function parameters in NSIP lung pattern of SSc disease for 3 years after the end of a 1-year therapy Objective The primary objective of the study was to explore safety and tolerability of hyperimmune caprine serum ( AIMS PRO ) in established diffuse cutaneous systemic sclerosis ( SSc ) . Secondary objectives included assessment of potential efficacy and biological activity and exploration of c and i date biomarkers . Methods This was a double-blind parallel group r and omised placebo-controlled clinical trial . After informed consent 20 patients with established diffuse cutaneous SSc of greater than 3 years duration not receiving immunosuppressive therapy were r and omised to receive either active ( n=10 ) or placebo formulation ( n=10 ) by subcutaneous twice weekly injection over 26 weeks . Clinical assessment s were evaluated over 26 weeks . Results There were no safety concerns during this study . Frequency of adverse events was not different between active and placebo groups . Mean modified Rodnan Skin Score ( mRSS ) fell by 1.4±4.7 units with active treatment but increased by 2.1±6.4 units on placebo when baseline values were compared with 26 weeks and responder analysis showed clinical ly meaningful improvement in mRSS at 26 weeks in 5 ( 50 % ) of actively treated patients compared with 1 ( 10 % ) in the control group ( p=0.062 ) . PIIINP ( µg/L ) showed a comparatively larger increase in the treatment group compared with the placebo group , ( p=0.0118 ) . Conclusions These results confirm tolerability and safety of this novel biological agent in established diffuse SSc . The value of a placebo treated control group in small clinical trials evaluating skin disease in SSc is confirmed . Potential improvement in mRSS and changes in PIIINP in cases receiving active therapy suggest that this intervention may be of clinical benefit and warrants further evaluation OBJECTIVES To evaluate the effect of adaptive oral hygiene devices and orofacial exercise to improve gingival health among adults with systemic sclerosis ( SSc ) . METHODS Forty-eight patients with SSc were assigned r and omly to the multifaceted oral health intervention or usual dental care control group . Participants in the intervention group received a rechargeable , powered Oral-B ® oscillating-rotating-pulsating toothbrush and a Reach ® Access ™ Flosser that has a toothbrush-like h and le . For those with an oral aperture of less than 40 mm , orofacial exercises were taught . Participants in the control group were each given a manual toothbrush and dental floss . Participants in both groups received instructions and demonstration on the use of the devices , and were requested to perform the respective intervention twice a day for 6 months . Evaluations were at baseline , 3- , and 6-months . The main outcome was gingival index ( GI ) , an indicator of gingival inflammation . RESULTS Both groups showed significant reduction in GI scores at 6 months ( ps<0.005 ) . Reduction in GI scores of the intervention group at 6 months was 20.8 % which is considered to be clinical ly significant . Compared to the control group , the intervention group showed a significant and larger reduction in GI score by 8 % at 6 months ( p=0.0007 ) . CONCLUSIONS Results support the use of adaptive devices and orofacial exercise to improve gingival health in adults with SSc when compared to use of manual toothbrushing and finger-held flossing . Recommending and educating patients with SSc to use adaptive devices to clean the tooth surfaces looks promising for long-term oral health improvement Drug development for SSc has been hindered by the relative paucity of vali date d outcome measures and biomarkers for use in clinical trials . The Scleroderma Clinical Trials Consortium ( SCTC ) conducted an interactive session at the Scleroderma International Workshop in Cambridge , UK in July 2011 to discuss clinical trial design in SSc . The following issues were discussed : 1 ) primary outcome for trials of SSc - skin vs. lung vs. composite ; 2 ) ischaemic digital ulcers in SSc - healing vs. repair vs. composite ; 3 ) pulmonary arterial hypertension in SSc ; and 4 ) neglected aspects of SSc - opportunities for study or of lower priority and feasibility . R and omised controlled trials with collection of biospecimens are necessary to assess efficacy of therapeutic agents , vali date novel outcome measures , and discover and vali date potential biomarkers for each of these areas . Although SSc is a rare , heterogeneous disease , collaborative efforts led by the SCTC and other international networks will ultimately improve the design of clinical trials of promising therapies for SSc Introduction Pulmonary involvement represents a major cause of death of systemic sclerosis ( SSc ) patients . Recent data suggest that tyrosine kinase inhibitors , such as imatinib , may be a therapeutic option for SSc patients . However , preliminary published clinical trials were inconclusive about imatinib efficacy and showed side effects . The purpose of this study was to verify efficacy and tolerability of low-dose imatinib on interstitial lung disease in a cohort of SSc patients unresponsive to cyclophosphamide therapy . Methods Thirty consecutive SSc patients with active pulmonary involvement , unresponsive to cyclophosphamide , were treated with imatinib 200 mg/day for 6 months followed by a 6-month follow-up . A “ good response ” was defined as an increase of forced vital capacity ( FVC ) by more of 15 % and /or increase of diffusing capacity of carbon monoxide ( DLCO ) > 15 % and PaO2 > 90 % of initial value and high-resolution computed tomography ( H RCT ) -scan pattern unchanged or improved . Results Twenty-six patients completed the study . Three patients died and one patient was lost to follow-up . Four patients ( 15.32 % ) had a good response , 7 worsened and 15 had a stabilized lung disease . Overall , 19 ( 73.07 % ) patients had an improved or stabilized lung disease . After a 6-month follow-up , 12 ( 54.5 % ) of the 22 patients showed an improved or stabilized lung disease . Conclusions Lung function was stabilized in a large proportion of patients unresponsive to cyclophosphamide therapy and a beneficial outcome emerged from the analysis of H RCT lung scans . There was no significant improvement of skin involvement , and the low dose was well tolerated . These data provide useful suggestions to design future r and omized clinical trials for SSc therapeutics . Trial registration Clinical Trials.gov NCT00573326 . Registered 13 December 2007 OBJECTIVE To determine whether exposure to angiotensin-converting enzyme ( ACE ) inhibitors prior to the onset of scleroderma renal crisis ( SRC ) leads to worse outcomes of SRC . METHODS Prospect i ve cohort study of incident SRC subjects . The exposure of interest was ACE inhibitors prior to the onset of SRC . The outcomes of interest were death or dialysis during the first year after the onset of SRC . RESULTS A total of 87 subjects with incident SRC were identified and 1-year follow-up data were obtained in 75 ( 86 % ) subjects . Overall , 27 ( 36 % ) subjects died within the first year and an additional 19 ( 25 % ) remained on dialysis 1 year after the onset of SRC . In adjusted analyses , exposure to ACE inhibitors prior to the onset of SRC was associated with an increased risk of death ( hazard ratio 2.42 , 95 % CI 1.02 , 5.75 , p < 0.05 in the primary analysis and 2.17 , 95 % CI 0.88 , 5.33 , p = 0.09 after post-hoc adjustment for pre-existing hypertension ) . CONCLUSION Overall , the 1-year outcomes of SRC were poor . Prior exposure to ACE inhibitors was associated with an increased risk of death after the onset of SRC , although there was uncertainty around the magnitude of the risk and the possibility of residual confounding could not be ruled out . Further studies will be needed to confirm these findings Objective . We sought to retrospectively review a single-center experience using intravenous immunoglobulin ( IVIG ) for the treatment of refractory , active diffuse cutaneous systemic sclerosis ( dcSSc ) . Methods . The mean modified Rodnan Skin score ( mRSS ) at baseline was compared to the mRSS at 6 , 12 , 18 , and 24 months post-IVIG initiation by the paired Student t test . Changes in mRSS at 6 and 12 months were also compared to data from historical controls of 3 large , negative , multicenter , r and omized clinical trials of other medications [ D-penicillamine ( D-pen ) , recombinant human relaxin ( relaxin ) , and oral bovine type I collagen ( collagen ) ] and to patients treated with mycophenolate mofetil ( MMF ) alone using the Student t test . Results . Thirty patients were treated with adjunctive IVIG ( 2 g/kg/mo ) for refractory , active dcSSc . The mean baseline mRSS of our cohort was 29.6 ± 7.2 , and this significantly decreased to 24.1 ± 9.6 ( n = 29 , p = 0.0011 ) at 6 months , 22.5 ± 10.0 ( n = 25 , p = 0.0001 ) at 12 months , 20.6 ± 11.8 ( n = 23 , p = 0.0001 ) at 18 months , and 15.3 ± 6.4 ( n = 15 , p < 0.0001 ) at 24 months . The mean change in mRSS at 6 months was not significantly different in the IVIG group ( −5.3 ± 7.9 ) compared to the relaxin trial ( −4.8 ± 6.99 , p = 0.74 ) or MMF group ( −3.4 ± 7.4 , p = 0.26 ) ; however , at 12 months , the mean change in mRSS was significantly better in the IVIG group ( −8 ± 8.3 ) than in the D-pen ( −2.47 ± 8.6 , p = 0.005 ) and collagen ( −3.4 ± 7.12 , p = 0.005 ) groups , and was comparable to the group of primary MMF responders ( −7.1 ± 9 , p = 0.67 ) . Conclusion . Our observational study suggests that IVIG may be an effective adjunctive therapy for active dcSSc in patients failing other therapies OBJECTIVE To examine the effect of sildenafil in patients with Raynaud 's phenomenon ( RP ) secondary to limited cutaneous systemic sclerosis ( lcSSc ) . METHODS In this double-blind , placebo-controlled study , 57 patients with RP secondary to lcSSc were r and omized to receive modified-release sildenafil 100 mg once daily for 3 days followed by modified-release sildenafil 200 mg once daily for 25 days or placebo . The primary assessment was the percentage change in the number of RP attacks per week in the per- protocol population . Secondary end points included Raynaud 's Condition Score , duration of attacks , RP pain score , endothelial dysfunction assessed by a peripheral arterial tonometric ( PAT ) device , and serum biomarker levels . RESULTS The mean percentage reduction from baseline to day 28 in attacks per week was greater for modified-release sildenafil than for placebo ( -44.0 % versus -18.1 % , P = 0.034 ) ; the mean number of attacks per week improved from 25.0 at baseline to 19.3 after placebo treatment and from 30.5 to 18.7 after modified-release sildenafil treatment ( P = 0.244 ) . Decreases from baseline in Raynaud 's Condition Score , duration of attacks , and RP pain score were not significantly different between groups . Mean values and changes from baseline in PAT responses and serum biomarker levels were similar between groups . The most frequent adverse events were headache and dyspepsia ; the majority of adverse events were mild or moderate . CONCLUSION Our findings indicate that modified-release sildenafil reduced attack frequency in patients with RP secondary to lcSSc and was well tolerated . Modified-release sildenafil may be a treatment option in this patient population OBJECTIVE To better underst and the feasibility of using imatinib , a tyrosine kinase inhibitor , to treat active diffuse cutaneous systemic sclerosis ( dcSSc ) . METHODS We performed a 6-month , r and omized , double-blind , placebo-controlled , proof-of-concept pilot study of imatinib in patients with active dcSSc . Data on safety , modified Rodnan skin thickness scores ( MRSS ) , Health Assessment Question naire ( HAQ ) scores , patient 's and physician 's global assessment s ( 100-mm visual analog scale ) , and biomarkers in serum and skin biopsy sample s were collected . We used a 4:1 r and omization strategy ( imatinib 200 mg administered twice a day versus placebo ) , stratifying according to current use of methotrexate . The plan was to enroll 20 dcSSc patients . RESULTS After enrolling 10 patients ( 9 receiving active drug and 1 receiving placebo ) , we found poor tolerability and high rates of adverse events with imatinib , and study enrollment was discontinued . There was no significant difference in the mean MRSS in all patients who took imatinib ( 31.1 at baseline versus 29.4 at 6 months ) or in only those who completed 6 months of imatinib ( 31.0 at baseline versus 30.3 at 6 months ) , and there was no difference in the C-reactive protein level , erythrocyte sedimentation rate , physician 's global assessment , patient 's global assessment , response to the Health Transition query , or the HAQ scores between those who did and those who did not complete 6 months of therapy . Side effects were edema , fluid retention , fatigue , nausea , cramps/myalgias , diarrhea , alopecia , and anemia . Most side effects occurred within the first week of treatment , and even when imatinib was reintroduced at a lower dosage ( 200 mg daily ) , it was poorly tolerated . Two patients were hospitalized because of side effects of the medication . In general , biomarker levels in plasma and skin did not change . CONCLUSION Imatinib was poorly tolerated , and this could limit its application in SSc . The study was too small to form conclusions about the efficacy of imatinib in SSc Purpose : To examine the effect of a home orofacial exercise program on increasing oral aperture among adults with systemic sclerosis ( SSc ) . Method : Forty-eight adults with SSc were assigned r and omly to the multifaceted oral-health intervention or usual dental care control group . Participants with an oral aperture of < 40 mm in the intervention group received an orofacial exercise program , which included daily manual mouth-stretching and oral-augmentation exercises twice a day with a total of 6 minutes for 6 months . The outcome measure was oral aperture which was measured at baseline , 3-months , and 6-months intervals . Results : A significantly larger increase in oral aperture for participants received the orofacial exercise program was found when compared to those in the usual care at 3 months ( P = 0.01 ) , but not at 6-months evaluation . Participants ’ adherence rate to the exercise program was low ( 48.9 % ) . Conclusions : The orofacial exercise program intervention for adults with SSc and microstomia did not show significant improvement at 6 months . In addition to the low exercise adherence rate , insufficient frequencies , repetitions , and duration s of the orofacial exercises may contribute to these results . Implication s for Rehabilitation Microstomia in adults with systemic sclerosis ( SSc ) has profound impacts on their quality of life . Orofacial exercise programs have the potential to improve the size of oral aperture . Brief daily orofacial home exercises for 6 months did not result in a significant increase in the size of oral aperture OBJECTIVES Scleroderma renal crisis ( SRC ) is a relative rare yet dramatic event in the history of systemic sclerosis ( SSc ) . Several factors that may precipitate or protect from the development of SRC have been described in previous case-control studies . To date , no attempt has been made to evaluate these factors in an observational fashion . METHODS Retrospective data from 410 SSc patients with disease duration < 5 years at referral were evaluated in an observational fashion for the development of hypertensive or normotensive SRC within 5 years from the first visit at our centre . Baseline characteristics as well as the use of steroids or dhiydropyridine calcium-channel blockers ( CCB ) were analysed via the Cox regression method with time-dependent covariates . RESULTS In the multivariate model the diffuse subset the disease ( HR=5.728 CI(95)=2.199 - 14.918 , p<0.001 ) and the use of prednisone ( HR=1.015 , CI(95)=1.004 - 1.026 , p=0.006 ) result ed to be predictors for the development of SRC , with a risk to develop SRC increased by 1.5 % for every mg of prednisone/day consumed the trimester prior SRC . Contrariwise , the risk to develop SRC was highly reduced in those who were prescribed CCBs ( HR=0.094 , CI(95)=0.038 - 0.236 , p<0.001 ) . CONCLUSIONS Steroids exhibits a weak effect on the risk to progress toward SRC in our case series , whilst dhyidrophyridines CCB appeared to be protective against that . Further larger prospect i ve studies are warranted to better define the role of CCB in this setting or as a background therapy for SSc Our aim was to evaluate the effect of deep oscillation and biofeedback on Raynaud ’s phenomenon ( RP ) secondary to systemic sclerosis ( SSc ) . A prospect i ve r and omized study was performed in SSc patients receiving either deep oscillation ( n = 10 ) or biofeedback ( n = 8) thrice a week for 4 weeks , or patients were r and omized into the waiting group untreated for vasculopathy ( n = 10 ) in time of running the study interventions . Biofeedback result ed in an improvement of RP as determined by score reduction of visual analogue scale compared with patients of the control group ( P < 0.05 ) , whereas deep oscillation revealed a tendency for improvement ( P = 0.055 ) . The study underlines the beneficial role of physiotherapy for the treatment of SSc-related RP Background Imatinib mesylate is a potent inhibitor of platelet‐derived growth factor and transforming growth factor‐β signalling pathways which may play a role in systemic sclerosis (SSc)‐associated skin changes OBJECTIVE Transforming growth factor β ( TGFβ ) and platelet-derived growth factor ( PDGF ) may play a critical role in systemic sclerosis (SSc)-related interstitial lung disease ( ILD ) , and imatinib is a potent inhibitor of TGFβ and PDGF production . In this 1-year , phase I/IIa open-label pilot study of imatinib in patients with SSc-related active ILD , our primary aim was to assess the safety of imatinib ; we also explored its efficacy . METHODS We recruited 20 SSc patients with a forced vital capacity ( FVC ) of < 85 % predicted , dyspnea on exertion , and presence of a ground-glass appearance on high-resolution computed tomography . Patients received oral therapy with imatinib ( up to 600 mg/day ) for a period of 1 year . Adverse events were recorded , pulmonary function was tested , and the modified Rodnan skin thickness score ( MRSS ) was assessed every 3 months . The course of changes in lung function , the Health Assessment Question naire ( HAQ ) disability index ( DI ) , and the MRSS were modeled over the period of study to explore treatment efficacy . RESULTS The majority of patients were female ( 65 % ) , Caucasian ( 75 % ) , and had diffuse cutaneous SSc ( 70 % ) . At baseline , the mean ± SD FVC % predicted was 65.2 ± 14.0 and the mean ± SD MRSS was 18.7 ± 10.1 . The mean ± SD dosage of imatinib was 445 ± 125 mg/day . Of the 20 SSc patients , 12 completed the study , 7 discontinued because of adverse events ( AEs ) , and 1 patient was lost to followup . Common AEs ( ≥20 % ) included fatigue , facial/lower extremity edema , nausea and vomiting , diarrhea , generalized rash , and new-onset proteinuria . Treatment with imatinib showed a trend toward improvement in the FVC % predicted ( 1.74 % ; P not significant ) and the MRSS ( 3.9 units ; P < 0.001 ) . CONCLUSION Use of high-dose daily therapy with imatinib ( 600 mg/day ) in SSc patients with ILD was associated with a large number of AEs . Our experience with AEs suggests that dosages of imatinib lower than 600 mg/day may be appropriate and that further dose ranging analysis is needed in order to underst and the therapeutic index of imatinib in SSc IMPORTANCE High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation ( HSCT ) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials . OBJECTIVE To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide . DESIGN , SETTING , AND PARTICIPANTS The Autologous Stem Cell Transplantation International Scleroderma ( ASTIS ) trial , a phase 3 , multicenter , r and omized ( 1:1 ) , open-label , parallel-group , clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility . From March 2001 to October 2009 , 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31 , 2013 . INTERVENTIONS HSCT vs intravenous pulse cyclophosphamide . MAIN OUTCOMES AND MEASURES The primary end point was event-free survival , defined as time from r and omization until the occurrence of death or persistent major organ failure . RESULTS A total of 156 patients were r and omly assigned to receive HSCT ( n = 79 ) or cyclophosphamide ( n = 77 ) . During a median follow-up of 5.8 years , 53 events occurred : 22 in the HSCT group ( 19 deaths and 3 irreversible organ failures ) and 31 in the control group ( 23 deaths and 8 irreversible organ failures ) . During the first year , there were more events in the HSCT group ( 13 events [ 16.5 % ] , including 8 treatment-related deaths ) than in the control group ( 8 events [ 10.4 % ] , with no treatment-related deaths ) . At 2 years , 14 events ( 17.7 % ) had occurred cumulatively in the HSCT group vs 14 events ( 18.2 % ) in the control group ; at 4 years , 15 events ( 19 % ) had occurred cumulatively in the HSCT group vs 20 events ( 26 % ) in the control group . Time-varying hazard ratios ( modeled with treatment × time interaction ) for event-free survival were 0.35 ( 95 % CI , 0.16 - 0.74 ) at 2 years and 0.34 ( 95 % CI , 0.16 - 0.74 ) at 4 years . CONCLUSIONS AND RELEVANCE Among patients with early diffuse cutaneous systemic sclerosis , HSCT was associated with increased treatment-related mortality in the first year after treatment . However , HCST conferred a significant long-term event-free survival benefit . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N54371254 OBJECTIVE RP is a reversible vasoconstriction of digital arteries that causes pain and skin discoloration . This study compared the efficacy of the new phosphodiesterase type 5 inhibitor udenafil with that of the calcium channel blocker amlodipine in the treatment of secondary RP . METHODS A total of 29 patients with secondary RP associated with connective tissue diseases were enrolled in this double-blind , r and omized , cross-over study . The patients were r and omized to receive udenafil 100 mg/day or amlodipine 10 mg/day for 4 weeks . After a washout period they were crossed over to the other drug for another 4 weeks . The primary outcome was RP frequency before and after treatment . The secondary outcomes were RP condition scores , RP duration , number of digital ulcers , HAQ , physician global assessment and digital artery flow before and after treatment . RESULTS Amlodipine and udenafil both decreased the rate of RP attack significantly . The drugs did not differ in terms of RP frequency or any of the secondary outcomes except for digital blood flow ; udenafil improved it significantly better than amlodipine ( P = 0.021 ) . Udenafil was well tolerated without serious adverse effects . CONCLUSION Udenafil and amlodipine have comparable efficacy in improving RP attacks . In addition , udenafil improves the blood flow in digital arteries compared with amlodipine . TRIAL REGISTRATION www . clinical trials.gov , protocol number NCT01280266 |
13,747 | 24,259,251 | All the subgroups analysed benefited from addition of radiotherapy .
This review confirms the benefit of adding radiotherapy to breast conserving surgery for the treatment of all women diagnosed with DCIS .
No long-term toxicity from use of radiotherapy was identified | BACKGROUND The addition of radiotherapy ( RT ) following breast conserving surgery ( BCS ) was first shown to reduce the risk of ipsilateral recurrence in the treatment of invasive breast cancer .
Ductal carcinoma in situ ( DCIS ) is a pre-invasive lesion .
Recurrence of ipsilateral disease following BCS can be either DCIS or invasive breast cancer .
R and omised controlled trials ( RCTs ) have shown that RT can reduce the risk of recurrence , but assessment of potential long-term complications from addition of RT following BSC for DCIS has not been reported for women participating in RCTs .
OBJECTIVES To summarise the data from RCTs testing the addition of RT to BCS for treatment of DCIS to determine the balance between the benefits and harms . | AIMS To evaluate the diagnostic and therapeutic procedures which were followed in a European Organization for Research and Treatment of Cancer ( EORTC ) r and omized clinical trial investigating the role of radiotherapy in breast-conserving treatment ( BCT ) for ductal carcinoma in situ ( DCIS ) of the breast . METHODS The medical files of 824 of the 1010 r and omized patients ( 82 % ) were review ed during site visits to 30 participating institutes . RESULTS Large variations occurred , particularly in the surgical procedures and histopathological work-up which were performed . Important risk factors like tumour size and margin status were poorly quantified in the medical files . CONCLUSIONS These findings emphasize the need for establishing uniform guidelines for diagnostic and therapeutic procedures for DCIS , and for clearly defined risk factors for recurrence after BCT for DCIS . Because of its r and omized nature , the main question of the trial , i.e. the effect of radiotherapy on the risk of local recurrence , will not be influenced by variation . The risk of local recurrence in itself , and hence the success of BCT for DCIS , may however be influenced by the quality of the initial procedures that were conducted AIM The primary aims were to study risk factors for an ipsilateral breast event ( IBE ) after sector resection for ductal carcinoma in situ of the breast ( DCIS ) in a trial comparing adjuvant radiotherapy to no therapy and to assess predictive factors for response to radiotherapy . Secondary aims were to analyse reproducibility of the histopathological evaluation and to estimate correctness of diagnosis in the trial . SETTING A r and omised trial in Sweden ( the SweDCIS trial ) , including 1046 women with a median of 5.2 years of follow-up in a population , offered routine mammographic screening . METHODS A case-cohort design with a total of 161 cases of IBE ( 42 of those being members of the subcohort ) and 284 sample d for the sub-cohort . Ninety five percent of the participants ' slides could be retrieved and were re-evaluated by three experienced pathologists . RESULTS Low nuclear grade ( NG 1 - 2 ) and absence of necrosis halves the risk of IBE in both irradiated and non-irradiated patients . Lesion size , margins of excision and age at diagnosis did not modify these associations . The presence of necrosis modified the effect of radiotherapy : relative risk was 0.40 with necrosis present and 0.07 with necrosis absent ( p-value for interaction 0.068 ) . In all subsets of prognostic factors , radiotherapy conferred a substantial benefit . The risk factors for in situ and invasive IBE were similar . The agreement between pathologists was moderate ( kappa=0.486 ) . Correctness of diagnosis in the subcohort of SweDCIS was 84.8 % . CONCLUSION Although nuclear grade and necrosis carry prognostic information , we could not define a group with very low risk after sector resection alone . Radiotherapy has a protective effect in all substrata of risk factors studied . The interaction between the presence of necrosis and radiotherapy is a clinical ly and biologically relevant research area PURPOSE Evaluate the effects of radiotherapy after sector resection for ductal carcinoma in situ of the breast ( DCIS ) in patient groups as defined by age , size of the lesion , focality , completeness of excision and mode of detection . PATIENTS AND METHODS A total of 1,067 women in Sweden were r and omly assigned to either postoperative radiotherapy ( RT ) or control from 1987 to 1999 , and 1,046 were followed for a mean of 8 years . The main outcome was new ipsilateral breast cancer events and distant metastasis-free survival analyzed according to intention to treat . RESULTS There were 64 ipsilateral events in the RT arm and 141 in the control group corresponding to a risk reduction of 16.0 percentage points at 10 years ( 95 % CI , 10.3 % to 21.6 % ) and a relative risk of 0.40 ( 95 % CI , 0.30 to 0.54 ) . There was no statistically significant difference in distant metastasis-free survival . There was an effect modification by age , yielding a low effect of RT in women younger than 50 , but substantial protection in women older than 60 years . The age effect was not confounded by focality , lesion size , completeness of excision , or detection mode . There was no group as defined by our stratification variables that had a low risk without radiotherapy . CONCLUSION Our results indicate that younger women have a low protective effect of conventional RT after sector resection . Older women benefit substantially . We caution that the age effect was seen in a subgroup analysis . Further search with conventional clinical variables for a low risk group that does not need RT does not seem fruitful BACKGROUND Inadequate surgical excision with residual involvement of resection margins by tumour after breast conservation results in increased local recurrence rates . To reduce this risk positive margins are , therefore , usually excised . Systemic treatment with tamoxifen or chemotherapy reduces local recurrence , along with radiotherapy . However , no studies to date have examined the correlation between chemoendocrine treatment , together with radiotherapy , and local relapse in patients with unexcised involved resection margins , having had breast conservation treatment . PATIENTS AND METHODS The histopathology reports were review ed of 184 patients who were treated from June 1991 to August 1995 within our r and omised study of neoadjuvant versus adjuvant chemoendocrine therapy with mitozantrone and methotrexate ( 2 M ) + /- mitomycin-C ( 3 M ) and tamoxifen , used concurrently with radiation following conservation surgical treatment . Histological resection margin was considered positive if ductal carcinoma in situ ( DCIS ) or invasive carcinoma was present microscopically less than 1 mm from the excision margin . RESULTS Although 38 % of patients had unexcised microscopically involved margins , local relapse rate as first site of relapse was only 1.9 % after a median follow up of 57 months . There was no difference in distant relapse ( P = 0.2 ) and survival ( P = 0.5 ) between the positive and negative margins groups . CONCLUSIONS The presence of positive unexcised margins does not have a significant effect on outcome in patients who are treated with chemoendocrine therapy together with radiotherapy . Further clinical trials are required PURPOSE The European Organisation for Research and Treatment of Cancer conducted a r and omized trial investigating the role of radiotherapy ( RT ) after local excision ( LE ) of ductal carcinoma-in-situ ( DCIS ) of the breast . We analyzed the efficacy of RT with 10 years follow-up on both the overall risk of local recurrence ( LR ) and related to clinical , histologic , and treatment factors . PATIENTS AND METHODS After complete LE , women with DCIS were r and omly assigned to no further treatment or RT ( 50 Gy ) . One thous and ten women with mostly ( 71 % ) mammographically detected DCIS were included . The median follow-up was 10.5 years . RESULTS The 10-year LR-free rate was 74 % in the group treated with LE alone compared with 85 % in the women treated by LE plus RT ( log-rank P < .0001 ; hazard ratio [ HR ] = 0.53 ) . The risk of DCIS and invasive LR was reduced by 48 % ( P = .0011 ) and 42 % ( P = .0065 ) respectively . Both groups had similar low risks of metastases and death . At multivariate analysis , factors significantly associated with an increased LR risk were young age ( < or = 40 years ; HR = 1.89 ) , symptomatic detection ( HR = 1.55 ) , intermediately or poorly differentiated DCIS ( as opposed to well-differentiated DCIS ; HR = 1.85 and HR = 1.61 respectively ) , cribriform or solid growth pattern ( as opposed to clinging/micropapillary subtypes ; HR = 2.39 and HR = 2.25 respectively ) , doubtful margins ( HR = 1.84 ) , and treatment by LE alone ( HR = 1.82 ) . The effect of RT was homogeneous across all assessed risk factors . CONCLUSION With long-term follow-up , RT after LE for DCIS continued to reduce the risk of LR , with a 47 % reduction at 10 years . All patient subgroups benefited from RT Selection of patients for r and omised clinical trials may have a large impact on the applicability of the study results to the general population presenting the same disorder . However , clinical characteristics and outcome data on non-entered patients are usually not available . The effects of patient selection for the EORTC 10853 trial investigating the role of radiotherapy in breast conserving therapy for ductal carcinoma in situ have been studied , in an analysis of all patients treated for ductal carcinoma in situ in five participating institutes . The reasons for not entering patients were evaluated and treatment results of the r and omised patients were compared to those not entered . A total of 910 patients were treated for ductal carcinoma in situ . Of these , 477 ( 52 % ) were ineligible , with the size of the lesion being the main reason for in eligibility ( 30 % of all ductal carcinoma in situ ) . Of the 433 eligible patients , 278 ( 64 % ) were r and omised into the trial . The main reasons for non-entry of eligible patients were either physicians ' preference for one of the treatment arms ( 26 % ) or patients ' refusal ( 9 % ) . These percentages showed significant variation among the institutes . At 4 years follow-up , those patients not entered in the trial and treated with local excision and radiotherapy , had higher local recurrence rates than the patients r and omised in the trial and treated with the same approach , ( 17 vs 2 % , P=0.03 ) . The patients treated with local excision alone had equal local recurrence rates ( 11 % in both groups ) . Selection of patients may explain the differences in outcome of the r and omised patients , and those not-entered . Thus , the results of this trial may not be applicable to all patients with ductal carcinoma in situ In EORTC trial 10853 , patients with histologically confirmed surgical clearance of ductal carcinoma in situ ( DCIS ) are being r and omised to observation alone or to receive external radiation to the breast ( 50 Gy ) . So far , 190 patients have been entered from 27 centres . An analysis has been conducted of patients with DCIS presenting to 6 of the participating hospitals . Within these centres there was a total of 216 patients with biopsy confirmed DCIS , without invasion , between 1985 and 1989 . However only 77 ( 36 % ) were entered into the trial . The major reason for non-entry was that DCIS was too extensive ( 76/139 , 55 % ) , so that in situ disease extended to the margins of excision . Other reasons for exclusion included prior breast cancer ( 18 % ) , delay in histological diagnosis ( 6 % ) and a lump measuring more than 3 cm in diameter ( 4 % ) . Only 6 patients ( 4 % ) refused to take part in the trial . Thus the eventual results of the trial may be applicable only to a minority of patients with DCIS The aim of this work is to report the preliminary results of the Hungarian multicentric r and omised DCIS study . Between 2000 and 2007 , 278 patients with ductal carcinoma in situ ( DCIS ) treated by breast-conserving surgery were r and omised according to predetermined risk groups . Low/intermediate-risk patients ( n=29 ) were r and omised to 50 Gy whole-breast irradiation ( WBI ) or observation . High-risk cases ( n=235 ) were allocated to receive 50 Gy WBI vs. 50 Gy WBI plus 16 Gy tumour bed boost . Very high-risk patients ( patients with involved surgical margins ; n=14 ) were r and omised to 50 Gy WBI plus 16 Gy tumour bed boost or reoperation ( reexcision plus radiotherapy or mastectomy alone ) . Immunohistochemistry ( IHC ) was performed to detect the expression of potential molecular prognostic markers ( ER , PR , Her2 , p53 , Bcl-2 and Ki-67 ) . At a median follow-up of 36 months no recurrence was observed in the low/intermediate- and very high-risk patient groups . In the high-risk group , 4 ( 1.7 % ) local recurrences and 1 ( 0.4 % ) distant metastasis occurred . No patient died of breast cancer . In the high-risk group of patients , the 3- and 5-year probability of local recurrence was 1.1 % and 3.1 % , respectively . The positive immunostaining for Her2 ( 38 % ) , p53 ( 37 % ) and Ki-67 ( 44 % ) correlated with a high nuclear grade . Significant inverse correlation was found between the expression of ER ( 77 % ) , PR ( 67 % ) , Bcl-2 ( 64 % ) and grade . Preliminary results suggest that breast-conserving surgery followed by radiotherapy yields an annual local recurrence rate of less than 1 % in patients with DCIS . IHC of molecular prognostic markers can assist to gain insight into the biologic heterogeneity of DCIS BACKGROUND As a consequence of mammographic breast screening programmes , ductal carcinoma in situ is diagnosed with increasing frequency . Mastectomy for localised ductal carcinoma in situ is thought to be an over-treatment by many physicians , but there is much controversy as to whether complete local excision alone is sufficient . We aim ed to assess the effectiveness of adjuvant radiotherapy and tamoxifen . METHODS We used a 2x2 factorial design in a r and omised controlled trial . Between May , 1990 , and August , 1998 , 1701 patients recruited from screening programmes were r and omised to both treatments in combination or singly , or to none , or to either one ( eg , radiotherapy ) with an elective decision to give or to withhold the other ( ie , in this case tamoxifen ) . Patients had complete surgical excision of the lesion confirmed by specimen radiography and histology . Patients have been followed up at least once a year . Median follow-up was 52.6 ( range 2.4 - 118.3 ) months . Our primary endpoint was the incidence of ipsilateral invasive disease . FINDINGS Ipsilateral invasive disease was not reduced by tamoxifen but recurrence of overall ductal carcinoma in situ was decreased ( hazard ratio 0.68 [ 0.49 - 0.96 ] ; p=0.03 ) . Radiotherapy reduced the incidence of ipsilateral invasive disease ( 0.45 [ 0.24 - 0.85 ] ; p=0.01 ) and ipsilateral ductal carcinoma in situ ( 0.36 [ 0.19 - 0.66 ] ; p=0.0004 ) , but there was no effect on the occurrence of contralateral disease . There was no evidence of interaction between radiotherapy and tamoxifen . INTERPRETATION Radiotherapy can be recommended for patients with ductal carcinoma in situ treated by complete local excision ; however , there is little evidence for the use of tamoxifen in these women OBJECTIVE To describe the patterns of initial management of node-negative breast cancer in Ontario and British Columbia and to compare the characteristics of the patients and tumours and of the physicians and hospitals involved in management . DESIGN Retrospective , population -based , cohort study . PARTICIPANTS All 942 newly diagnosed cases of node-negative breast cancer in 1991 in British Columbia and a r and om sample of 938 newly diagnosed cases in Ontario in the same year . OUTCOME MEASURES Number and proportion of patients with newly diagnosed node-negative breast cancer who received breast-conserving surgery ( BCS ) or mastectomy and who received radiation therapy after BCS . RESULTS BCS was used in 413 cases ( 43.8 % ) in British Columbia and in 634 cases ( 67.6 % ) in Ontario ( p < 0.001 ) . After BCS , radiation therapy was received by 378 patients ( 91.5 % of those who had undergone BCS ) in British Columbia and 479 patients ( 75.6 % of those who had undergone BCS ) in Ontario ( p < 0.001 ) . In both provinces , lower patient age , smaller tumour size , a non central unifocal tumour , absence of extensive ductal carcinoma in situ and initial surgery by a surgeon with an academic affiliation were associated with greater use of BCS . Lower patient age and larger tumour size were associated with greater use of radiation therapy after BCS in both provinces . CONCLUSION Patient , tumour and physician factors are associated with the choice of initial management of breast cancer in these two Canadian provinces . However , the differences in management between the two provinces are only partly explained by these factors . Other possible explanations , such as the presence of provincial guidelines , differences in the organization of the health care system or differences in patient preference , require further research Of 213 consecutive patients with intraductal carcinoma , 109 were selectively treated with mastectomy and 104 with radiation therapy . There were eight local recurrences , seven in patients treated with radiation therapy and one in a patient treated with mastectomy . Histologically , there were 110 comedocarcinomas and 103 noncomedocarcinomas . Seven local recurrences occurred in patients with comedocarcinomas and one in a patient with a noncomedo tumor . Three ( 38 % ) of eight local recurrences ( all comedo ) were invasive . The 5-year actuarial survival for all subgroups was 100 % . The median follow-up was 51 months . Intraductal carcinoma is unlikely to metastasize to axillary lymph nodes , and routine dissection is unnecessary . Ductal carcinoma in situ of the comedo variety is more aggressive and more likely to recur than its noncomedo counterpart . We currently view conservative therapy for patients with intraductal comedocarcinoma with caution BACKGROUND Ductal carcinoma in situ ( DCIS ) of the breast is a disorder that has become more common since it may manifest as microcalcifications that can be detected by screening mammography . Since selected women with invasive cancer can be treated safely with breast conservation therapy it is paradoxical that total mastectomy has remained the st and ard treatment for DCIS . We did a r and omised phase III clinical trial to investigate the role of radiotherapy after complete local excision of DCIS . METHODS Between 1986 and 1996 , women with clinical ly or mammographically detected DCIS measuring less than or equal to 5 cm were treated by complete local excision of the lesion and then r and omly assigned to either no further treatment ( n=503 ) or to radiotherapy ( n=507 ; 50 Gy in 5 weeks to the whole breast ) . The median duration of follow-up was 4.25 years ( maximum 12.0 years ) . All analyses were by intention to treat . FINDINGS 500 patients were followed up in the no further treatment group and 502 in the radiotherapy group . In the no further treatment group 83 women had local recurrence ( 44 recurrences of DCIS , and 40 invasive breast cancer ) . In the radiotherapy group 53 women had local recurrences ( 29 recurrences of DCIS , and 24 invasive breast cancer ) . The 4-year local relapse-free was 84 % in the group treated with local excision alone compared with 91 % in the women treated by local excision plus radiotherapy ( log rank p=0.005 ; hazard ratio 0.62 ) . Similar reductions in the risk of invasive ( 40 % , p=0.04 ) and non-invasive ( 35 % , p=0.06 ) local recurrence were seen . CONCLUSIONS Radiotherapy after local excision for DCIS , as compared with local excision alone , reduced the overall number of both invasive and non-invasive recurrences in the ipsilateral breast at a median follow-up of 4.25 years PURPOSE In 1993 , findings from a National Surgical Adjuvant Breast and Bowel Project ( NSABP ) trial to evaluate the worth of radiation therapy after lumpectomy concluded that the combination was more beneficial than lumpectomy alone for localized intraductal carcinoma-in-situ ( DCIS ) . This report extends those findings . PATIENTS AND METHODS Women ( N = 818 ) with localized DCIS were r and omly assigned to lumpectomy or lumpectomy plus radiation ( 50 Gy ) . Tissue was removed so that resected specimen margins were histologically tumor-free . Mean follow-up time was 90 months ( range , 67 to 130 ) . Size and method of tumor detection were determined by central clinical , mammographic , and pathologic assessment . Life-table estimates of event-free survival and survival , average annual rates of occurrence for specific events , relative risks for event-specific end points , and cumulative probability of specific events comprising event-free survival are presented . RESULTS The benefit of lumpectomy plus radiation was virtually unchanged between 5 and 8 years of follow-up and was due to a reduction in invasive and noninvasive ipsilateral breast tumors ( IBTs ) . Incidence of locoregional and distant events remained similar in both treatment groups ; deaths were only infrequently related to breast cancer . Incidence of noninvasive IBT was reduced from 13.4 % to 8.2 % ( P = .007 ) , and of invasive IBT , from 13.4 % to 3.9 % ( P < .0001 ) . All cohorts benefited from radiation regardless of clinical or mammographic tumor characteristics . CONCLUSION Through 8 years of follow-up , our findings continue to indicate that lumpectomy plus radiation is more beneficial than lumpectomy alone for women with localized , mammographically detected DCIS . When evaluated according to the mammographic characteristics of their DCIS , all groups benefited from radiation PURPOSE To detail the outcome , in terms of local recurrence , local invasive recurrence , distant recurrence , and breast cancer mortality for patients previously treated for ductal carcinoma in situ ( DCIS ) . PATIENTS AND METHODS Clinical , pathologic , and outcome data were collected prospect ively for 707 patients with DCIS accrued from 1972 through June 1997 . RESULTS There were 74 local recurrences ; 39 were noninvasive ( DCIS ) and 35 were invasive . Fifty-one percent of patients with invasive recurrences presented with stage 1 disease ; the remainder presented with more advanced disease . Invasive local recurrence after mastectomy was a rare event that occurred in 0.8 % of patients . Invasive recurrence after breast preservation was more common and occurred in 7.4 % of patients . The 8-year probability of breast cancer mortality after breast preservation was 2.1 % , a number that is likely to increase with longer follow-up . The 8-year breast cancer-specific mortality and distant-disease probability for the subgroup of 74 patients with locally recurrent disease was 8.8 % and 20.8 % , respectively . If only the 35 invasive recurrences are considered as events , the 8-year breast cancer-specific mortality and distant-disease probability was 14.4 % and 27.1 % , respectively . CONCLUSION Invasive local recurrence after breast-preservation treatment for patients with DCIS is a serious event that converts patients with previous stage 0 disease to patients with disease that ranges from stage I to stage IV . These results , however , indicate that most DCIS patients with local recurrence can be salvaged We studied the effect of postoperative radiotherapy ( RT ) after breast sector resection for ductal carcinoma in situ ( DCIS ) . The study protocol stipulated radical surgery but microscopically clear margins were not m and atory . We r and omised 1 046 operated women to postoperative RT or control between 1987 and 1999 . The primary endpoint was ipsilateral local recurrence . Secondary endpoints were contralateral breast cancer , distant metastasis and death . After a median follow-up of 5.2 years ( range 0.1–13.8 ) there were 44 recurrences in the RT group corresponding to a cumulative incidence of 0.07 ( 95 % confidence interval ( CI ) 0.05–0.10 ) . In the control group there were 117 recurrences giving a cumulative incidence of 0.22 ( 95 % CI 0.18–0.26 ) giving an overall hazard ratio of 0.33 ( 95 % CI 0.24–0.47 , p < 0.0001 ) . Twenty two percent of the patients had microscopically unknown or involved margins . We found no evidence for different effects of RT on the relative risk of invasive or in situ recurrence . Secondary endpoints did not differ . Women undergoing sector resection for DCIS under conditions of population based screening mammography benefit from postoperative RT to the breast . Seven patients needed RT-treatment to prevent one recurrence The National Surgical Adjuvant Breast and Bowel Project ( NSABP ) conducted two sequential r and omized clinical trials to aid in resolving uncertainty about the treatment of women with small , localized , mammographically detected ductal carcinoma in situ ( DCIS ) . After removal of the tumor and normal breast tissue so that specimen margins were histologically tumor-free ( lumpectomy ) , 818 patients in the B-17 trial were r and omly assigned to receive either radiation therapy to the ipsilateral breast or no radiation therapy . B-24 , the second study , which involved 1,804 women , tested the hypothesis that , in DCIS patients with or without positive tumor specimen margins , lumpectomy , radiation , and tamoxifen ( TAM ) would be more effective than lumpectomy , radiation , and placebo in preventing invasive and noninvasive ipsilateral breast tumor recurrences ( IBTRs ) , contralateral breast tumors ( CBTs ) , and tumors at metastatic sites . The findings in this report continue to demonstrate through 12 years of follow-up that radiation after lumpectomy reduces the incidence rate of all IBTRs by 58 % . They also demonstrate that the administration of TAM after lumpectomy and radiation therapy results in a significant decrease in the rate of all breast cancer events , particularly in invasive cancer . The findings from the B-17 and B-24 studies are related to those from the NSABP prevention ( P-1 ) trial , which demonstrated a 50 % reduction in the risk of invasive cancer in women with a history of atypical ductal hyperplasia ( ADH ) or lobular carcinoma in situ ( LCIS ) and a reduction in the incidence of both DCIS and LCIS in women without a history of those tumors . The B-17 findings demonstrated that patients treated with lumpectomy alone were at greater risk for invasive cancer than were women in P-1 who had a history of ADH or LCIS and who received no radiation therapy or TAM . Although women who received radiation benefited from that therapy , they remained at higher risk for invasive cancer than women in P-1 who had a history of LCIS and who received placebo or TAM . Thus , if it is accepted from the P-1 findings that women at increased risk for invasive cancer are c and i date s for an intervention such as TAM , then it would seem that women with a history of DCIS should also be considered for such therapy in addition to radiation therapy . That statement does not imply that , as a result of the findings presented here , all DCIS patients should receive radiation and TAM . It does suggest , however , that , in the treatment of DCIS , the appropriate use of current and better therapeutic agents that become available could diminish the significance of breast cancer as a public health problem BACKGROUND Although the conservation management of breast cancer has become a routine method of treatment in most centers , there is still considerable controversy surrounding the ultimate minimum treatment required for node-negative breast cancer to achieve adequate local control . PURPOSE Our purpose was to assess the value of breast irradiation in reducing breast relapse following conservation surgery for node-negative breast cancer . We attempted to define low-risk groups of women for breast and distant site relapse ( i.e. , recurrence outside the breast ) who might be spared breast irradiation or adjuvant systemic therapy . METHODS Eight hundred thirty-seven patients were r and omly assigned to receive radiation therapy or no radiation therapy following lumpectomy and axillary dissection for node-negative breast cancer . RESULTS Breast irradiation reduced relapse in the breast from 25.7 % in the controls to 5.5 % in the irradiated patients . There was no difference in survival between the two groups ( median follow-up , 43 months ) . A low-risk group ( less than 5 % chance of relapse in the breast without irradiation ) could not be defined . Tumor size ( greater than 2 cm ) , age ( less than 40 years ) , and poor nuclear grade were important predictors for breast relapse . Age ( less than 50 years ) and poor nuclear grade were important predictors for mortality . The presence of ductal carcinoma in situ did not predict breast relapse . CONCLUSIONS Breast irradiation significantly reduces breast relapse , but it does not influence survival . Important predictors of breast relapse are age , tumor size , and nuclear grade , but not the presence of ductal carcinoma in situ . Age and , in particular , nuclear grade predict survival . IMPLICATION S Further follow-up may define an acceptable low-risk group for breast relapse . Until then , we recommend that all patients receive breast irradiation . Systemic adjuvant therapy should be considered for patients with poor nuclear grade tumors Background . Controversy exists concerning the natural history of ductal carcinoma in situ ( DCIS ) of the breast , including its pathologic expression and treatment . This controversy has been fostered largely by the retrospective nature and limited sample sizes of extant studies |
13,748 | 21,948,804 | The authors observed positive short-term effects on risk perception , motivation to quit smoking and smoking cessation , but these effects fade at longer follow-ups .
Importantly , the authors did not find any evidence of adverse effect of testing negative on the risk-predisposing gene .
This systematic review does not provide solid evidence for the proposed beneficial effects of genetic testing for smoking-related diseases on smoking cessation , but does suggest the presence of an immediate motivational effect , such that genetic testing result ed in higher risk perception and more motivation to quit smoking | OBJECTIVE To examine whether genetic testing for smoking-related diseases benefits smoking cessation . | As genetic tests for common gene variants and multifactorial , lifestyle‐related conditions become available , it will be increasingly important to determine the psychological and behavioral impact of this emerging class of genetic tests . Our aim was to examine the potential impact of genetic testing for heart disease susceptibility on psychological predictors of smoking cessation . Two hundred and sixty‐one smokers were asked to imagine that they had undergone a test for heart disease risk . They were r and omly assigned to a genetic test scenario ( low‐ or high‐risk result ) or an oxidative test scenario ( high‐risk result ) . Smokers in the genetic test‐high risk group reported greater intention to quit smoking than smokers in the oxidative test‐high risk group ( p = 0.009 ) ; 30 % of this was mediated by their holding stronger beliefs that quitting would reduce their heart disease risk ( outcome expectations ) ( p = 0.011 ) . The effect of genetic test‐high risk feedback on outcome expectations was greatest amongst smokers with no heart disease family history ( p = 0.038 ) . The results suggest that genetic testing for heart disease risk may enhance interventions design ed to improve health via increasing smoking cessation rates . Whether the findings hold true in studies that use real rather than hypothetical genetic tests remains to be seen Background : As genetic testing for health risk becomes increasingly available , it becomes important to study the prospect i ve impact of testing on modifiable health behavior . Purpose : This study examines the impact of genetic testing for alpha-1 antitrypsin ( AAT ) deficiency , a condition that usually results in emphysema in individuals exposed to cigarette smoke . We evaluated whether AAT testing , performed in the home and with minimal contact ( reading material s including advice on cessation ) , results in quit attempts and abstinence . Methods : Identified smokers ( N=199 ) from a larger study of genetic testing were surveyed 3 months following receipt of their AAT genotype . The primary endpoint was the incidence of quit attempts . Results : Smokers who tested severely AAT deficient were significantly more likely to report a 24-hr quit attempt ( 59 % ) than were those who tested normal ( 26 % ) . Carriers had a 34 % quit attempt rate . Severely AAT deficient smokers were more likely than both carriers and normals to seek information on treatment , use pharmacotherapy for smoking cessation , and report greater reductions in their smoking . There were no group differences in 3-month abstinence rates . Conclusions : Knowledge of severe AAT deficiency , but not carrier status , may motivate smokers toward cessation . The AAT testing experience may have consequences for outcomes of other genetic conditions with modifiable health behaviors PURPOSE Markers of genetic susceptibility to tobacco-related cancers could personalize harms of smoking and motivate cessation . Our objective was to assess whether a multicomponent intervention that included feedback about genetic susceptibility to lung cancer increased risk perceptions and rates of smoking cessation compared with a st and ard cessation intervention . EXPERIMENTAL DESIGN Our design was a two-arm trial with eligible smokers r and omized in a 1:2 ratio to Enhanced Usual Care or Biomarker Feedback ( BF ) . Surveys were conducted at baseline , 6 , and 12 months later . The setting was an inner city community health clinic . African-American patients who were current smokers ( n = 557 ) were identified by chart abstract ion and provider referral . All smokers received a self-help manual and , if appropriate , nicotine patches . Smokers in the BF arm also were offered a blood test for genotyping the GST(3 ) gene ( GSTM1 ) , sent a test result booklet , and called up to four times by a health educator . Prevalent abstinence was assessed by self-report of having smoked no cigarettes in the prior 7 days at the 6- and 12-month follow-ups and sustained abstinence , i.e. , not smoking at either follow-up or in-between . RESULTS Smoking cessation was greater for the BF arm than the Enhanced Usual Care arm ( 19 % versus 10 % , respectively ; P < 0.006 ) at 6 months but not at 12 months . CONCLUSIONS Smokers agreed to genetic feedback as part of a multicomponent cessation program . Although the program increased short-term cessation rates compared with st and ard intervention , genetic feedback of susceptibility may not benefit smokers with high baseline risk perceptions Twin studies document substantial heritability for successful abstinence from smoking . A genome-wide association study has identified markers whose allele frequencies differ with nominal P<0.005 in nicotine-dependent clinical trial participants who were successful vs unsuccessful in abstaining from smoking ; many of these results are also supported by data from two additional sample s. More study is required to precisely determine the variance in quitting success that can be accounted for by the single-nucleotide polymorphisms that are currently identified and to precisely classify individuals who may display varying degrees of genetic vs environmental effects into quitters or nonquitters . However , the data at h and do allow us to model the effects of genotypic stratification in smoking cessation trials . We identify relationships between the costs of identifying and genotyping prospect i ve trial participants vs the costs of performing the clinical trials . We quantitate the increasing savings that result from genetically stratified design s as recruiting/genotyping costs go down and trial costs increase . This model helps to define the circumstances in which genetically stratified design s may enhance power and reduce costs for smoking cessation clinical trials This trial tests the hypothesis that confirming a clinical diagnosis of familial hypercholesterolemia ( FH ) by finding a genetic mutation reduces patients ' perceptions of control over the disease and adherence to risk‐reducing behaviors . Three hundred forty‐one families , comprising 341 hypercholesterolemia prob and s and 128 adult relatives , were r and omized to one of two groups : ( a ) routine clinical diagnosis ; ( b ) routine clinical diagnosis plus genetic testing ( mutation search ing in prob and s and direct gene testing in relatives ) . The main outcome measures were perceptions of control over hypercholesterolemia , adherence to cholesterol‐lowering medication , diet , physical activity , and smoking . There was no support for the main hypothesis : finding a mutation had no impact on perceived control or adherence to risk‐reducing behavior ( all P‐values > 0.10 ) . While all groups believed that lowering cholesterol was an effective way of reducing the risk of a heart attack , participants in whom a mutation was found believed less strongly in the efficacy of diet in reducing their cholesterol level ( P = 0.02 at 6 months ) and showed a trend in believing more strongly in the efficacy of cholesterol‐lowering medication ( P = 0.06 at 6 months ) . In conclusion , finding a mutation to confirm a clinical diagnosis of FH in a previously aware population does not reduce perceptions of control or adherence to risk‐reducing behaviors . The pattern of findings leads to the new hypothesis that genetic testing does not affect the extent to which people feel they have control over a condition , but does affect their perceptions of how control is most effectively achieved . Further work is needed to determine whether similar results will be obtained in population s with little previous awareness of their risks . © 2004 Wiley‐Liss , OBJECTIVES It is well-known that smoking causes many diseases including cancers . Informing smokers of their genotypes associated with the vulnerability to the harms of smoking may be effective measures for smoking cessation . The present study examined the effects of genotype notification of an oncogene ( L-myc ) genotype to smokers on their behavior to quit smoking . METHODS Subjects were 562 employees of a bank who answered to be a smoker for a question naire used at annual health checkup at workplace from July to December 2002 . Those enrolled on August , October , and December were allocated into the genotype notification group ( intervention group ) , and the rest into the controls . Among 286 smokers allocated into the intervention group , 257 participants ( 89.9 % ) agreed to genotype testing . One year after the enrollment , a follow-up question naire survey was conducted for all smokers including controls . RESULTS Those who stated to have quitted smoking were 22 ( 8.0 % ) among the 276 controls and 15 ( 5.8 % ) among the 257 genotype notified participants , providing that the odds ratio ( OR ) of cessation for the intervention was 0.64 ( 95 % confidence interval , 0.32 - 1.28 ) . No psychological problems associated with genotype notification were observed . CONCLUSION The present study did not show positive effects of genotype notification on smoking cessation rate . To elevate the cessation rate , methods to explain and notify genotypes should be improved This study examined the role of dopaminergic genes in prospect i ve smoking cessation and response to bupropion treatment in a placebo-controlled clinical trial . Smokers of European ancestry ( N=418 ) provided blood sample s for genetic analysis and received either bupropion or placebo ( 10 weeks ) plus counseling . Assessment s included the dopamine D2 receptor ( DRD2 ) genotype , dopamine transporter ( SLC6A3 ) genotype , demographic factors , and nicotine dependence . Smoking status was verified at the end of treatment ( EOT ) and at 6-month follow-up . The results provided evidence for a significant DRD2 * SLC6A3 interaction effect on prolonged smoking abstinence and time to relapse at EOT , independent of treatment condition . Such effects were no longer significant at 6-month follow-up , however . These results provide the first evidence from a prospect i ve clinical trial that genes that alter dopamine function may influence smoking cessation and relapse during the treatment phase OBJECTIVE To determine the relationship between joint variation in 2 dopaminergic genes and the likelihood of nonsmoking following treatment with bupropion sustained release ( SR ) . DESIGN Three hundred twenty-three participants in a bupropion SR smoking cessation effectiveness trial with 12-month follow-up were genotyped for variants of dopamine receptor gene DRD2 and dopamine transporter SLC6A3 . MAIN OUTCOME MEASURES Self-reported 7-day point prevalence of nonsmoking . RESULTS Neither genotype alone was associated with 7-day point-prevalent nonsmoking at the 12-month follow-up . However , in the presence of the DRD2 A1 allele , SLC6A3 status was significantly associated with the likelihood of nonsmoking at the 12-month follow-up ( individuals with DRD2 A1 + and SLC6A3 9- were more likely to be smoking ) . In the absence of the DRD2 A1 allele , the association between SLC6A3 status and nonsmoking was nonsignificant . CONCLUSION Although these results are suggestive , a more compelling test is needed of the hypothesis that dopaminergic gene interaction underlies , in part , the likelihood of smoking following treatment with bupropion SR . Most likely this will come from larger studies involving prospect i ve r and omization to treatment based on genotype Risk information for Alzheimer disease ( AD ) may be communicated through susceptibility gene disclosure , even though this is not currently in clinical use . The REVEAL Study is the first r and omized clinical trial of risk assessment for AD with apolipoprotein E ( APOE ) genotype and numerical risk estimate disclosure . We examined whether APOE genotype and numerical risk disclosure to asymptomatic individuals at high risk for AD alters health behaviors . One hundred sixty-two participants were r and omized to either intervention ( APOE disclosure ) or control ( no genotype disclosure ) groups . Subjects in both groups received numerical lifetime risk estimates of future AD development based on sex and family history of AD . The intervention group received their APOE genotype . Subjects were informed that no proven preventive measures for AD existed and given an information sheet on preventative therapies under investigation . Participants who learned they were ϵ4 positive were significantly more likely than ϵ4 negative participants to report AD-specific health behavior change 1 year after disclosure ( adjusted odds ratio : 2.73 ; 95 % confidence interval : 1.14 , 6.54 ; P=0.02 ) . Post hoc analyses revealed similar significant associations between numerical lifetime risk estimates and self-report of AD-specific health behavior change . Despite lack of preventive measures for AD , knowledge of APOE genotype , numerical lifetime risk , or both , influences health behavior BACKGROUND To evaluate whether feedback of genetic information regarding an L-myc polymorphism , identified as impacting on tobacco-related cancer risk , has an influence on smoking cessation , an intervention study was conducted . METHODS We recruited smokers from first-visit out patients at Aichi Cancer Center Hospital . Six hundred and seventeen participated and were allocated into two groups : the biomarker feedback group ( BF ) and the follow-up smoking status group ( FS ) . The subjects were asked for their smoking status at enrolment and at 3- and 9-month follow-ups . BF subjects were notified about their L-myc genotype . RESULTS The smoking cessation rate at 9-month follow-up was essentially the same for both BF and FS cases , at 18.8 % and 17.0 % , respectively ( P = 0.798 ) . However , a difference in the rate was evident with non-cancer subjects ( 12.7 % and 8.4 % , respectively , P = 0.237 ) , especially in females ( 15.0 % and 4.2 % , respectively , P = 0.024 ) . The non-cancer subjects informed of their genotype were more likely to quit smoking than the FS patients ; particularly in those having a risky genotype , this was significant ( odds ratio : 2.87 , P = 0.003 ) . Again it was most prominent in females . CONCLUSION Feedback regarding an L-myc polymorphism did not impact on smoking cessation overall but appeared to benefit smokers without cancer . In addition , gender could affect the response to the feedback The behavioural and psychological impact of genetic testing for lung cancer susceptibility was examined among smokers ( N = 61 ) who were r and omly allocated to a GSTM1 genetic testing group ( with GSTM1-missing or GSTM1-present result ) or no-test control group . The GSTM1-missing ( higher risk ) group reported greater motivation to quit smoking , and both genetic testing groups reported lower depression than the control group at one-week follow-up ( p < .05 for all ) . Differences were not significant at two months follow-up . This study indicates the feasibility of much-needed research into the risks and benefits for individuals of emerging lifestyle-related genetic susceptibility tests This study evaluated the long-term impact of genetic susceptibility biomarker feedback on smoking behavior change and symptoms of depression in 426 male and female smokers . Smokers were r and omized to one of three smoking-cessation interventions : minimal contact quit-smoking counseling ( QSC ) , QSC + exposure biomarker feedback ( EBF ) , and QSC + EBF + biomarker feedback about genetic susceptibility to lung cancer ( SBF ) . The logistic regression model for quit attempt revealed a significant main effect for treatment such that participants in the SBF group were more than two times more likely to make a quit attempt than participants in the QSC group . There was not a significant difference between EBF and QSC participants . The results also revealed a significant effect for baseline stage of change . Those smokers in the preparation stage at baseline were more than three times more likely to make a quit attempt over the 12 months following treatment . The models for 30-day cessation and follow-up smoking rate revealed no significant main or interacting effects for treatment . A repeated measures analysis of variance revealed a significant main effect for time , indicating that an initial increase in depression in the genetic susceptibility group was not maintained over time . Genetic susceptibility feedback has the intended effects on motivation to quit , but it may need to be delivered within a more intensive smoking-cessation treatment for the heightened motivation to translate into smoking cessation PURPOSE Quitting smoking may prevent oral cancer . Behavioral intervention to quit smoking may be more efficient if persons are assigned an individual risk of cancer . PATIENTS AND METHODS In this prospect i ve study , we provided counseling and behavioral intervention toward smoking cessation , supplemented by genetic analyses in clinical ly normal oral mucosa of heavy smokers . Measurement of serum cotinine was used to assess changes in smoking habits . RESULTS In cytologic scrapings from 275 heavy smokers with clinical ly normal mucosa , we found tetraploidy in four and aneuploidy in 19 persons ( 23 of 275 ; 8 % ) . Twenty one ( 91 % ) of 23 persons with aneuploidy had quit or reduced their smoking habits at the 3-month follow-up , 20 ( 87 % ) of 23 persons had done so at 12 months , and 21 ( 91 % ) of 23 persons had done so at 24 months . Fifty-one ( 20 % ) of the 252 persons without genetic changes in their mucosa had quit or reduced their tobacco habits at the 3-month follow-up , 23 ( 9 % ) had done so at 12 months , and 17 ( 7 % ) had done so at 24 months ( P < .001 ) . After 24 months , normalization of DNA content to diploidy was observed in two of four persons with tetraploid ( 50 % ) , and in 11 of 19 persons ( 58 % ) with aneuploid scrapings . One patient developed an oral carcinoma in the floor of the mouth : this patient had an aneuploid scraping obtained 43 months earlier and developed a leukoplakia 28 months before the carcinoma . CONCLUSION Risk markers of oral cancer are present in clinical ly normal mucosa of heavy smokers , and such findings enhance the adherence to smoking cessation on counseling . Cytogenetic aberrations may normalize after quitting smoking |
13,749 | 19,370,605 | Studies of a Clinical Nurse Specialist intervention , Psychoeducational Group Therapy and a Couple-Coping intervention , did not show any significant benefit .
There is no convincing evidence to support the use of any interventions for psychosexual dysfunction in women treated for gynaecological cancer . | BACKGROUND Psychosexual dysfunction ( sexual difficulties not directly due to physical factors ) is known to be a common complication of treatment for gynaecological cancer .
It has a considerable impact on quality of life ( QoL ) for the increasing number of women who are survivors of gynaecological cancer .
OBJECTIVES To determine the effectiveness of interventions for psychosexual dysfunction in women who have been treated for gynaecological malignancy ( cancer of uterine cervix , uterine corpus , ovary , vulva ) . | Cancer diagnosis affects the psychological well-being of both patients and their partners , and effective coping has been suggested to be a conjoint process of mutual support . Ninety-four married women with early stage cancer and their partners were r and omly assigned to couples-based coping training ( CanCOPE ) , individual coping training for the woman , or a medical education control . Couples ' observed support communication and self-reported psychological distress , coping effort , and sexual adjustment were assessed at diagnosis , after cancer surgery , and at 6- and 12-month follow-ups . CanCOPE produced significant improvements in couples ' supportive communication , reduced psychological distress and coping effort , and improved sexual adjustment . Training in couples rather than individual coping was more effective in facilitating adaptation to cancer PURPOSE The analysis of complications in a prospect i ve r and omized trial comparing two preoperative brachytherapy low-dose rates in early stage cervical cancer is presented . METHODS AND MATERIAL S Between 1985 and 1988 , 204 patients with Stage I and limited Stage II cervical cancer were r and omized to receive one of two preoperative brachytherapy low-dose rates ( 0.4 and 0.8 Gy/hr ) . The objective of this trial was to determine the benefits , if any , of the higher-dose rate within the therapeutic arsenal for this patient population , in terms of survival , local control , and complications . The type and severity of all complications were evaluated according to a common glossary and a strict follow-up schedule was established given that the treatment of cervical cancer is multidisciplinary , involving gynecologists , surgeons , and radiotherapists . RESULTS Overall survival : 85 % at 2 years and local control : 93 % at 2 years , were similarly distributed between the two groups . Regardless of their nature and severity , 139 and 175 complications were observed among 63 % and 75 % of patients , in the 0.4 and 0.8 Gy/h dose rate groups respectively . Gynecologic and urinary complications were the most frequent ( 38 % and 28 % of all complications ) , followed by vascular ( 15 % ) , digestive ( 10 % ) , nervous ( 5 % ) and cutaneous ( 5 % ) . A total of 14 and 17 severe complications ( Grade 3 ) were observed in 7 % and 13 % of patients , respectively in the 0.4 and 0.8 Gy/h dose rate groups ( p = 0.12 ) . Nonparametric survival methods used to compare the time to the first complication did not show a significant difference between the two groups : 62 % and 72 % at 2 years ( p = 0.27 ) . When the first complication and its evolution were considered ( early complications ) , the prevalence of complications was not significantly different between the two groups : 28 % vs. 34 % at 2 years ( p = 0.31 ) . In this prospect i ve trial , patients were regularly followed-up and complications of varying nature and severity were observed in succession during follow-up . When successive complications and their evolution were taken into account , the prevalence of complications was significantly greater in the higher-dose rate group : 30 % vs. 45 % at 2 years ( p = 0.03 ) . CONCLUSION The results of this trial showed that long-term effects of treatment , when represented by prevalence of complications over time , were more frequent in the higher dose rate group . This underlines the importance of the regular follow-up of patients and of coding , not only the occurrence of all complications , but also their evolution over time PURPOSE The purpose of this pilot study was to evaluate the efficacy of the clitoral therapy device ( Eros Therapy ) in alleviating sexual dysfunction in irradiated cervical cancer patients . METHODS AND MATERIAL S Eligible patients had a history of cervical cancer treated with radiotherapy and self-reported sexual dysfunction of sexual arousal and /or orgasmic disorders . Patients used the noninvasive , nonpharmacologic clitoral therapy device using a h and -held , battery-powered vacuum to cause clitoral engorgement four times weekly for 3 months during foreplay and self-stimulation . Study instruments included the Female Sexual Function Index , Derogatis Interview for Sexual Functioning , and Dyadic Adjustment Scale . The outcome evaluation was performed at 3 months . RESULTS Between 2001 and 2002 , 15 women were enrolled and 13 completed the study . The median patient age and radiotherapy-enrollment interval was 43.5 years and 2 years , respectively . At baseline , all patients reported symptoms of sexual arousal and /or orgasmic disorders , and some also had sexual desire and pain disorders . At 3 months , statistically significant improvements were seen in all domains tested , including sexual desire , arousal , lubrication , orgasm , sexual satisfaction , and reduced pain . The median Female Sexual Function Index total score increased from 17 to 29.4 ( maximal score , 36 ; p < 0.001 ) . The median Derogatis Interview for Sexual Functioning total raw score increased from 46 to 95 ( maximal score , 118 ; p < 0.001 ) . At baseline , the Derogatis Interview for Sexual Functioning total T-score corresponded to the bottom 10th percentile of normal sexual functioning . At 3 months , the total T-score placed the patients at the normalcy cutoff . Gynecologic examinations revealed improved mucosal color and moisture and vaginal elasticity and decreased bleeding and ulceration . CONCLUSION Our results from this pilot study suggest that the clitoral therapy device may alleviate sexual dysfunction in irradiated cervical cancer patients . A r and omized , controlled trial is warranted to assess the full benefits of this approach Gynaecological malignancy has an immense impact on the well-being of women . For many women , however , treatment such as surgery is curative and healthcare intervention focuses on the physiological status of the women . The psychological , social and sexual consequences of the malignancy and its treatment have received little attention in research or in practice . The present study used a mixed quantitative and qualitative design to analyse a specialist nurse intervention ( including psychosexual intervention ) , and to explain the impact of the illness on women 's lives . The qualitative arm of the study collected interview data from 20 women and six partners . The r and omized controlled trial sample consisted of 36 women , with data collected using a quality of life measure ( the EORTC QLQ-C30 ) and the Lasry Sexual Functioning scale . This paper focuses on the r and omized controlled trial data , which identified that sexual functioning and quality of life were improved in the active group who received specialist psychosexual counselling . However , the validity of the sexual functioning scale is challenged by the qualitative results of the study , which emphasize the social meaning of sexuality PURPOSE The association between radiotherapy for gynecological carcinoma and sexual dysfunction is well established . Regular vaginal dilation is widely recommended to these women as a way for them to maintain vaginal health and good sexual functioning . However , the compliance rate with this recommendation is low . The purpose of this study was to test the effectiveness of a group psychoeducational program based on the " information-motivation-behavioral skills " model of behavior change in increasing the rate of compliance . METHODS AND MATERIAL S Thirty-two women with Stage I or II cervical or endometrial carcinoma who were being treated with radiotherapy were r and omized and received either the experimental group program or the control intervention that consisted of written information and brief counseling . Outcome measures included global sexual health , knowledge about sexuality and cancer , fears about sexuality after cancer , and vaginal dilation compliance . RESULTS Younger women attending the experimental program ( 44.4 % ) were significantly more likely to follow recommendations for vaginal dilation than those who received the control intervention ( 5.6 % ) . Women , regardless of age , who received the experimental intervention reported less fear about sex after cancer treatment . The older women who received the experimental intervention gained more sexual knowledge . There was no evidence that the experimental intervention improved global sexual health . CONCLUSIONS This is the first controlled study to provide evidence of an intervention 's effectiveness 1 . in increasing women 's vaginal dilation following radiotherapy for gynecological carcinoma and 2 . in reducing their fears about sex after cancer . Most women , particularly younger women , are unlikely to follow the recommendation to dilate unless they are given assistance in overcoming their fears and taught behavioral skills BACKGROUND AND PURPOSE Radiation-induced tissue fibrosis is a common adverse effect of curative treatment for pelvic cancer . Pilot studies testing alpha-tocopherol and pentoxifylline provide evidence of clinical regression of superficial radiation fibrosis after radiotherapy . PATIENTS AND METHODS Twenty-seven eligible research volunteers with a minimum of one grade 3 or 4 disability ( LENT SOMA ) due to previous radiotherapy were entered into the study . Volunteers were given dl-alpha tocopheryl acetate 500 mg twice a day orally plus pentoxifylline 400 mg twice a day orally over a period of 6 months . Clinical assessment of late side effects recorded using LENT SOMA scales was selected as the primary endpoint , taken at baseline and at 6 and 12 months post- registration . Patient self- assessment of function and quality of life was assessed as a secondary endpoint using the EORTC QLQ-C30 core question naire and the EORTC QLQ-CR38 pelvic module . Magnetic resonance imaging was undertaken in 13/23 evaluable volunteers before and after 6 months of therapy . RESULTS At 12 months post- registration there were 4 out of 23 responders . At 6 months post- registration there was a statistically significant improvement ( i.e. reduction ) in the median of the LENT SOMA summed scores in all areas assessed apart from ' male sexual dysfunction ' , ' vulva ' and ' vagina ' which were unchanged at 6 months . The median total LENT SOMA score at baseline and 6 months was 49 and 34 , respectively , with a median change in total LENT SOMA score between baseline and 6 months of 9 ( IQR 7 - 18 ) ( P<0.001 ) . The maximum LENT SOMA scores improved over the study period , with a total number of 82 maximum grade 3 or 4 normal tissue scores at baseline ( median of four complications per person ) reduced to a total number of 67 maximum grade 3 or 4 scores at 6 months post- registration ( median of 3 complications per person ) , i.e. a median reduction in severe complications of one per person . LENT SOMA scores at 12 months were similar to those observed at 6 month suggesting no further improvement nor deterioration in late side effects . These findings were , however , not reflected in the patient self- assessment of function and quality of life , raising question about the possibility of observer bias in recording LENT SOMA scores . No significant changes were reported on magnetic resonance images at 6 months from baseline . CONCLUSIONS Despite only seeing four a priori defined responders in this pilot study testing dl-alpha tocopheryl acetate plus pentoxifylline in patients suffering complications of pelvic radiotherapy , changes in LENT SOMA scores suggest beneficial effects . However , we are not convinced that these effects are real , since no significant changes in symptoms and functional status were recorded by detailed prospect i ve patient self- assessment Abstract Conization is known to be an adequate treatment for cervical dysplasia and CIS . However , there are practically no papers on the long-term morbidity after conization . A prospect i ve interview survey of sexual function was done with 64 patients with conizations , the follow-up period being 1 year . There was found to be a significant decrease in the number of patients with dysmenorrhea and dyspareunia and there was no change in libido , experience of orgasm , coital frequency , or in overall satisfaction of sex life . Thus , in these respects , conization is a suitable conservative method when treating dysplasia and CIS |
13,750 | 27,821,320 | In recent years , the proportion of patients with synchronous compared with metachronous mCRC enrolled in first-line systemic therapy RCTs increased .
Uniform definitions and consistent reporting of the proportion of synchronous versus metachronous metastases could improve cross- study comparisons and interpretation of reported data in all mCRC studies | BACKGROUND Although synchronous and metachronous metastases are considered as separate entities of metastatic colorectal cancer ( mCRC ) with different outcomes , its proportion is reported infrequently .
We compared inclusion rates and survival of synchronous versus metachronous mCRC in different types of studies investigating initial systemic therapy or surgical treatment of mCRC . | BACKGROUND In the non-curative setting , the sequence in which anticancer agents are used , singly or in combination , may be important if patients are to receive the maximum period of disease control with the minimum of adverse effects . We compared sequential and combination chemotherapy strategies in patients with unpretreated advanced or metastatic colorectal cancer , who were regarded as not potentially curable irrespective of response . METHODS We studied patients with advanced colorectal cancer , starting treatment with non-curative intent . 2135 unpretreated patients were r and omly assigned to three treatment strategies in the ratio 1:1:1 . Strategy A ( control group ) was single-agent fluorouracil ( given with levofolinate over 48 h every 2 weeks ) until failure , then single-agent irinotecan . Strategy B was fluorouracil until failure , then combination chemotherapy . Strategy C was combination chemotherapy from the outset . Within strategies B and C , patients were r and omly assigned to receive , as the combination regimen , fluorouracil plus irinotecan ( groups B-ir and C-ir ) or fluorouracil plus oxaliplatin ( groups B-ox and C-ox ) . The primary endpoint was overall survival , analysed by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N 79877428 . RESULTS Median survival of patients allocated to control strategy A was 13.9 months . Median survival of each of the other groups was longer ( B-ir 15.0 , B-ox 15.2 , C-ir 16.7 , and C-ox 15.4 months ) . However , log-rank comparison of each group against control showed that only C-ir -- the first-line combination strategy including irinotecan -- satisfied the statistical test for superiority ( p=0.01 ) . Overall comparison of strategy B with strategy C was within the predetermined non-inferiority boundary of HR=1.18 or less ( HR=1.06 , 90 % CI 0.97 - 1.17 ) . INTERPRETATION Our data challenge the assumption that , in this non-curative setting , maximum tolerable treatment must necessarily be used first-line . The staged approach of initial single-agent treatment up grade d to combination when required is not worse than first-line combination , and is an alternative option for discussion with patients Summary Background When cure is impossible , cancer treatment should focus on both length and quality of life . Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals . The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim . Methods COIN was a r and omised controlled trial in patients with previously untreated advanced colorectal cancer . Patients received either continuous oxaliplatin and fluoropyrimidine combination ( arm A ) , continuous chemotherapy plus cetuximab ( arm B ) , or intermittent ( arm C ) chemotherapy . In arms A and B , treatment continued until development of progressive disease , cumulative toxic effects , or the patient chose to stop . In arm C , patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression , when the same treatment was restarted . R and omisation was done central ly ( via telephone ) by the MRC Clinical Trials Unit using minimisation . Treatment allocation was not masked . The comparison of arms A and B is described in a companion paper . Here , we compare arms A and C , with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy , with a predefined non-inferiority boundary of 1·162 . Intention-to-treat ( ITT ) and per- protocol analyses were done . This trial is registered , IS RCT N27286448 . Findings 1630 patients were r and omly assigned to treatment groups ( 815 to continuous and 815 to intermittent therapy ) . Median survival in the ITT population ( n=815 in both groups ) was 15·8 months ( IQR 9·4–26·1 ) in arm A and 14·4 months ( 8·0–24·7 ) in arm C ( hazard ratio [ HR ] 1·084 , 80 % CI 1·008–1·165 ) . In the per- protocol population ( arm A , n=467 ; arm C , n=511 ) , median survival was 19·6 months ( 13·0–28·1 ) in arm A and 18·0 months ( 12·1–29·3 ) in arm C ( HR 1·087 , 0·986–1·198 ) . The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary . Preplanned subgroup analyses in the per- protocol population showed that a raised baseline platelet count , defined as 400 000 per μL or higher ( 271 [ 28 % ] of 978 patients ) , was associated with poor survival with intermittent chemotherapy : the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 ( 95 % CI 0·80–1·15 , p=0·66 ) , versus 1·54 ( 1·17–2·03 , p=0·0018 ) in patients with a raised platelet count ( p=0·0027 for interaction ) . In the per- protocol population , more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects ( 72 [ 15 % ] vs 60 [ 12 % ] ) , whereas nausea and vomiting were more common on intermittent treatment ( 11 [ 2 % ] vs 43 [ 8 % ] ) . Grade 3 or worse peripheral neuropathy ( 126 [ 27 % ] vs 25 [ 5 % ] ) and h and –foot syndrome ( 21 [ 4 % ] vs 15 [ 3 % ] ) were more frequent on continuous than on intermittent treatment . Interpretation Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival , chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer , offering reduced time on chemotherapy , reduced cumulative toxic effects , and improved quality of life . Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival , whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break . Funding Cancer Research UK PURPOSE To compare the efficacy of cediranib ( a vascular endothelial growth factor receptor tyrosine kinase inhibitor [ VEGFR TKI ] ) with that of bevacizumab ( anti-VEGF-A monoclonal antibody ) in combination with chemotherapy as first-line treatment for advanced metastatic colorectal cancer ( mCRC ) . PATIENTS AND METHODS HORIZON III [ Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer ] had an adaptive phase II/III design . Patients r and omly assigned 1:1:1 received mFOLFOX6 [ oxaliplatin 85 mg/m(2 ) and leucovorin 400 mg/m(2 ) intravenously followed by fluorouracil 400 mg/m(2 ) intravenously on day 1 and then continuous infusion of 2,400 mg/m(2 ) over the next 46 hours every 2 weeks ] with cediranib ( 20 or 30 mg per day ) or bevacizumab ( 5 mg/kg every 14 days ) . An independent end-of-phase II analysis concluded that mFOLFOX6/cediranib 20 mg met predefined criteria for continuation ; subsequent patients received mFOLFOX6/cediranib 20 mg or mFOLFOX6/bevacizumab ( r and omly assigned 1:1 ) . The primary objective was to compare progression-free survival ( PFS ) . RESULTS In all , 1,422 patients received mFOLFOX6/cediranib 20 mg ( n = 709 ) or mFOLFOX6/bevacizumab ( n = 713 ) . Primary analysis revealed no significant difference between arms for PFS ( hazard ratio [ HR ] , 1.10 ; 95 % CI , 0.97 to 1.25 ; P = .119 ) , overall survival ( OS ; HR , 0.95 ; 95 % CI , 0.82 to 1.10 ; P = .541 ) , or overall response rate ( 46.3 % v 47.3 % ) . Median PFS and OS were 9.9 and 22.8 months for mFOLFOX6/cediranib and 10.3 and 21.3 months for mFOLFOX6/bevacizumab . The PFS upper 95 % CI was outside the predefined noninferiority limit ( HR < 1.2 ) . Common adverse events with more than 5 % incidence in the cediranib arm included diarrhea , neutropenia , and hypertension . Cediranib-treated patients completed fewer chemotherapy cycles than bevacizumab-treated patients ( median 10 v 12 cycles ) . Patient-reported outcomes ( PROs ) were significantly less favorable in cediranib-treated versus bevacizumab-treated patients ( P < .001 ) . CONCLUSION Cediranib activity , in terms of PFS and OS , was comparable to that of bevacizumab when added to mFOLFOX6 ; however , the predefined boundary for PFS noninferiority was not met . The cediranib safety profile was consistent with previous studies but led to less favorable PROs compared with bevacizumab . Investigation of oral TKIs in CRC continues This study investigated the antitumour and chemosensitizing effects of celecoxib in the treatment of advanced colorectal cancer . A total of 90 patients were r and omly divided into two groups : group CF was treated with a combination of celecoxib and the folinic acid-fluorouracil-oxaliplatin ( FOLFOX4 ) regimen ; and group F was treated with the FOLFOX4 regimen alone . Immunohistochemical analysis of tumour tissues for cyclooxygenase-2 ( COX-2 ) protein was performed . With regard to short-term efficacy , the response and disease control rates were significantly greater in group CF than group F. A log-rank test showed that the 3-year survival rate was significantly greater in group CF than group F. It was concluded that the addition of celecoxib to the FOLFOX4 regimen increased the short-term efficacy and the 3-year survival rate , and improved the quality of life of patients with advanced colorectal cancer . The antitumour and chemosensitizing effects of celecoxib appeared to be independent of COX-2 |
13,751 | 29,420,364 | Conclusions Vulva cancer treatment is associated with considerable morbidity deteriorating QoL. To date , there is no vali date d PROM available that provides adequate coverage of VC-related issues . | Objectives Vulva cancer ( VC ) treatment carries a high risk of severe late effects that may have a negative impact on quality of life ( QoL ) .
Patient-reported outcome measures ( PROMs ) are increasingly used when evaluating disease- and treatment-specific effects .
However , the adequacy of measures used to assess sequelae and QoL in VC remains unclear .
The aims of the present study were to evaluate disease- and treatment-related effects as measured by PROMs in VC patients and to identify available VC-specific PROMs . | Objective : To retrospectively investigate the outcome and toxicity of concurrent chemo-radiotherapy in the treatment of locally advanced vulvar cancer ( LAVC ) . Patients and Methods : Between 1996 and 2007 , 28 consecutive patients with LAVC were treated with chemoradiation ( 20 primary tumors and 8 loco-regional recurrences ) . Treatment consists of 2 separate courses of external-beam radiotherapy ( 40 Gy-2 weeks split-20 Gy ) . During each course of radiotherapy , 5-fluorouracil ( 1000 mg/m2/d ) , was given as a continuous intravenous infusion over the first 4 days , and mitomycin-C ( 10 mg/m2 on day 1 ) , as a bolus intravenous injection . Outcome measures were rates of complete and partial response , loco-regional control , progression-free survival , overall survival , and toxicity . Results : The median follow-up was 42 months and the median age of patients was 68 years . Twenty patients ( 72 % ) achieved complete remission , 4 patients ( 14 % ) partial remission , for an overall response rate of 86 % . Four patients ( 14 % ) had progressive disease directly after chemo-radiotherapy . The actuarial rates of loco-regional control , progression-free survival and overall survival at 4 years were 75 % , 71 % , and 65 % , respectively . There was no treatment break for acute toxicity . Vulvar desquamation was the main acute treatment-related side effect ( 93 % ) . Three patients developed transient grade 2 neutropenia or thrombocytopenia . Mild skin fibrosis and atrophy ( n = 6 , 21 % ) , radiation ulcer ( n = 4 , 14 % , in one patient treatment was needed ) , telangectasia ( n = 3 , 11 % ) , and lymphoedema ( n = 2 , 7 % ) were the most common late toxicity of chemoradiation . Conclusion : These data support the use of concurrent chemoradiotherapy as an effective alternative to primary ultra-radical surgery to treat LAVC with an acceptable toxicity profile Objective Vulvectomy for vulvar malignancy can affect sexual functioning based on anatomic , physiologic , psychologic , and relational mechanisms . The aims of this study were to prospect ively investigate sexual adjustment of women with vulvar malignancy during a follow-up period of 1 year after vulvectomy and to compare the results with healthy control women . Methods In this prospect i ve controlled study , participants completed the Beck Depression Inventory scale , World Health Organization-5 Well-being scale , Dyadic Adjustment Scale , Short Sexual Functioning Scale , and Specific Sexual Problems Question naire to assess various aspects of psychosocial and sexual functioning just before surgery , 6 months , and 1 year after treatment . Results Twenty-nine women with vulvar malignancy and 29 healthy controls completed the survey . Compared with the presurgery status , no significant differences were found in psychologic , relational , and sexual functioning in women after surgery for vulvar malignancy . Compared with healthy control women , women with vulvar malignancy reported significantly lower psychologic well-being and quality of partner relationship , both before and after treatment . Moreover , significantly more patients with vulvar malignancy reported preoperative and postoperatively sexual dysfunctions than healthy controls , including entry and deep dyspareunia , abdominal pain during intercourse , reduced ability to achieve orgasm , and reduced intensity of orgasm . Conclusions This prospect i ve study yielded no differences in psychosocial and sexual functioning for women with vulvar malignancy before and after vulvectomy . However , when compared with healthy controls , patients with vulvar malignancy are at high risk for sexual dysfunctions , both before and after surgical treatment PURPOSE To investigate the safety and clinical utility of the sentinel node procedure in early-stage vulvar cancer patients . PATIENTS AND METHODS A multicenter observational study on sentinel node detection using radioactive tracer and blue dye was performed in patients with T1/2 ( < 4 cm ) squamous cell cancer of the vulva . When the sentinel node was found to be negative at pathologic ultrastaging , inguinofemoral lymphadenectomy was omitted , and the patient was observed with follow-up for 2 years at intervals of every 2 months . Stopping rules were defined for the occurrence of groin recurrences . RESULTS From March 2000 until June 2006 , a sentinel node procedure was performed in 623 groins of 403 assessable patients . In 259 patients with unifocal vulvar disease and a negative sentinel node ( median follow-up time , 35 months ) , six groin recurrences were diagnosed ( 2.3 % ; 95 % CI , 0.6 % to 5 % ) , and 3-year survival rate was 97 % ( 95 % CI , 91 % to 99 % ) . Short-term morbidity was decreased in patients after sentinel node dissection only when compared with patients with a positive sentinel node who underwent inguinofemoral lymphadenectomy ( wound breakdown in groin : 11.7 % v 34.0 % , respectively ; P < .0001 ; and cellulitis : 4.5 % v 21.3 % , respectively ; P < .0001 ) . Long-term morbidity also was less frequently observed after removal of only the sentinel node compared with sentinel node removal and inguinofemoral lymphadenectomy ( recurrent erysipelas : 0.4 % v 16.2 % , respectively ; P < .0001 ; and lymphedema of the legs : 1.9 % v 25.2 % , respectively ; P < .0001 ) . CONCLUSION In early-stage vulvar cancer patients with a negative sentinel node , the groin recurrence rate is low , survival is excellent , and treatment-related morbidity is minimal . We suggest that sentinel node dissection , performed by a quality -controlled multidisciplinary team , should be part of the st and ard treatment in selected patients with early-stage vulvar cancer Abstract Objective To measure the long‐term impact of surgical treatment for vulval cancer upon health‐related quality of life and pelvic floor outcomes during the first year of therapy . Methods Prospect i ve , longitudinal , mixed‐ methods study . Twenty‐three women aged > 18 years with a new diagnosis of vulval cancer were recruited . The EORTC QLQ C30 , SF‐36 and an electronic pelvic floor assessment question naire ( ePAQ‐PF ) were administered at baseline ( pre‐treatment ) and 3 , 6 , 9 and 12 months post‐treatment . Mixed effects repeated measures models ( all adjusted for age and BMI ) were used to investigate changes over time and differences between cancer stage . Qualitative interviews were carried out with 11 of the women and analysed using a thematic approach . Results Mean age was 59.9 years ( SD = 15.3 ; range = 23.8–86.6 yrs ) . Mean BMI was 30.0 ( SD = 4.5 ; range = 24.4–38.2 ) . Sixteen women had early ( Stage 1 to 2B ) , and seven women had advanced stage disease ( Stage 3 to 4B ) . Question naire scores revealed that physical and social functioning , fatigue , pain and general sex life were significantly worse at 12 months than pre‐treatment ( p = < 0.05 ) . Qualitative analysis revealed multiple treatment side effects which were perceived as severe and enduring . Women with advanced vulval cancer had significantly worse SF‐36 mental health scores at 12 months compared to women with early stage disease ( p = 0.037 ) . Conclusions Surgery for vulval cancer has long‐term implication s which can be persistent 12 months post‐treatment . High rates of morbidity relating to lymphoedema and sexual function re‐enforce the need for specialist clinics to support women who suffer these complications . © 2015 The Authors . Psycho‐Oncology published by John Wiley & Sons OBJECTIVES To determine the efficacy and toxicity of radiation therapy and concurrent weekly cisplatin chemotherapy in achieving a complete clinical and pathologic response when used for the primary treatment of locally-advanced vulvar carcinoma . METHODS Patients with locally-advanced ( T3 or T4 tumors not amenable to surgical resection via radical vulvectomy ) , previously untreated squamous cell carcinoma of the vulva were treated with radiation ( 1.8 Gy daily × 32 fractions=57.6 Gy ) plus weekly cisplatin ( 40 mg/m(2 ) ) followed by surgical resection of residual tumor ( or biopsy to confirm complete clinical response ) . Management of the groin lymph nodes was st and ardized and was not a statistical endpoint . Primary endpoints were complete clinical and pathologic response rates of the primary vulvar tumor . RESULTS A planned interim analysis indicated sufficient activity to reopen the study to a second stage of accrual . Among 58 evaluable patients , there were 40 ( 69 % ) who completed study treatment . Reasons for prematurely discontinuing treatment included : patient refusal ( N=4 ) , toxicity ( N=9 ) , death ( N=2 ) , other ( N=3 ) . There were 37 patients with a complete clinical response ( 37/58 ; 64 % ) . Among these women there were 34 who underwent surgical biopsy and 29 ( 78 % ) who also had a complete pathological response . Common adverse effects included leukopenia , pain , radiation dermatitis , pain , or metabolic changes . CONCLUSIONS This combination of radiation therapy plus weekly cisplatin successfully yielded high complete clinical and pathologic response rates with acceptable toxicity Objective The aim of this study was to prospect ively monitor the patients ’ quality of life ( QoL ) after vulvar cancer surgery . Design The design was prospect i ve clinical study . Setting The study was set in the Department of Obstetrics and Gynecology , 2nd Medical Faculty of the Charles University and University Hospital Motol , Prague , Czech Republic . Methods A group of 36 patients underwent vulvar cancer surgery : 24 patients were subject to inguinofemoral lymphadenectomy ( RAD ) and 12 to sentinel lymph node biopsy . To evaluate QoL , the European Organisation for Research and Treatment of Cancer , QoL question naires ( QLQ-C30 and QLQ-CX24 ) were administered to patients before and 6 and 12 months after surgery . Results In patients with vulvar cancer after inguinofemoral lymphadenectomy , increased fatigue and impaired lymphedema were observed . In the group of patients after sentinel lymph node biopsy , none of the QoL variables worsened postoperatively . Comparing both groups 12 months after surgery , the RAD group had significantly worse outcomes in body image and cognitive functioning than the sentinel lymph node biopsy group . Patients in the RAD group , who received adjuvant radiotherapy ( n = 13 ) , had worse QoL in symptom experience ( P < 0.05 ) at 6 and 12 months after the surgery than patients without radiotherapy ( n = 11 ) . Conclusions Less radical surgery showed objective ly better QoL results PURPOSE To determine the safety of sentinel lymph node biopsy as a replacement for inguinal femoral lymphadenectomy in selected women with vulvar cancer . PATIENTS AND METHODS Eligible women had squamous cell carcinoma , at least 1-mm invasion , and tumor size ≥ 2 cm and ≤ 6 cm . The primary tumor was limited to the vulva , and there were no groin lymph nodes that were clinical ly suggestive of cancer . All women underwent intraoperative lymphatic mapping , sentinel lymph node biopsy , and inguinal femoral lymphadenectomy . Histologic ultra staging of the sentinel lymph node was prescribed . RESULTS In all , 452 women underwent the planned procedures , and 418 had at least one sentinel lymph node identified . There were 132 node-positive women , including 11 ( 8.3 % ) with false-negative nodes . Twenty-three percent of the true-positive patients were detected by immunohistochemical analysis of the sentinel lymph node . The sensitivity was 91.7 % ( 90 % lower confidence bound , 86.7 % ) and the false-negative predictive value ( 1-negative predictive value ) was 3.7 % ( 90 % upper confidence bound , 6.1 % ) . In women with tumor less than 4 cm , the false-negative predictive value was 2.0 % ( 90 % upper confidence bound , 4.5 % ) . CONCLUSION Sentinel lymph node biopsy is a reasonable alternative to inguinal femoral lymphadenectomy in selected women with squamous cell carcinoma of the vulva BACKGROUND AND PURPOSE As late radiotherapy toxicity impacts negatively on the quality -of-life of cancer survivors and is often under reported , a study was set up to prospect ively collect patient-reported data in an unselected series of patients with gynaecological malignancy . Aim 1 - To provide 3 year results for the longitudinal study . Aim 2 - To improve the question naire used to collect data by identifying redundant items and modifying for use to collect Common Terminology Criteria for Adverse Events ( CTCAE ) data . MATERIAL AND METHODS Aim 1 - Patient reported outcome data were collected prospect ively by 226 patients before and up to 3 years following radiotherapy for gynaecological cancer using a question naire developed to collect LENT subjective data . Aim 2 - A factor analysis was performed to identify which questions gave the most and least information . RESULTS Aim 1 - Faecal urgency and incontinence ( all grade s ) peaked at 79 % and 24 % , respectively at 1 year then settled to 69 % and 18 % at 3 years , respectively . Urinary urgency ( all grade s ) increased with time and was described in 75 % at 3 years . Other symptoms reported at 3 years include diarrhoea in 12 % , urinary incontinence in 27 % and vaginal dryness in 29 % . A third of patients did not feel their sex life had changed following treatment , while a quarter felt that it had . Aim 2 - some questions overlapped and others were non-specific . The question naire has subsequently been altered . CONCLUSIONS The extent of late toxicity is substantial . This detailed information is important for both patients and clinicians in terms of treatment decisions and follow-up care . The LENT question naire provides a feasible tool for capture of this information in the clinic |
13,752 | 30,225,826 | Conclusions IMT , FMD and arterial stiffness are impaired in acromegaly showing that these patients may be at increased risk of atherosclerosis .
In patients with active disease these pre clinical markers of atherosclerosis are worse compared to patients with inactive disease but the role of diabetes and hypertension is prevailing on growth hormone excess | Objective Multiple studies investigated pre clinical markers of peripheral vascular damage in acromegaly ( ACRO ) reporting discordant results .
The aim of this study was to run a meta- analysis to examine whether intima media thickness ( IMT ) , flow mediated dilation ( FMD ) and arterial pulse wave velocity ( PWV ) are affected in acromegalic patients and to assess the impact of effective treatment of growth hormone excess on these outcomes . | We studied premature atherosclerosis with carotid Doppler ultrasonography in active acromegaly before and after treatment . Patients ( n = 27 ) with active acromegaly and 12 age- , gender- , and body mass index-matched healthy individuals were included in the study . Carotid intima – media thickness was decreased significantly in the inactive group after treatment ( median : 0.6 mm , interquartile range [ IQR ] : 0.55 - 0.80 ] ) when compared with the active group ( median : 0.9 mm [ IQR : 0.75 - 1.15 ] , P < .0001 ) , but there was no significant difference between the inactive and control groups . There was a correlation between homeostasis model of assessment –insulin resistance ( P = .01 , r = .41 ) and growth hormone ( GH ; P < .0001 , r = .46 ) . In conclusion , premature atherosclerosis was demonstrated in active acromegaly patients probably as a consequence of insulin resistance and direct vascular effects of GH and /or insulin-like growth factor 1 BACKGROUND Acromegaly is known to be associated to vascular damage characterized by an increase of vascular wall thickness and an impairment of vascular function . AIM The aim of this study was to evaluate the effect of medical treatment with the GH receptor antagonist pegvisomant on vascular structure and function in acromegalic patients resistant to somatostatin analogues . PATIENTS Ten patients ( 4 males and 6 females , 28 - 58 yr ) and 20 sex- , age- , and body mass index-matched healthy controls entered the study . All patients were treated for 18 months with pegvisomant at doses ranging from 10 to 40 mg/day . OUTCOME MEASURES Primary outcome measures were measurement of carotid arteries intima-media thickness ( IMT ) , and brachial arteries flow mediated dilation ( FMD ) ; secondary outcome measures were blood pressure , blood glucose and lipids levels . RESULTS Carotid arteries maximal IMT was significantly higher in patients than in controls at baseline ( 1.18±0.59 vs 0.69±0.13 , p=0.001 ) and slightly , but not significantly , decreased after treatment ( 0.97±0.17 ) . Brachial arteries FMD was significantly lower in patients than controls at baseline ( 7.5±2.5 vs 13.1±1.4 , p<0.001 ) and significantly increased after treatment ( 8.8±3.7 , p=0.016 ) . Systolic ( SBP ) and diastolic ( DBP ) blood pressure values , serum glucose and insulin levels and homeostasis model assessment ( HOMA ) index were higher , whereas HDL-cholesterol levels were lower in patients than controls at baseline . After treatment , SBP and DBP , as well as serum glucose and insulin levels and HOMA index significantly decreased whereas no significant change was found in serum lipid profile . CONCLUSIONS The results of the current study suggested that long-term treatment with pegvisomant induced a slight reduction of carotid arteries wall thickness and a significant improvement of brachial arteries vascular function in patients with acromegaly resistant to somatostatin analogues UNLABELLED Vascular changes are common in acromegaly ( ACM ) . Current therapies can normalise the levels of both growth hormone ( GH ) and insulin-like growth factor ( IGF1 ) . OBJECTIVE To establish whether the ACM vascular changes in patients with effectively managed disease are different from those in patients with an active condition . METHODS 64 ACM patients were tested for serum GH ( r and om and during an oral glucose tolerance test ) and IGF1 . Ultrasonography of the right common carotid ( RCC ) explored structural ( the carotid diameter and intima-media thickness index ( IMT ) ) and functional ( the augmentation index ( AIx ) , elastic modulus ( Ep ) , and local pulse wave velocity ( PWV ) ) arterial parameters in the ACM patients ( groups A and B ) and an age- and sex-matched control group of 21 patients without acromegaly ( group C ) . RESULTS The ACM patients were divided into 2 subgroups that had similar cardiovascular risk factor profiles : A ( n=10 , with controlled ACM ) , and B ( n=54 , with active ACM ) . The AIx was higher in groups A ( 27.7 % [ 2.2 - 54.3 ] ) and B ( 20.0 % [ - 38.2 - 97.1 ] ) than in group C ( 3.5 % [ - 11.3 - 31.1 ] ) , p=0.01 and 0.002 , respectively . The group B patients presented with poorer functional carotid wall parameters than the control subjects : Ep-95.5 [ 33 - 280 ] KPa vs. 77.5 [ 39 - 146 ] KPa , p=0.01 ; and PWV-6 [ 3.6 - 10.4 ] m/s vs. 5.4 [ 3.9 - 7.2 ] m/s , p=0.03.The ACM patients had greater RCC diameters ( 6.4 ± 0.6 mm vs. 5.7 ± 0.6 mm , p<0.001 ) and IMT values ( 0.72 ± 0.13 mm vs. 0.58 ± 0.08 mm , p<0.001 ) than the subjects in group C. CONCLUSIONS Both the controlled and active ACM patients showed structural arterial changes . After 1 year of disease control , the patients with controlled ACM showed improvements in the functional , but not the structural , arterial parameters compared with the patients with an active condition OBJECTIVE Transsphenoidal surgery results in biochemical remission of acromegaly in 45–80 % of patients ; however , few studies have addressed the impact of transsphenoidal surgery on cardiovascular function in acromegalic patients . The aim of this prospect i ve study was to investigate the effects of postoperative GH/IGF‐I normalization on echocardiographic parameters and blood pressure ( BP ) in a series of patients with active acromegaly Objective : The aim of this study was to assess flow-mediated dilatation ( FMD ) of the brachial artery in patients with acromegaly . Subjects and Methods : We prospect ively evaluated 25 patients with acromegaly ( 14 females , 11 males ; aged 42 ± 12 years ; growth hormone ( GH ) levels 34 ± 14 ng/ml ) and 27 control subjects ( 15 females , 12 males ; aged 45 ± 8 years ; GH levels 3 ± 1.5 ng/ml ) . The patients and controls were matched for age , gender , body mass index , cigarette smoking , blood pressure , lipid levels , diabetes mellitus , hypertension , and its duration . Endothelial function , measured as FMD of the brachial artery using ultrasound , was calculated in the 2 groups . The endothelial function was evaluated by assessing 1-min postischemic FMD of the brachial artery . Results : The FMD was lower in patients with acromegaly ( 9.97 ± 3.5 % ) than in controls ( 16.1 ± 3.4 % ) , and the difference was statistically significant ( p = 0.0001 ) . Conclusion : Endothelial dysfunction may develop in the pre clinical phase of atherosclerosis in patients with acromegaly . Endothelium-dependent FMD may be impaired in acromegalic patients , and measurement of endothelial function may identify high-risk individuals earlier OBJECTIVE To evaluate the effect of a 6-month treatment with slow-release lanreotide ( LAN ) on cardiovascular risk and atherosclerosis in 24 normotensive patients with active acromegaly ( GH=67.4 + /- 12.6 mU/l , IGF -- I=866.0 + /- 55.8 microg/l ) and 24 healthy subjects sex- , age- and body mass index-matched with the patients ( as controls ) . DESIGN Open , prospect i ve , multicenter . METHODS The following were measured before and after 6 months of LAN treatment ( dose 60 - 90 mg/month ) : fasting GH , IGF-I , LDL , HDL and total cholesterol , triglyceride , glucose , glycosylated hemoglobin , insulin and fibrinogen levels , intima-media thickness ( IMT ) and blood systolic and diastolic peak velocity ( SPV and DPV respectively ) in both common carotids . RESULTS At study entry , insulin , total and LDL cholesterol , triglyceride and fibrinogen levels were higher while HDL cholesterol levels were lower in patients than in controls . At the right ( 0.88 + /- 0.04 vs 0.77 + /- 0.03 mm , P=0.05 ) and left ( 0.93 + /- 0.03 vs 0.78 + /- 0.02 mm , P=0.01 ) common carotid IMT was significantly higher in patients than in controls ; 12 patients and two controls showed an IMT of > or = 1 mm ( chi(2)=8.2 , P=0.004 ) . After 6 months of LAN treatment , disease control was achieved in 15 patients ( 62.5 % ) . Insulin , triglyceride and fibrinogen levels were significantly decreased , and a trend toward a decrease of IMT in the right ( from 0.90 + /- 0.05 to 0.78 + /- 0.04 mm , P=0.06 ) and left ( from 0.95 + /- 0.04 to 0.84 + /- 0.04 mm , P=0.06 ) common carotid arteries was observed only in patients with disease control , while SPV and DPV did not change . CONCLUSIONS LAN treatment for 6 months significantly lowered GH , IGF-I , insulin and fibrinogen levels and reduced IMT of both common carotid arteries in normotensive patients with acromegaly It is well established , that the increased mortality in patients with acromegaly is due to cardiac diseases . Cardiomyopathy is the predominant cardiac alteration in patients with acromegaly . There are less data about coronary heart disease or coronary calcifications . Electron beam computed tomography ( EBCT ) is the st and ard imaging modality for identification of coronary artery calcifications ( CAC ) and can determine the extent and severity of coronary atherosclerosis . Coronary risk was evaluated by the Framingham risk score ( FRS ) . The prospect i ve study included 30 patients with acromegaly ( mean age 53+/-14 year ; 16 females , 14 males ; BMI 28.1+/-3.6 kg/m ( 2 ) ; mean+/-SD ) , 12 patients had active disease ( IGF-1 751+/-338 microg/L ; GH 25.6+/-36.4 microg/L ) , 9 were well-controlled ( IGF-1 157+/-58 microg/L ; GH 1.8+/-1.1 microg/L ) under somatostatin analogue octreotide ( n=5 ) , dopamine agonists ( n=2 ) , and the GH receptor antagonist pegvisomant ( n=2 ; GH levels were not determined in this subgroup ) and 9 were cured IGF-1 ( 148+/-57 microg/L ; GH 0.5+/-0.2 microg/L ) . Increased left ventricular muscle mass index ( LVMI > 132 g/m ( 2 ) ) was focused in 53 % , hypercholesterinemia in 63 % , hypertension in 43 % , diabetes mellitus/impaired glucose tolerance in 27 % , and smokers in 53 % ( pack per year 9+/-15 yr ) . For quantification of CAC the EBCT was used and the Agatston calcium score was determined . Results were composed to established age and sex adjusted percentile distribution of CAC . CAC was present in 53 % , high CAC score ( 75 ( th ) percentile ) in 37 % and were categorized as cardiovascular high risk patients . FRS was related to the CAC score ( p=0.008 , r (2)=0.22 ) and the disease duration ( p=0.002 , r (2)=0.29 ) . The CAC score correlated with LVMI ( p=0.02 , r (2)=0.17 ) , the disease duration of acromegaly ( p=0.004 , r (2)=0.36 ) , and the FRS ( p=0.008 , r (2)=0.22 ) . Patients with a high CAC score had a longer disease duration of 9.6+/-4.7 versus 5.4+/-2.8 years with CAC<75 ( th ) percentile ( p=0.02 ) . In summary , the disease duration and consequently the accompanying metabolic disorders appear to influence the degree of CAC in patients with acromegaly . The observations underline the importance of early and sufficient treatment of acromegaly in high risk patients BACKGROUND Data on coronary heart disease ( CHD ) are scanty and matter of argument in acromegalic patients . OBJECTIVE The objective of this study was to evaluate risk factors for development of CHD and the occurrence of cardiac events in acromegalic patients during a 5-yr prospect i ve study . DESIGN Ten-year likelihood for CHD development was estimated by the Framingham scoring system ( FS ) ; patients were stratified as having low ( FS < 10 ) , intermediate ( > or= 10 FS < 20 ) , or high ( FS > or= 20 ) risk . Coronary artery calcium content was measured using the Agatston score ( AS ) in all patients ; those with positive AS were su bmi tted to myocardial single-photon emission computed tomography ; cardiac events were recorded during a 5-yr follow-up period . PATIENTS Fifty-two consecutive patients ( 31 women , mean age 52 + /- 11 yr ) with controlled or uncontrolled acromegaly were followed prospect ively for 5 yr . RESULTS Thirty-seven patients ( 71 % ) had low , 14 patients ( 27 % ) had intermediate , and one patient ( 2 % ) had high CHD risk . CHD risk was unrelated to acromegaly activity or the estimated duration of disease . Among patients with FS less than 10 % , 24 had AS equal to 0 , eight had AS of 1 or greater and less than 100 , and five had AS 100 or greater and less than 300 , respectively . Among patients with FS 10 or greater and less than 20 % , nine had AS equal to 0 , two had AS of one or greater and less than 100 , one had AS of 100 or greater and less than 300 , and two had AS of 300 or greater ; a patient of the latter group , having AS of 400 or greater , increased his CHD risk from 11 % to 20 % or more . FS or AS did not differ in patients with controlled or uncontrolled acromegaly ( P = 0.981 ) . All patients with positive AS had no single photon emission computed tomography perfusion defects . During the 5-yr follow-up period no patient developed ischemic cardiac events . CONCLUSIONS CHD risk in acromegalic patients , predicted by FS as in nonacromegalic subjects , is low ; AS might have adjunctive role only in a subset of patients . However , most patients have systemic complications of acromegaly , which participate in the assessment of global CHD risk Purpose Acromegaly is a rare disease generally brought about by a benign tumour in the pituitary and characterized by growth hormone ( GH ) and insulin-like growth factor 1 ( IGF-1 ) excess . Increased mortality has been related to cardiovascular events that could be linked to these hormones and patients suffer from high rates of diabetes and hypertension . In this study , we examine if the incidence of myocardial infa rct ion ( MI ) and stroke differ from that of the general population . Methods Data from the German Acromegaly Registry in seven specialized endocrine centres were analysed ( n = 479 , 56 % female , 46 years old at diagnosis , 5549 person-years from diagnosis ) . St and ardized incidence ratios ( SIR ) were calculated as compared to the general population . Results MI and stroke incidences were very close to those of the general population with an SIR ( 95 % CI ) of 0.89 ( 0.47–1.52 , p = 0.80 ) for MI and 1.17 ( 0.66–1.93 , p = 0.61 ) for stroke . Acromegaly was uncontrolled in 16 % of patients with MI or stroke versus 21 % in those without ( p = 0.56 ) . Prevalence of hypertension at the initial visit was much higher in those with MI or stroke than those without ( 94 vs. 43 % , p < 0.001 ) . No association was seen between radiation therapy and stroke . Conclusions For acromegaly patients being treated at specialized centres , the incidence of MIs and strokes does not seem to differ from the general population . Certainty regarding such statements requires large , prospect i ve studies however |
13,753 | 30,392,086 | These significance s were reflected in the subgroup of melanoma metastases .
Conclusion Based on the trends of our findings , there appears to exist an optimal time window around SRS of which ICI may confer the most survival benefit . | Background Immune checkpoint inhibition ( ICI ) is an emerging immunotherapy for metastatic brain disease ( MBD ) .
Current management options include stereotactic radiosurgery ( SRS ) , which has been shown to confer prognostic benefit in combination with ICI .
However , the effect , if any , of ICI timing on this benefit is currently unclear .
The aim of this study was to evaluate the effect of concurrent ICI with SRS on survival outcomes in MBD compared to non-concurrent ICI administered before or after SRS . | BACKGROUND Nivolumab ( a programmed death 1 [ PD-1 ] checkpoint inhibitor ) and ipilimumab ( a cytotoxic T-lymphocyte-associated antigen 4 [ CTLA-4 ] checkpoint inhibitor ) have been shown to have complementary activity in metastatic melanoma . In this r and omized , double-blind , phase 3 study , nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma . METHODS We assigned , in a 1:1:1 ratio , 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone , nivolumab plus ipilimumab , or ipilimumab alone . Progression-free survival and overall survival were co primary end points . Results regarding progression-free survival are presented here . RESULTS The median progression-free survival was 11.5 months ( 95 % confidence interval [ CI ] , 8.9 to 16.7 ) with nivolumab plus ipilimumab , as compared with 2.9 months ( 95 % CI , 2.8 to 3.4 ) with ipilimumab ( hazard ratio for death or disease progression , 0.42 ; 99.5 % CI , 0.31 to 0.57 ; P<0.001 ) , and 6.9 months ( 95 % CI , 4.3 to 9.5 ) with nivolumab ( hazard ratio for the comparison with ipilimumab , 0.57 ; 99.5 % CI , 0.43 to 0.76 ; P<0.001 ) . In patients with tumors positive for the PD-1 lig and ( PD-L1 ) , the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group , but in patients with PD-L1-negative tumors , progression-free survival was longer with the combination therapy than with nivolumab alone ( 11.2 months [ 95 % CI , 8.0 to not reached ] vs. 5.3 months [ 95 % CI , 2.8 to 7.1 ] ) . Treatment-related adverse events of grade 3 or 4 occurred in 16.3 % of the patients in the nivolumab group , 55.0 % of those in the nivolumab-plus-ipilimumab group , and 27.3 % of those in the ipilimumab group . CONCLUSIONS Among previously untreated patients with metastatic melanoma , nivolumab alone or combined with ipilimumab result ed in significantly longer progression-free survival than ipilimumab alone . In patients with PD-L1-negative tumors , the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone . ( Funded by Bristol-Myers Squibb ; CheckMate 067 Clinical Trials.gov number , NCT01844505 . ) PURPOSE Nivolumab , a programmed death-1 ( PD-1 ) immune checkpoint inhibitor antibody , has demonstrated improved survival over docetaxel in previously treated advanced non-small-cell lung cancer ( NSCLC ) . First-line monotherapy with nivolumab for advanced NSCLC was evaluated in the phase I , multicohort , Checkmate 012 trial . METHODS Fifty-two patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity ; postprogression treatment was permitted per protocol . The primary objective was to assess safety ; secondary objectives included objective response rate ( ORR ) and 24-week progression-free survival ( PFS ) rate ; overall survival ( OS ) was an exploratory end point . RESULTS Any- grade treatment-related adverse events ( AEs ) occurred in 71 % of patients , most commonly : fatigue ( 29 % ) , rash ( 19 % ) , nausea ( 14 % ) , diarrhea ( 12 % ) , pruritus ( 12 % ) , and arthralgia ( 10 % ) . Ten patients ( 19 % ) reported grade 3 to 4 treatment-related AEs ; grade 3 rash was the only grade 3 to 4 event occurring in more than one patient ( n = 2 ; 4 % ) . Six patients ( 12 % ) discontinued because of a treatment-related AE . The confirmed ORR was 23 % ( 12 of 52 ) , including four ongoing complete responses . Nine of 12 responses ( 75 % ) occurred by first tumor assessment ( week 11 ) ; eight ( 67 % ) were ongoing ( range , 5.3 + to 25.8 + months ) at the time of data lock . ORR was 28 % ( nine of 32 ) in patients with any degree of tumor PD-lig and 1 expression and 14 % ( two of 14 ) in patients with no PD-lig and 1 expression . Median PFS was 3.6 months , and the 24-week PFS rate was 41 % ( 95 % CI , 27 to 54 ) . Median OS was 19.4 months , and the 1-year and 18-month OS rates were 73 % ( 95 % CI , 59 to 83 ) and 57 % ( 95 % CI , 42 to 70 ) , respectively . CONCLUSION First-line nivolumab monotherapy demonstrated a tolerable safety profile and durable responses in first-line advanced NSCLC PURPOSE Blockade of the programmed death-1 inhibitory cell-surface molecule on immune cells using the fully human immunoglobulin G4 antibody nivolumab mediates tumor regression in a portion of patients with advanced treatment-refractory solid tumors . We report clinical activity , survival , and long-term safety in patients with advanced renal cell carcinoma ( RCC ) treated with nivolumab in a phase I study with expansion cohorts . PATIENTS AND METHODS A total of 34 patients with previously treated advanced RCC , enrolled between 2008 and 2012 , received intravenous nivolumab ( 1 or 10 mg/kg ) in an outpatient setting once every two weeks for up to 96 weeks and were observed for survival and duration of response after treatment discontinuation . RESULTS Ten patients ( 29 % ) achieved objective responses ( according to RECIST [ version 1.0 ] ) , with median response duration of 12.9 months ; nine additional patients ( 27 % ) demonstrated stable disease lasting > 24 weeks . Three of five patients who stopped treatment while in response continued to respond for ≥ 45 weeks . Median overall survival in all patients ( 71 % with two to five prior systemic therapies ) was 22.4 months ; 1- , 2- , and 3-year survival rates were 71 % , 48 % , and 44 % , respectively . Grade 3 to 4 treatment-related adverse events occurred in 18 % of patients ; all were reversible . CONCLUSION Patients with advanced treatment-refractory RCC treated with nivolumab demonstrated durable responses that in some responders persisted after drug discontinuation . Overall survival is encouraging , and toxicities were generally manageable . Ongoing r and omized clinical trials will further assess the impact of nivolumab on overall survival in patients with advanced RCC BACKGROUND The immune checkpoint inhibitor ipilimumab is the st and ard-of-care treatment for patients with advanced melanoma . Pembrolizumab inhibits the programmed cell death 1 ( PD-1 ) immune checkpoint and has antitumor activity in patients with advanced melanoma . METHODS In this r and omized , controlled , phase 3 study , we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab ( at a dose of 10 mg per kilogram of body weight ) every 2 weeks or every 3 weeks or four doses of ipilimumab ( at 3 mg per kilogram ) every 3 weeks . Primary end points were progression-free and overall survival . RESULTS The estimated 6-month progression-free-survival rates were 47.3 % for pembrolizumab every 2 weeks , 46.4 % for pembrolizumab every 3 weeks , and 26.5 % for ipilimumab ( hazard ratio for disease progression , 0.58 ; P<0.001 for both pembrolizumab regimens versus ipilimumab ; 95 % confidence intervals [ CIs ] , 0.46 to 0.72 and 0.47 to 0.72 , respectively ) . Estimated 12-month survival rates were 74.1 % , 68.4 % , and 58.2 % , respectively ( hazard ratio for death for pembrolizumab every 2 weeks , 0.63 ; 95 % CI , 0.47 to 0.83 ; P=0.0005 ; hazard ratio for pembrolizumab every 3 weeks , 0.69 ; 95 % CI , 0.52 to 0.90 ; P=0.0036 ) . The response rate was improved with pembrolizumab administered every 2 weeks ( 33.7 % ) and every 3 weeks ( 32.9 % ) , as compared with ipilimumab ( 11.9 % ) ( P<0.001 for both comparisons ) . Responses were ongoing in 89.4 % , 96.7 % , and 87.9 % of patients , respectively , after a median follow-up of 7.9 months . Efficacy was similar in the two pembrolizumab groups . Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups ( 13.3 % and 10.1 % ) than in the ipilimumab group ( 19.9 % ) . CONCLUSIONS The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high- grade toxicity than did ipilimumab in patients with advanced melanoma . ( Funded by Merck Sharp & Dohme ; KEYNOTE-006 Clinical Trials.gov number , NCT01866319 . ) |
13,754 | 30,536,140 | Conclusions If the outcomes of the trials underpinning the evidence of clinical effectiveness can be replicated , then mechanical thrombectomy is likely to be cost-effective by typical willingness-to-pay thresholds .
This finding holds under the assumption that no investment is required to develop stroke centres to the st and ard required to provide a safe emergency endovascular service and that additional expenditure on timely patient transport is not required | Purpose Although good evidence exists regarding the clinical effectiveness of mechanical thrombectomy for people with acute ischaemic stroke , cost-effectiveness should also be considered .
The aim of this study was to systematic ally review the evidence of cost-effectiveness of emergency endovascular therapy using mechanical thrombectomy in the management of acute ischaemic stroke . | Background and Purpose — Mechanical thrombectomy has the potential to improve recanalization rates and outcomes for patients with ischemic stroke , but potential gains could be offset by procedural complications and costs . We evaluated the cost and utility of combined intravenous ( IV ) tissue-type plasminogen activator ( tPA ) and mechanical thrombectomy compared to IV tPA alone for acute large-vessel ischemic stroke . Methods — We constructed a decision tree for a hypothetical 68-year-old with a large-vessel ischemic stroke who is eligible for IV tPA . The interventional strategy was IV tPA , a cerebral angiogram , and mechanical thrombectomy and thrombolysis if indicated . Recanalization , hemorrhage complications , and outcomes for the interventional strategy were from the Multi-MERCI study . The medical strategy was IV tPA using inputs from a comprehensive systematic review . Costs were estimated from Medicare reimbursements . We modeled lifetime costs and utilities for disability using a Markov model and Monte-Carlo multivariable sensitivity analysis . Results — For the baseline scenario , the recanalization rate was 72.9 % for the interventional strategy and 46.2 % for the medical strategy . For the interventional strategy , the symptomatic hemorrhage rate was 8.6 % with recanalization and 15.4 % without . For the medical strategy , the corresponding rates were 3.6 % and 13.3 % , respectively . The interventional strategy was cost-effective in 97.6 % of simulations ( incremental cost-effectiveness ratio $ 16 001/ quality -adjusted life year ; 95 % CI , $ 2736–$39 232 ) . Conclusions — Based on observational data , the combination of IV tPA and mechanical thrombectomy for large-vessel ischemic stroke appears to be cost-effective compared to IV tPA alone . These findings require additional validation with r and omized trial data Background and Purpose — Clinical trials have demonstrated improved 90-day outcomes for patients with acute ischemic stroke treated with stent retriever thrombectomy plus tissue-type plasminogen activator ( SST+tPA ) compared with tPA . Previous studies suggested that this strategy may be cost-effective , but models were derived from pooled data and older assumptions . Methods — In this prospect i ve economic sub study conducted alongside the SWIFT-PRIME trial ( Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke ) , in-trial costs were measured for patients using detailed medical re source utilization and hospital billing data . Utility weights were assessed at 30 and 90 days using the EuroQol-5 dimension question naire . Post-trial costs and life-expectancy were estimated for each surviving patient using a model based on trial data and inputs derived from a contemporary cohort of ischemic stroke survivors . Results — Index hospitalization costs were $ 17 183 per patient higher for SST+tPA than for tPA ( $ 45 761 versus $ 28 578 ; P<0.001 ) , driven by initial procedure costs . Between discharge and 90 days , costs were $ 4904 per patient lower for SST+tPA than for tPA ( $ 11 270 versus $ 16 174 ; P=0.014 ) ; total 90-day costs remained higher with SST+tPA ( $ 57 031 versus $ 44 752 ; P<0.001 ) . Higher utility values for SST+tPA led to higher in-trial quality -adjusted life years ( 0.131 versus 0.105 ; P=0.005 ) . In lifetime projections , SST+tPA was associated with substantial gains in quality -adjusted life years ( 6.79 versus 5.05 ) , cost savings of $ 23 203 per patient and was economically dominant when compared with tPA in 90 % of bootstrap replicates . Conclusions — Among patients with acute ischemic stroke enrolled in the SWIFT-PRIME trial , SST increased initial treatment costs , but was projected to improve quality -adjusted life-expectancy and reduce healthcare costs over a lifetime horizon compared with tPA . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT01657461 Objective : To evaluate the cost-effectiveness of adding endovascular thrombectomy to st and ard care in patients with acute ischemic stroke . Methods : The cost-effectiveness analysis of endovascular thrombectomy in patients with acute ischemic stroke was based on a decision-analytic Markov model . Primary outcomes from ESCAPE , Extending the Time for Thrombolysis in Emergency Neurological Deficits – Intra-Arterial ( EXTEND-IA ) , Multicenter R and omized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherl and s ( MR CLEAN ) , Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours ( REVASCAT ) , and Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke ( SWIFT PRIME ) along with data from published studies and registries were used in this analysis . We used a health care payer perspective and a lifelong time horizon to estimate costs and effects . Results : The model showed that adding thrombectomy with stent retrievers to guideline -based care ( including IV thrombolysis ) result ed in a gain of 0.40 life-years and 0.99 quality -adjusted life-years along with a cost savings of approximately $ 221 per patient . The sensitivity analysis showed that the results were not sensitive to changes in uncertain parameters or assumptions . Conclusions : Adding endovascular treatment to st and ard care result ed in substantial clinical benefits at low costs . The results were consistent throughout irrespective of whether data from ESCAPE , EXTEND-IA , MR CLEAN , REVASCAT , or SWIFT PRIME were used in this model OBJECT Mechanical thrombectomy is increasingly being used for the treatment of large-vessel ischemic stroke in patients who arrive outside of the 3-hour tissue plasminogen activator time window . In this study , the authors evaluated the cost and effectiveness of mechanical thrombectomy compared with st and ard medical therapy in patients who are ineligible to receive tissue plasminogen activator . METHODS Clinical outcomes of an open-label study of mechanical thrombectomy were compared with a hypothetical control group with a lower recanalization rate ( 18 vs 60 % ) and a lower rate of symptomatic intracranial hemorrhage ( 0.6 vs 7.8 % ) than the active treatment group . A Markov cost-effectiveness model was built to compare the health benefits and costs associated with mechanical thrombectomy compared with st and ard medical therapy . All probabilities , quality -of-life factors , and costs were estimated from the published literature . Univariate sensitivity analyses were performed to assess how variations in model parameters affect health and economic outcomes . RESULTS Treatment of acute ischemic stroke with mechanical thrombectomy increased survival time by 0.54 quality -adjusted life years ( QALYs ) , compared with st and ard medical therapy ( 2.37 vs 1.83 QALYs ) , at an increased cost of $ 6600 . This yielded an incremental cost-effectiveness ratio ( ICER ) of $ 12,120 per QALY gained , a value generally considered cost-effective . Sensitivity analysis showed that mechanical thrombectomy remained cost-effective ( ICER < $ 50,000 per QALY gained ) for all model inputs varied over a reasonable range , except for age at stroke treatment . For patients older than 82 years of age , the treatment was only borderline cost-effective ( ICER of $ 50,000 - 100,000 per QALY gained ) . CONCLUSIONS The treatment of large-vessel ischemic stroke with mechanical thrombectomy appears to be costeffective . These results require validation when data from a r and omized , controlled trial of mechanical thrombectomy become available Background and Purpose — The objective of this study was to determine the cost-effectiveness of intra-arterial treatment within the 0- to 6-hour window after intravenous tissue-type plasminogen activator within 0- to 4.5-hour compared with intravenous tissue-type plasminogen activator alone , in the US setting and from a social perspective . Methods — A decision analytic model estimated the lifetime costs and outcomes associated with the additional benefit of intra-arterial therapy compared with st and ard treatment with intravenous tissue-type plasminogen activator alone . Model inputs were obtained from published literature , the Multicenter R and omized Clinical Trial of Endovascular Therapy for Acute Ischemic Stroke in the Netherl and s ( MR CLEAN ) study , and cl aims data bases in the United States . Health outcomes were measured in quality -adjusted life years ( QALYs ) . Treatment benefit was assessed by calculating the cost per QALY gained . One-way and probabilistic sensitivity analyses were performed to estimate the overall uncertainty of model results . Results — The addition of intra-arterial therapy compared with st and ard treatment alone yielded a lifetime gain of 0.7 QALY for an additional cost of $ 9911 , which result ed in a cost of $ 14 137 per QALY . Multivariable sensitivity analysis predicted cost-effectiveness ( ⩽$50 000 per QALY ) in 97.6 % of simulation runs . Conclusions — Intra-arterial treatment after intravenous tissue-type plasminogen activator for patients with anterior circulation strokes within the 6-hour window is likely cost-effective . From a societal perspective , increased investment in access to intra-arterial treatment for acute stroke may be justified BACKGROUND AND PURPOSE : It is unclear whether the costs and risks of mechanical therapies make them cost-effective . We examined whether interventions such as mechanical clot removal or disruption with angioplasty are cost-effective for acute ischemic stroke compared with best medical therapy . MATERIAL S AND METHODS : We performed a cost-utility analysis of patients with acute stroke due to large intracranial artery occlusion presenting beyond the 3-hour window for IV tPA . Model inputs for the mechanical arm were derived from Multi MERCI trial data and a recent meta- analysis . For best medical therapy , we used rates of spontaneous recanalization , ICH , and functional outcomes based on a systematic literature review . Discounted QALYs were determined by using the Markov modeling for 65-year-old patients with acute ischemic stroke . RESULTS : On the basis of a systematic literature review , we modeled an 84 % rate of recanalization with mechanical intervention and a 6.3 % rate of symptomatic ICH . For best medical therapy , we modeled a spontaneous recanalization rate of 24 % with a 2 % rate of symptomatic ICH . Mechanical therapies were associated with a $ 7718 net cost and a gain of a 0.82 QALYs for each use , thus yielding a net of $ 9386/QALY gained . In sensitivity analyses , results were dependent on the rates of recanalization , symptomatic ICH rates , and costs of treatment . CONCLUSIONS : On the basis of available data , mechanical therapies in qualified patients with acute stroke beyond the window for IV tPA appear to be cost-effective . However , the inputs are not derived from r and omized trials , and results are sensitive to several assumptions BACKGROUND Thrombolytic therapy for acute ischemic stroke has been approached cautiously because there were high rates of intracerebral hemorrhage in early clinical trials . We performed a r and omized , double-blind trial of intravenous recombinant tissue plasminogen activator ( t-PA ) for ischemic stroke after recent pilot studies suggested that t-PA was beneficial when treatment was begun within three hours of the onset of stroke . METHODS The trial had two parts . Part 1 ( in which 291 patients were enrolled ) tested whether t-PA had clinical activity , as indicated by an improvement of 4 points over base-line values in the score of the National Institutes of Health stroke scale ( NIHSS ) or the resolution of the neurologic deficit within 24 hours of the onset of stroke . Part 2 ( in which 333 patients were enrolled ) used a global test statistic to assess clinical outcome at three months , according to scores on the Barthel index , modified Rankin scale , Glasgow outcome scale , and NIHSS : RESULTS In part 1 , there was no significant difference between the group given t-PA and that given placebo in the percentages of patients with neurologic improvement at 24 hours , although a benefit was observed for the t-PA group at three months for all four outcome measures . In part 2 , the long-term clinical benefit of t-PA predicted by the results of part 1 was confirmed ( global odds ratio for a favorable outcome , 1.7 ; 95 percent confidence interval , 1.2 to 2.6 ) . As compared with patients given placebo , patients treated with t-PA were at least 30 percent more likely to have minimal or no disability at three months on the assessment scales . Symptomatic intracerebral hemorrhage within 36 hours after the onset of stroke occurred in 6.4 percent of patients given t-PA but only 0.6 percent of patients given placebo ( P < 0.001 ) . Mortality at three months was 17 percent in the t-PA group and 21 percent in the placebo group ( P = 0.30 ) . CONCLUSIONS Despite an increased incidence of symptomatic intracerebral hemorrhage , treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months Background Twelve r and omised controlled trials ( RCTs ) comparing mechanical thrombectomy against traditional treatment options for patients experiencing acute ischaemic stroke ( AIS ) have been published . Aims To evaluate whether this technology is more effective and /or safer than traditional treatment options and to assess the potential for implementation of this technology as a treatment strategy for acute ischaemic stroke in Irel and . Methods RCTs published up to February 2017 were included . Meta- analysis was performed for two primary ( mortality at 90 days , mRS at 90 days ) and four secondary outcomes . Cumulative meta- analysis was used to investigate the point at which a consistent treatment effect was observed for outcomes that had a statistically significant pooled effect . Results Mechanical thrombectomy was associated with higher likelihood of being independent ( mRS , p < 0.01 ; Barthel index , p < 0.01 ) at 90 days post-AIS ( p < 0.001 ) . Cumulative meta- analysis demonstrated a consistent treatment effect in favour of mechanical thrombectomy after each trial was added to the analysis . There was no evidence of a difference in mortality rates ( p = 0.21 ) or rates of SICH ( p = 0.71 ) between patients r and omised to intervention and control arms . Although the intervention appears to be associated with higher rates of any cerebral haemorrhage ( p < 0.01 ) and recurrent ischaemic stroke ( p = 0.03 ) , considerable uncertainty remains as to these treatment effects . Conclusions The trials published most recently have acted as a ‘ watershed ’ for mechanical thrombectomy , and while there are significant caveats , the data suggests that mechanical thrombectomy needs to be factored into the planning and delivery of services for the management of patients with acute ischaemic stroke in Irel and |
13,755 | 28,417,451 | Prophylaxis:1 .
There was no significant difference between groups in infant or conventional lung function ( moderate quality evidence ) .
We found no significant effect on nutrition ( low quality evidence ) , hospital admissions , additional courses of antibiotics ( low quality evidence ) or adverse effects ( moderate quality evidence ) .
There was no significant difference in the number of isolates of Pseudomonas aeruginosa between groups ( low quality evidence ) , though there was a trend towards a lower cumulative isolation rate of Pseudomonas aeruginosa in the prophylaxis group at two and three years and towards a higher rate from four to six years .
As the studies review ed lasted six years or less , conclusions can not be drawn about the long-term effects of prophylaxis .
Anti-staphylococcal antibiotic prophylaxis leads to fewer children having isolates of Staphylococcus aureus , when commenced early in infancy and continued up to six years of age . | BACKGROUND Staphylococcus aureus causes pulmonary infection in young children with cystic fibrosis .
Prophylactic antibiotics are prescribed hoping to prevent such infection and lung damage .
Antibiotics have adverse effects and long-term use might lead to infection with Pseudomonas aeruginosa .
This is an up date of a previously published review .
OBJECTIVES To assess continuous oral antibiotic prophylaxis to prevent the acquisition of Staphylococcus aureus versus no prophylaxis in people with cystic fibrosis , we tested these hypotheses .
improves clinical status , lung function and survival;2 .
causes adverse effects ( e.g. diarrhoea , skin rash , c and idiasis);3 .
leads to fewer isolates of common pathogens from respiratory secretions;4 .
leads to the emergence of antibiotic resistance and colonisation of the respiratory tract with Pseudomonas aeruginosa . | All newborn infants in East Anglia are screened for cystic fibrosis by blood immunoreactive trypsin assay at 7 days . Thirty eight infants with cystic fibrosis were r and omised to treatment with either continuous oral flucloxacillin 250 mg/day ( group P , n = 18 ) or with episodic antimicrobials as clinical ly indicated ( group E , n = 20 ) . Their progress was monitored from diagnosis to 24 months by a nurse coordinator who visited all infants regularly , at home and in hospital , to collect anthropometric , dietary , clinical , and microbiological data . Mean ( range ) age of confirmation of diagnosis was 5.7 weeks ( 1 - 14 weeks ) . There was no significant difference in birth weight , genotype , immunoreactive trypsin concentration , neonatal history , symptoms at diagnosis , pancreatic enzyme supplementation , or parental smoking history between the groups . Infants in group E had more frequent cough and a greater number of Staphylococcus aureus isolates than infants in group P. More infants of group E were admitted to hospital , had higher admission rates during the second year ( 19 v 5 ) , for longer periods ( 6.4 v 2.2 days ) , despite receiving more than double the number of courses of antibiotics than group P infants ( in addition to flucloxacillin ) . Continuous prophylactic flucloxacillin from early diagnosis of cystic fibrosis is associated with improved clinical progress during the first two years of life The nature and timing of lower respiratory infections in infants with cystic fibrosis is largely unknown1 because infants do not produce sputum and throat cultures may not predict lower respiratory pathogens.2 We performed a prospect i ve cross sectional study of an unselected cohort of infants with cystic fibrosis in which bronchoalveolar lavage was used to determine lower respiratory infection and inflammation during the first three months of life . The state of Victoria , Australia ( 66000 births per year ) has a cystic fibrosis screening programme , all patients being managed by one centre . Between February 1992 and September 1994 we recruited 45 ( 27 boys ) of the 52 infants with newly diagnosed disease ; 32 were identified by screening , 12 from meconium ileus , and one by failure to thrive , and all cases were confirmed by sweat testing . Sixteen infants had respiratory symptoms , and seven of them were receiving oral antibiotics when bronchoalveolar lavage was performed at a mean age of 2.6 ( SD 1.6 ) months . Nine otherwise healthy infants ( five boys ) aged ABSTRACT Linezolid is a treatment option for methicillin-resistant Staphylococcus aureus ( MRSA ) infections in cystic fibrosis ( CF ) patients . Little is known , however , about its pharmacokinetics in this population . Eight adults with CF were r and omized to receive intravenous ( i.v . ) and oral linezolid at 600 mg twice daily for 9 doses in a crossover design with a 9-day washout . Plasma sample s were collected after the first and ninth doses of each phase . Population pharmacokinetic analyses were performed by nonlinear mixed-effects modeling using a previously described 2-compartment model with time-dependent clearance inhibition . Monte Carlo simulation was performed to assess the activities of the linezolid dosing regimens against 42 contemporary MRSA isolates recovered from CF patients . The following pharmacokinetic parameter estimates were observed for the population : absorption rate constant , 1.91 h−1 ; clearance , 9.54 liters/h ; volume of central compartment , 26.8 liters ; volume of peripheral compartment , 17.3 liters ; and intercompartmental clearance , 104 liters/h . Linezolid demonstrated nonlinear clearance after 9 doses , which was reduced by a mean of 38.9 % ( range , 28.8 to 59.9 % ) . Mean bioavailability was 85 % ( range , 47 to 131 % ) . At steady state , 600 mg given twice daily produced 93.0 % and 87.2 % probabilities of obtaining the target pharmacodynamic exposure against the MRSA isolates for the i.v . and oral formulations , respectively . Thrice-daily dosing increased the probabilities to 97.0 % and 95.6 % , respectively . Linezolid pharmacokinetics in these adults with CF were well described by a 2-compartment model with time-dependent clearance inhibition . St and ard i.v . and oral dosing regimens should be sufficient to reliably attain pharmacodynamic targets against most MRSA isolates ; however , more frequent dosing may be required for isolates with MICs of ≥2 μg/ml RATIONALE Better underst and ing of evolution of lung function in infants with cystic fibrosis ( CF ) and its association with pulmonary inflammation and infection is crucial in informing both early intervention studies aim ed at limiting lung damage and the role of lung function as outcomes in such studies . OBJECTIVES To describe longitudinal change in lung function in infants with CF and its association with pulmonary infection and inflammation . METHODS Infants diagnosed after newborn screening or clinical presentation were recruited prospect ively . FVC , forced expiratory volume in 0.5 seconds ( FEV(0.5 ) ) , and forced expiratory flows at 75 % of exhaled vital capacity ( FEF(75 ) ) were measured using the raised-volume technique , and z-scores were calculated from published reference equations . Pulmonary infection and inflammation were measured in bronchoalveolar lavage within 48 hours of lung function testing . MEASUREMENTS AND MAIN RESULTS Thirty-seven infants had at least two successful repeat lung function measurements . Mean ( SD ) z-scores for FVC were -0.8 ( 1.0 ) , -0.9 ( 1.1 ) , and -1.7 ( 1.2 ) when measured at the first visit , 1-year visit , or 2-year visit , respectively . Mean ( SD ) z-scores for FEV(0.5 ) were -1.4 ( 1.2 ) , -2.4 ( 1.1 ) , and -4.3 ( 1.6 ) , respectively . In those infants in whom free neutrophil elastase was detected , FVC z-scores were 0.81 lower ( P=0.003 ) , and FEV(0.5 ) z-scores 0.96 lower ( P=0.001 ) , respectively . Significantly greater decline in FEV(0.5 ) z-scores occurred in those infected with Staphylococcus aureus ( P=0.018 ) or Pseudomonas aeruginosa ( P=0.021 ) . CONCLUSIONS In infants with CF , pulmonary inflammation is associated with lower lung function , whereas pulmonary infection is associated with a greater rate of decline in lung function . Strategies targeting pulmonary inflammation and infection are required to prevent early decline in lung function in infants with CF The effect of prophylactic antibiotics on bacterial colonization of the respiratory tract and on general progression of cystic fibrosis was studied in a two-year prospect i ve study of 47 mildly to moderately affected patients . One group of patients received inhaled cephaloridine and the other received no inhaled antibiotic ; both groups received cloxacillin orally . Carriage of Haemophilus influenzae was greater in the group not receiving inhaled antibiotic ( 55 % vs 20 % ) . Rates of carriage of Staphylococcus aureus ( 23 % ) . Pseudomonas aeruginosa ( greater than 90 % ) . Pseudomonas cepacia ( 45 % ) , and other organisms were similar in both groups . There were no significant differences between the two groups in incidence of respiratory tract infections or hospital admissions , clinical scores , radiologic scores , or rate of change of pulmonary function . Although continuous antistaphylococcal antibiotic prophylaxis may be successful in suppressing colonization with S. aureus , it may also contribute to the high rates of carriage of Ps . aeruginosa and Ps . cepacia observed in patients with cystic fibrosis On the basis of their answers to a self-administered question naire , 697 nonsmoking healthy subjects were chosen from a r and omly selected sample representative of the white non-Mexican-American population of Tucson , Arizona , enrolled in a longitudinal study of respiratory health . For each subject , the first satisfactory set of flow-volume data obtained during the first 3 consecutive surveys was selected for analysis . For forced vital capacity ( FVC ) and forced expiratory volume in one second ( FEV1 ) , the single best value for each subject was selected . Other flow-volume measurements were derived from the single test with the best sum FEV , plus FVC . These data were used to derive improved prediction equations for each sex by age group for 5 spirometric and flow-volume variables . The result ing predicted values demonstrate the effects of development , maturation , and senescence on ventilatory function . " Normal " limits are proposed that take into consideration the between-subject variability and non-Gaussian distribution of the various measurements Since 1982 all infants born within the East Anglian Regional Health Authority have been screened for cystic fibrosis . Between April 1985 and April 1992 infants identified in this way have been entered into a r and omised prospect i ve controlled trial of antibiotic prophylaxis . Approximately half the infants received continuous oral flucloxacillin and the remainder received antibiotics when clinical ly indicated . Infants underwent tests of respiratory function at 3 - 4 months and at 1 year of age . Measurements of thoracic gas volume and airway conductance were made with an infant whole body plethysmograph , and maximum expiratory flow by the ' squeeze ' technique . A total of 73 tests was performed of 42 infants . To facilitate comparisons , measurements were expressed as scores . The mean values of the scores for the two groups of infants fell within normal limits . There was no difference between the treatment groups at either age . A reduction in airways conductance was observed between the two tests The effects of oral administration of cephalexin were evaluated in a double-blind , placebo-controlled , crossover study in 17 patients with mild to moderate pulmonary disease due to cystic fibrosis . For two years , four-month periods with cephalexin were alternated with four-month placebo periods . Thus , patients served as their own control subjects . Fungal vulvovaginitis occurred in two patients and a cephalexin-resistant Enterobacter cloacae was acquired in the sputum of another patient during cephalexin therapy . During the 2 years of study , the rate of colonization with mucoid strains of Pseudomonas aeruginosa increased and disease severity deteriorated in patients initially colonized with P. aeruginosa . Short-term courses of sputum culture-specific antibiotics improved the course of some patients with mild to moderate pulmonary disease due to cystic fibrosis . Treatment with cephalexin decreased the frequency of respiratory illnesses , respiratory illnesses requiring antibiotics , and hospitalizations for respiratory illnesses in patients initially colonized with Staphylococcus aureus and /or Haemophilus influenzae , and also reduced colonization with these organisms . Improved weight gain in 16 of 17 patients was associated with periods of cephalexin therapy . Pulmonary function tests remained stable or improved in 10 of 14 patients . Disease severity improved in patients not colonized with P. aeruginosa OBJECTIVES To evaluate whether antistaphylococcal prophylaxis in infants and young children with cystic fibrosis ( CF ) would suppress the acquisition of Staphylococcus aureus and delay the onset of the manifestations of bronchopulmonary disease . STUDY DESIGN A 7-year , multicenter , double-blind , placebo-controlled study of continuous antistaphylococcal therapy . Otherwise healthy children < 2 years of age with CF were r and omly assigned to be treated with daily cephalexin ( 80 - 100 mg/kg/day ) or placebo . Clinical , microbiologic , laboratory , radiographic , and anthropometric outcomes were evaluated . RESULTS Of 209 children enrolled , 119 completed a 5- to 7-year course of therapy . Mean age at enrollment was 15.6 and 14.1 months in the cephalexin and placebo groups , respectively . Respiratory cultures from children treated with cephalexin were significantly less likely to be positive for S aureus ( 6.0 % vs 30.4 % ; P < .001 ) . They were , however , much more likely to be positive for Pseudomonas aeruginosa ( 25.6 % vs 13.5 % ; P < .009 ) . These differences became apparent in the first year after enrollment and persisted over the duration of the study . In contrast to these microbiologic differences , there were no differences in clinical outcome measures , including radiographic ( Brasfield score , 23.4 vs 23.2 ) or anthropometric scores or pulmonary function . CONCLUSIONS Although long-term prophylaxis with cephalexin successfully delayed the acquisition of S aureus , it enhanced colonization with P aeruginosa and did not lead to clinical ly significant improvement in major health outcomes . These data do not support routine antistaphylococcal prophylaxisin otherwise healthy infants and young children with CF [ N PATIENTS with cystic fibrosis , the progression of pulmonary disease following Staphylococcus aureus colonization and the improvement after its eradication suggest that S. aureus may be more important than Pseudomonas aeruginosa and Haemophilus influenzae as primary pathogens . 1'~ The favorable results in CF patients using continuous antistaphylococcal therapy with cloxacillin 3 support this idea . Moreover , S. aureus produces microabscesses of the lung 4 and remains in a CF patient 's sputum despite prolonged administration of antibiotics ? Patients with cystic fibrosis developed precipitating antibodies against S. aureus more frequently than against other sputum pathogens . We therefore studied 29 CF patients receiving prophylactic pulmonary care 6 at the University of Minnesota Hospitals who gave informed consent for treatment of staphylococcal infections with clindamycin Screening of the newborn for cystic fibrosis by measurement of immunoreactive trypsin has been undertaken on alternate weeks in Wales and the West Midl and s for five years since 1985 to evaluate the possible clinical benefits of early diagnosis . Patients detected by screening and those diagnosed by clinical symptoms alone were assessed annually for differences in clinical , anthropometric , and biochemical variables . Fifty eight infants not considered to be at risk of cystic fibrosis ( they did not present with meconium ileus and do not have a sibling with cystic fibrosis ) have been detected by screening and they have been compared with 44 children who were diagnosed clinical ly . This latter group includes nine children whose screening was negative but who were recognised subsequently to have cystic fibrosis . The mean age at diagnosis of the screened group was significantly lower than that of the group diagnosed clinical ly . Excluding admissions for diagnostic tests for cystic fibrosis , the screened group spent a significantly shorter time in hospital during the first year of life . The results of all other comparisons made between the screened group and those diagnosed clinical ly were similar up to the age of 4 years To comprehend the results of a r and omised controlled trial ( RCT ) , readers must underst and its design , conduct , analysis , and interpretation . That goal can be achieved only through total transparency from authors . Despite several decades of educational efforts , the reporting of RCTs needs improvement . Investigators and editors developed the original CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to help authors improve reporting by use of a checklist and flow diagram . The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement . The checklist items pertain to the content of the Title , Abstract , Introduction , Methods , Results , and Discussion . The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect , or because the information is essential to judge the reliability or relevance of the findings . We intended the flow diagram to depict the passage of participants through an RCT . The revised flow diagram depicts information from four stages of a trial ( enrollment , intervention allocation , follow- up , and analysis ) . The diagram explicitly shows the number of participants , for each intervention group , included in the primary data analysis . Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis . In sum , the CONSORT statement is intended to improve the reporting of an RCT , enabling readers to underst and a trial 's conduct and to assess the validity of its results |
13,756 | 27,113,367 | At the end of the treatment course ( two to three weeks ) there is an improvement in health-related quality of life and symptom severity in patients with chronic rhinosinusitis with nasal polyps taking oral corticosteroids compared with placebo or no treatment .
At three to six months after the end of the oral steroid treatment period , there is little or no improvement in health-related quality of life or symptom severity for patients taking an initial course of oral steroids compared with placebo or no treatment .
The data on the adverse effects associated with short courses of oral corticosteroids indicate that there may be an increase in insomnia and gastrointestinal disturbances but it is not clear whether there is an increase in mood disturbances .
There is no evidence for oral steroids compared with other treatments | BACKGROUND This review is one of a suite of six Cochrane review s looking at the primary medical management options for patients with chronic rhinosinusitis .
Chronic rhinosinusitis is a common condition involving inflammation of the lining of the nose and paranasal sinuses .
It is characterised by nasal blockage and nasal discharge , facial pressure/pain and loss of sense of smell .
The condition can occur with or without nasal polyps .
Oral corticosteroids are used to control the inflammatory response and improve symptoms .
OBJECTIVES To assess the effects of oral corticosteroids compared with placebo/no intervention or other pharmacological interventions ( intranasal corticosteroids , antibiotics , antifungals ) for chronic rhinosinusitis . | Treatment of naso-sinus polyposis has been the subject of much controversy . The large number of reports in the literature suggest that role of surgical treatment is on the uprise . There is however general agreement that medical treatment is fundamental although an insufficient number of studies have evaluated its efficacy . The aim of this prospect i ve study was to evaluate results 6 months , 12 months and 2 years after medical treatment of polyposis in 181 patients . Despite a well-coduced information protocol , nearly 19 % of the patients were lost to follow-up . Less than 32 % of the patients have been operated . Patients treated medically were given a st and ard regimen according to a protocol combining short-term oral corticosteroids ( prednisolone ) and steroid nasal spray ( beclometasone ) . Treatment was successful in 68 % of the patients given medical treatment alone . Mean symptom intensity declined by 35 to 80 % at 6 months then remained unchanged to the end of the study ( 2 years follow-up ) . Mean doses of prednisolone and beclomethasone were evaluated . Doses could be tapered off progressively allowing satisfactory nasal comfort . Medical treatment should be the first line therapy for nasal polyposis . Surgery should not be proposed until corticosteroid therapy has been found to be unsuccessful over a mean 6 months of a well-conducted treatment and good patient compliance We started therapy sinusitis of our patients with antibiotics cefuroxime axetil ( Zinnat , GSK ) , clarithromycin ( Klacid Uno , Abbott ) and orally given steroid-prednisone in one group ( A+S ) 56 patients . Second group of 60 patients were cured only with antibiotics ( A ) . We compare effects of this therapy . There were 50 % totally cured patients in the first group ( A+S ) and 46.6 % cured in the second group . Percentage totally cured patients with ( A+S ) is 3.4 % better that cured only with antibiotics in the same time . It is statistically important . We present benefits for patients who were operated in the next step . Post therapy with the use of antibiotics and steroids there were less bleeding from the mucosal membrane , and there was no edema . It is a good method of therapy if patients have no contraindications A r and omized comparison of the usual surgical removal of nasal polyps versus systemic steroid treatment was performed in 53 patients . In all , continuous topical steroid treatment was given during the one year period of observation . In both groups the initial treatment result ed in a continuous increase in mean nasal expiratory peak flow as well as in the sense of smell ; these two parameters showed a temporary statistically significant difference in favour of the medically treated group . In general though , the results in the two treatment groups were alike . Therefore medical treatment is recommended for routine use . Surgical removal should be reserved for those few cases in which the presence of residual or recurrent polyps justifies the inherent risks and discomfort for the patient BACKGROUND There is little scientific evidence to support the current practice of using oral glucocorticosteroids and antibiotics to treat patients with chronic rhinosinusitis and nasal polyps . OBJECTIVE We evaluated the effects of oral glucocorticoids and doxycycline on symptoms and objective clinical and biological parameters in patients with chronic rhinosinusitis and nasal polyps . METHODS In a double-blind , placebo-controlled , multicenter trial , we r and omly assigned 47 participants with bilateral nasal polyps to receive either methylprednisolone in decreasing doses ( 32 - 8 mg once daily ) , doxycycline ( 200 mg on the first day , followed by 100 mg once daily ) , or placebo for 20 days . Participants were followed for 12 weeks . Patients were assessed for nasal peak inspiratory flow and symptoms and by nasal endoscopy . Markers of inflammation such as eosinophilic cationic protein ( ECP ) , IL-5 , myeloperoxidase , matrix metalloproteinase 9 , and IgE were measured in nasal secretions . Concentrations of eosinophils , ECP , and soluble IL-5 receptor alpha were measured in peripheral blood sample s. RESULTS Methylprednisolone and doxycycline each significantly decreased nasal polyp size compared with placebo . The effect of methylprednisolone was maximal at week 3 and lasted until week 8 , whereas the effect of doxycycline was moderate but present for 12 weeks . Methylprednisolone significantly reduced levels of ECP , IL-5 , and IgE in nasal secretions , whereas doxycycline significantly reduced levels of myeloperoxidase , ECP , and matrix metalloproteinase 9 in nasal secretions . CONCLUSION This is the first double-blind , placebo-controlled study to show a significant effect of oral methylprednisolone and doxycycline on size of nasal polyps , nasal symptoms , and mucosal and systemic markers of inflammation Background Although combined oral and nasal steroid therapy is widely used in nasal polyposis , a subset of patients show an unfavorable therapeutic outcome . This study aim ed to evaluate whether oral prednisolone produces any additive effects on subsequent nasal steroid therapy and to evaluate if any clinical variables can predict therapeutic outcome . Methods Using a 3:2 r and omization ratio , 67 patients with nasal polyposis received 50 mg of prednisolone and 47 patients received placebo daily for 2 weeks , followed by mometasone furoate nasal spray ( MFNS ) at 200 micrograms twice daily for 10 weeks . Clinical response was evaluated by nasal symptom score ( NSS ) , peak expiratory flow index ( PEFI ) , and total nasal polyps score ( TNPS ) . Potential predictor variables were assessed by clinical history , nasal endoscopy , allergy skin test , and sinus radiography . Results At the end of the 2-week oral steroid phase , the prednisolone group showed significantly greater improvements in all nasal symptoms , nasal airflow , and polyp size than the placebo group . In the nasal steroid phase , while the MFNS maintained the outcome improvements in the prednisolone group , all outcome variables in the placebo group showed continuing improvements . At the end of the nasal steroid phase , there re no significant differences of most outcome improvements between the two groups , except in hyposmia , PEFI , and TNPS ( p = 0.049 , p = 0.029 , and p = 0.005 , respectively ) . In the prednisolone group , patients with polyps grade 3 and endoscopic signs of meatal discharge showed significantly less improvement in total NSS , PEFI , and TNPS than patients with grade 1–2 size and negative metal discharge . Conclusion In the 12-week treatment evaluation of nasal polyposis , pretreatment with oral steroids had no significant advantage for most nasal symptoms other than earlier relief ; however , combined oral and nasal steroid therapy more effectively improved hyposmia , polyps size , and nasal airflow . Polyps size grade 3 and /or endoscopic signs of meatal discharge predisposed to a poorer treatment outcome BACKGROUND Controlled prospect i ve studies are needed to determine whether surgical treatment in fact has an effect additive to that of medical treatment of nasal polyposis . OBJECTIVE We sought to compare the effect of medical treatment versus combined surgical and medical treatment on olfaction , polyp score , and symptoms in nasal polyposis . METHODS Thirty-two patients with nasal polyposis and symmetrical nasal airways were r and omized to unilateral endoscopic sinus surgery after pretreatment with oral prednisolone for 10 days and local nasal budesonide bilaterally for 1 month . Postoperatively , patients were given local nasal steroids ( budesonide ) . Patients were evaluated with nasal endoscopy , symptom scores , and olfactory thresholds . They were followed for 12 months . RESULTS The sense of smell was improved by the combination of local and oral steroids . Surgery had no additional effect . Symptom scores improved significantly with medical treatment alone , but surgery had additional beneficial effects on nasal obstruction and secretion . After surgery , the polyp score decreased significantly on the operated side but remained the same on the unoperated side . Twenty-five percent of the patients were willing to undergo an operation also on the unoperated side at the end of the study . CONCLUSIONS Medical treatment seems to be sufficient to treat most symptoms of nasal polyposis . When hyposmia is the primary symptom , no additional benefit seems to be gained from surgical treatment . If nasal obstruction is the main problem after steroid treatment , surgical treatment is indicated . Selection of those who will benefit from surgery should be based on the patient 's symptoms and not on the examiner 's polyp score The effects of rhinosinusitis treatment upon asthma are disputed . The first r and omised prospect i ve study of surgical compared with medical therapy of chronic rhinosinusitis in 90 patients with and without nasal polyps was previously reported . Asthma symptoms , control , forced expiratory volume in one second ( FEV1 ) , peak flow , exhaled nitric oxide , medication use and hospitalisation at 6 and 12 months from the start of the study were also monitored . This paper reports these results in 43 of those patients with concomitant asthma . Both medical and surgical treatment of chronic rhinosinusitis were associated with subjective and objective improvements in asthma . Overall asthma control improved significantly following both treatment modalities , but was better maintained after medical therapy , where improvement could also be demonstrated in the subgroup with nasal polyps . Medicine was superior to surgery with respect to a decrease in exhaled nitric oxide and increase in FEV1 in the polyp patients . Two patients noted worsening of asthma post-operatively . Improvement in upper airway symptoms , as assessed using a visual analogue scale , correlated with improvement in asthma symptoms and control . Treatment of chronic rhinosinusitis , medical or surgical , benefits concomitant asthma ; that associated with nasal polyposis benefits more from medical therapy OBJECTIVES /HYPOTHESIS To assess the effect of oral plus intranasal corticosteroids on subjective outcomes ( smell and nasal congestion ) and objective outcomes ( tissue eosinophilia and nitric oxide ) in severe nasal polyposis ( NP ) . STUDY DESIGN After a 4-week steroid washout period ( w0 ) , severe NP were r and omized into a treatment group ( n = 67 ) that receive oral prednisone for 2 weeks ( w2 ) plus intranasal budesonide for 12 weeks ( w12 ) , and a control group ( n = 22 ) that received no steroid treatment . METHODS Barcelona Smell Test 24 ( BAST-24 ) , nasal congestion , tissue eosinophilia , and nasal nitric oxide ( nNO ) were assessed . RESULTS Before treatment , patients showed a significant impairment of smell detection ( 30.7 ± 39.5 % ) , identification ( 7.1 ± 16.1 % ) , and forced choice ( 13.8 ± 23.3 % ) in BAST-24 compared to healthy population . At w2 , the treatment group showed a significant improvement in detection , identification , and forced choice . Positive effect was also seen after 12 weeks of intranasal corticosteroids . A significant reduction of nasal congestion ( 1.17 ± 1.0 vs. 2.73 ± 0.5 ) and polyp tissue eosinophilia ( 10.9 ± 4.2 vs. 41.2 ± 12.2 ) with an increase of nNO ( 650 ± 317 vs. 420 ± 221 ppb ) were observed at w2 compared to w0 and to the control group . These effects were also seen at w12 . CONCLUSIONS Combined oral and intranasal corticosteroids improve smell and nasal congestion and decrease nasal inflammation , as measured by reduced tissue eosinophilia and increased detection of nNO . Severity of smell loss correlates with degree of nasal congestion but not with inflammation , as measured by tissue eosinophilia or nasally exhaled nNO . Our findings suggest that improvement in smell may be related to improved conduction of odorants to the olfactory neuroepithelium OBJECTIVE To investigate endoscopic staging , and nitric oxide levels in the polyp tissue , in patients with nasal polyposis undergoing glucocorticoid therapy . METHODS Nasal polyposis was evaluated using endoscopic staging and measurement of polyp tissue nitric oxide levels ( chemiluminescence method ) . Forty-five nasal polyposis patients received either nasal therapy ( n = 15 ) , oral therapy ( n = 15 ) or combined therapy ( n = 15 ) . Pre-treatment and post-treatment staging and nitric oxide levels were evaluated . RESULTS Endoscopic grading indicated significant post-treatment staging improvements in the oral ( p = 0.016 ) and combined ( p = 0.016 ) groups . Post-treatment staging differed significantly between the three groups ( p = 0.041 ) , with greater improvements in the oral and combined groups . All groups showed significantly lower post-treatment nitric oxide levels , compared with baseline , but post-treatment levels did not differ significantly between groups . A significant association was found between treatment response and nitric oxide level alteration . CONCLUSION This study demonstrates the favourable effects of glucocorticoids on nasal polyposis , and alteration in nitric oxide tissue levels post-treatment . Nitric oxide level in nasal polyp tissue could be an indicator of treatment response , and may aid surgical decision-making by detecting cases that probably will not respond to medical treatment OBJECTIVES To conduct the first prospect i ve r and omized controlled trial , evaluating and comparing the effect of medical and surgical treatment of chronic rhinosinusitis ( CRS ) on quality of life . MATERIAL S AND METHODS Ninety patients with CRS , who remained symptomatic after initial medical treatment with Dexarhinaspray duo and nasal douche , were r and omized either to medical or surgical therapy . All patients underwent pre- and post-treatment assessment s of the Sinonasal Outcome Test-20 ( SNOT-20 ) , and the Short Form 36 Health Survey ( SF-36 ) . Each patient had three assessment s : before starting the r and omized treatment , after six months and finally after one year . RESULTS Both the medical and surgical treatment of CRS significantly improved almost all the parameters of SNOT and SF-36 ( p<0.05 ) , with no significant difference being found between the medical and surgical groups ( p>0.05 ) . CONCLUSION Both maximal medical and surgical therapy of CRS improves the quality of life of CRS patients , providing further evidence that chronic rhinosinusitis should be targeted with maximal medical therapy in the first instance , with surgical treatment being reserved for cases refractory to medical therapy . The presence of nasal polyps does not imply any negative effect on the quality of life after CRS therapy , either medical or surgical OBJECTIVE The objectives of the management of nasal polyposis are to eliminate or reduce the size of polyps , reestablish nasal breathing , reduce symptoms of rhinitis , restore the sense of smell , and prevent the recurrence of nasal polyps . Local or systemic steroids have been used in the treatment of nasal polyps , but efficacy of combined ( local and systemic ) steroids in nasal polyposis has been little investigated . The aim of this study was to evaluate the influence of combined steroid therapy on the symptoms and extent of the disease in patients with nasal polyposis . METHODS Seventeen patients with nasal polyps were treated with combined steroids . Before and after the therapy , polyp size , nasal symptoms , sense of smell , and headache or facial pain were assessed by an established scoring system . RESULTS After the therapy , symptom scores of all the patients improved . Of the patients , 12 % showed a polyp-free nasal cavity , 76 % a clear involution of polyps , and 12 % no response to the therapy . There were statistically significant differences ( P<0.001 ) for symptom scores and polyp size . Medical ablation of polyps using steroids was not achieved in 88 % patients . CONCLUSION Steroids can reduce polyp sizes and improve the symptoms , but are inadequate to eradicate the polyps . Surgery still plays a major part in the treatment of the nasal polyposis , but steroids can delay the necessity for surgical intervention BACKGROUND The place of systemic corticosteroids in the treatment of children with chronic rhinosinusitis ( CRS ) remains unclear . OBJECTIVE We sought to assess the effectiveness and tolerability of oral methylprednisolone as an anti-inflammatory adjunct in the treatment of CRS in children . METHODS Forty-eight children ( age , 6 - 17 years ) with clinical ly and radiologically proved CRS were included . Patients were r and omly assigned to either oral amoxicillin/clavulanate ( AMX/C ) and methylprednisolone or AMX/C and placebo twice daily for 30 days . Oral methylprednisolone was administered for the first 15 days with a tapering schedule . Primary parameters were mean change in symptom and sinus computed tomographic ( CT ) scan scores after treatment . Secondary study parameters were mean changes in individual symptom scores after treatment , relapse rate , and tolerability . RESULTS Forty-five patients completed the study : 22 received AMX/C and methylprednisolone , and 23 received AMX/C and placebo . Both groups demonstrated significant improvements in symptom and sinus CT scores when comparing baseline values with end-of-treatment values ( P < .001 ) . Methylprednisolone as an adjunct was significantly more effective than placebo in reducing CT scores ( P = .004 ) , total rhinosinusitis symptoms ( P = .001 ) , and individual symptoms of nasal obstruction ( P = .001 ) , postnasal discharge ( P = .007 ) , and cough ( P = .009 ) . At the end of treatment , 48 % of the children in the placebo group still had abnormal findings on CT scans versus 14 % in the methylprednisolone group ( P = .013 ) . Therapy-related adverse events were not different between groups . Although insignificant , the incidence of clinical relapses was also less in the methylprednisolone group ( 25 % ) compared with that in the placebo group ( 43 % , P = .137 ) . CONCLUSION Oral methylprednisolone is well tolerated and provides added benefit to treatment with antibiotics for children with CRS Conclusions . CT of the sinuses showed long-lasting improvement in the total and CT scores of the osteomeatal complex ( OMC ) after combined surgical and corticosteroid treatment as compared with medical treatment alone . However , the correlations between the improved CT scores and the patients ’ symptoms , olfactory thresholds or polyp scores were generally not significant . Objective . To evaluate CT scans as a method for comparing the effect of medical treatment versus combined surgical and medical treatment of nasal polyposis . Patients and methods . Thirty-two patients with nasal polyposis were r and omized to unilateral endoscopic sinus surgery after pretreatment with oral prednisolone for 10 days and nasal budesonide bilaterally for 1 month . Postoperatively , they were given nasal steroids ( budesonide ) bilaterally for 1 year . They were assessed with nasal endoscopy , symptom scores , and olfactory thresholds and followed for 12 months . CT of the sinuses was performed before and 1 year after operation . The CT scans were evaluated using the Lund staging system . Results . From before surgery to 1 year after surgery , we found a significant improvement on the operated side in the CT total scores , and scores of the OMC and the maxillary sinus , but no significant differences on the unoperated side . Significant correlations were also noted between the differences in olfactory thresholds between the operated and unoperated sides Objective The purpose of this study was to compare the apoptotic responses to systemic , topical , and intrapolyp injection of glucocorticoid with no treatment in nasal polyps . Study Design Prospect i ve , r and omized controlled study . Setting Tertiary training hospital . Subjects and Methods The study was performed on 48 patients with nasal polyposis in the Department of Otorhinolaryngology between 2008 and 2009 . Patients were assigned to 1 of 4 groups of 12 patients . Group A was treated with oral methylprednisolone 1 mg/kg/d , and the dose was tapered gradually . Group B received 0.3 mL triamcinolone acetonide ( 40 mg/mL ) , which was injected into polyp tissue . Group C was treated with topical 55 µg triamcinolone acetonide 2 times daily for 1 month . Group D received no medication . Sample s were collected endoscopically after the seventh day for groups A and B , the first month for group C , and the first visit for group D. Apoptotic indexes were determined using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method . Results Statistically significant differences in apoptotic index were found between each steroid-medicated group and the control group ( PD-A = .0001 ; PD-B = .003 ; PD-C = .026 ) and between groups A and C ( PA-C = .012 ) . Group B did not differ significantly from either group A or C ( PA-B = .11 ; PB-C = .75 ) . Conclusions The apoptotic index in nasal polyps treated with systemic , topical , and intrapolyp injection forms of glucocorticoids was higher than that in the control group . Systemic steroid treatment induced the most apoptosis The aim of this study is to determine the effectiveness of postoperative oral steroid in controlling disease in patients with allergic fungal sinusitis ( AFS ) . The study design includes prospect i ve , r and omised , double-blind , placebo-controlled trial using oral prednisolone . Twenty-four patients diagnosed with AFS underwent sinus surgery ( endoscopic sinus surgery with or without open surgery ) to completely excise disease . Patients were r and omised to receive either oral steroid ( n = 12 ) or placebo ( n = 12 ) soon after surgery . All patients were also administered itraconazole and steroid nasal spray in the postoperative period . Subjective evaluation of symptom relief and objective evaluation by rigid nasal endoscopy at 6 and 12 weeks following surgery was performed . After 12 weeks , the code was broken and the two groups of patients were identified to note their response to treatment . At 6 weeks , complete relief of preoperative symptoms was obtained in eight patients who had received oral steroid and none who had received placebo ( p = 0.001 ) . Partial relief of preoperative symptoms was obtained in four who had received oral steroid and eight who had received placebo . Nasal endoscopy revealed that 8 of 12 patients who had received oral steroid and 1 patient who had received placebo were disease free ( p = 0.009 ) . At 12 weeks , complete symptom relief was obtained by all patients who received oral steroid but only one who received placebo ( p = 0.0001 ) . Nasal endoscopy at 12 weeks revealed that all 12 patients who had received oral steroid and only 1 patient ( the same patient ) who had received placebo were disease free ( p = 0.0001 ) . In conclusion , postoperative oral steroid in a tapering dose produces significant subjective and objective improvement of patients with AFS . It is also effective in preventing early recurrence . Inclusion of postoperative oral steroid therapy for at least 12 weeks is recommended in all patients who undergo excisive surgery for AFS AIM In this prospect i ve study the effect of medical and surgical treatment on subjective olfaction was studied in patients with nasal polyposis ( NPS ) . The effects on nasal obstruction , anterior and posterior rhinorrhea , sneezing and itching are reported in another article in this issue . PATIENTS AND METHODS Protocol 1 . Twenty-four patients with NPS who complained about anosmia were treated with a 7-days course of systemic steroids . Their subjective overall sense of smell was determined with a visual analog scale ( VAS ) before treatment , immediately after treatment , and two months later . Subsequently all patients underwent surgery bilaterally according to the nasalization principles . The sense of smell was re-evaluated at 1 , 3 , 6 , 9 , and 12 months postoperatively . Protocol 2 . Thirty-two patients with NPS not responding to medical therapy who , for different reasons , did not receive oral steroid treatment , received surgery only and were followed up during one year after nasalization . Of these patients , 25 were anosmic and 7 normosmic . RESULTS Protocol 1 . Following the 7-day treatment with systemic steroids the olfactory score increased significantly . During the waiting time for surgery ( 64 + /- 39 days ) this score deteriorated again in a significant way . One month after nasalization which included a depot injection of triamcinolone 80 mg the day after surgery , the olfactory score ameliorated again and remained stable at 3 , 6 , 9 , and 12 months . None of the patients reported any intake of systemic steroids during the one-year of follow-up . Statistically , there was a trend suggesting that the 12 month post-nasalization score was better than the immediate post-oral steroid score . A good correlation between the improvement of the sense of smell after 7 days of systemic steroids and one year after nasalization was found . Protocol 2 One month after the nasalization protocol , olfaction in patients of the hypo-anosmic group had improved considerably . Scores at 3 , 6 , 9 , and 12 remained very stable . The sense of smell in the normosmic group did not change after surgery and remained stable during the year of follow-up . In total , 49 patients with a severe loss of smell showed a significant improvement at 12 months after surgery . CONCLUSION The present study shows that 1 ) long-lasting correction of olfactory dysfunction produced by nasal polyposis can be achieved through the combination of nasalization and low dose of nasal steroids , 2 ) middle turbinate resection does not alter the possibilities to restore the sense of smell BACKGROUND Chronic rhinosinusitis ( CRS ) with nasal polyposis is common . The long-term efficacy and safety of approaches to medical management are not well-known . OBJECTIVE To evaluate the efficacy and safety of a 2-week regimen of oral steroid therapy followed by 26 weeks of sequential topical steroid maintenance therapy . DESIGN Parallel r and omized trial with computer-generated block r and omization and central allocation . Patients and investigators were blinded to group assignment . ( Clinical Trials.gov registration number : NCT00788749 ) SETTING A specialty rhinology clinic in Tayside , Scotl and . PATIENTS 60 adults with CRS and moderate-sized or larger nasal polyps who were referred by their primary physicians for specialty care . INTERVENTIONS Patients were r and omly assigned in a 1:1 ratio to receive oral prednisolone , 25 mg/d , or placebo for 2 weeks , followed in both groups by fluticasone propionate nasal drops , 400 µg twice daily , for 8 weeks and then fluticasone propionate nasal spray , 200 µg twice daily , for 18 weeks . MEASUREMENTS Polyp grading ( primary outcome ) , hyposmia score , quality of life , symptoms , nasal patency , adrenal function , and bone turnover . RESULTS The mean decrease in polyp grade from baseline to 2 weeks was 2.1 units ( SD , 1.1 ) in the prednisolone group and 0.1 unit ( SD , 1.0 ) in the placebo group ( mean difference between groups , -1.8 units [ 95 % CI , -2.4 to -1.2 units ] ; P < 0.001 ) . The difference between groups was -1.08 units ( CI , -1.74 to -0.42 unit ; P = 0.001 ) at 10 weeks and -0.8 unit ( CI , -1.8 to 0.2 unit ; P = 0.11 ) at 28 weeks . The mean decrease in hyposmia score from baseline to 2 weeks was 31.12 mm ( SD , 30.1 ) in the prednisolone group and 1.41 mm ( SD , 30.6 ) in the placebo group ( mean difference between groups , -28.33 mm [ CI , -42.71 to -13.96 mm ] ; P = 0.002 ) . The difference between groups was -16.06 mm ( CI , -30.99 to -1.13 mm ; P = 0.03 ) at 10 weeks and -12.13 mm ( CI , -30.55 to 6.29 mm ; P = 0.19 ) at 28 weeks . Prednisolone therapy result ed in transient suppression of adrenal function and increase in bone turnover after 2 weeks , with a return to baseline at 10 and 28 weeks . LIMITATIONS Patients were referred from primary care to a single-center rhinology clinic , which limits the generalizability of results . Serial measurements of surrogates of nasal inflammation ( such as nitric oxide or cytokine levels ) were not performed . CONCLUSION Initial oral steroid therapy followed by topical steroid therapy seems to be more effective over 6 months than topical steroid therapy alone in decreasing polyp size and improving olfaction in patients referred for specialty care of CRS with at least moderate nasal polyposis . PRIMARY FUNDING SOURCE Chief Scientist Office , Scotl and ; National Health Service Tayside Small Grants Scheme ; and an Anonymous Trust grant from University of Dundee The efficacy of topical nasal furosemide treatment has been shown in the protection of nasal polyp recurrence . The aim of the study was to compare the effect of oral steroid , as st and ard preoperative treatment , and inhaled furosemide , as alternative treatment , for 7 days preoperatively in terms of subjective improvement of nasal symptoms , polyp size reduction , inflammation in the polyp tissue , and intraoperative blood loss . A group of 40 patients with nasal polyposis entered the study and they were r and omly allocated to 7-day preoperative treatment with either oral methylprednisolon ( 1 mg/kg/day ) or topical furosemide by inhalation ( 6.6 mmol/l solution ) . Subjective scores of rhinosinusitis symptoms , polyp scores at endoscopy , and biopsy of the most superficial polyp were taken at inclusion . All procedures were repeated on day 7 . Intraoperative blood loss was estimated ( scores 0–10 ) by the surgeon at the operation . Eosinophils , mastocytes , and oedema were quantified by histomorphometry . Subjective symptoms and endoscopy scores did not differ significantly between the groups after the treatment although improvement of olfaction was insignificantly better in the steroid group . Steroid treatment significantly reduced eosinophil count , with no effect on mastocytes and oedema . Furosemide treatment did not affect inflammatory cells count significantly , but it has significantly reduced oedema in previously unoperated patients . No difference in intraoperative bleeding was observed between the groups Purpose : To determine the effects of a st and ardized therapeutic protocol ( short-term oral administration of prednisolone and daily intranasal spray of beclometasone ) on stage I nasal polyposis over a follow-up period of 3 years . Procedures : Assessment s ( evaluation of nasal function and drug consumption ) were conducted at baseline and every 3 months on 54 consecutive patients with stage I nasal polyposis during 3 years . Results : Over the follow-up period of 3 years , this dual modality proved to be successful in 87 % of the subjects ; only 13 % had to undergo surgery after its failure . The average symptom reduction reached an improvement rate varying from 66 to 94.8 % , according to the symptom type . The daily dosage of prednisolone and beclometasone was progressively decreased , while the gain in nasal comfort was being preserved . Conclusion : Management of stage I nasal polyps should be primarily medical BACKGROUND Although oral steroids are widely used for the treatment of nasal polyposis , a subset of patients shows an unfavorable therapeutic outcome . The aim of this study was to evaluate the efficacy of a short course of oral prednisolone in nasal polyposis and to evaluate which , if any , clinical variables can predict treatment outcome in these patients . METHODOLOGY /PRINCIPAL Using a 3:2 r and omization ratio , 63 patients with nasal polyposis received 50 mg of prednisolone and 46 patients received placebo daily for 14 days . Clinical response was evaluated by total nasal symptoms score ( TNSS ) , peak expiratory flow index ( PEFI ) and total nasal polyps score ( TNPS ) . Potential predictor variables were assessed by clinical history , nasal endoscopy , allergy skin test and sinus radiography . RESULTS The prednisolone-treated group showed significantly greater improvements in all nasal symptoms , nasal flow and polyp size than the placebo-treated group ( p < 0.001 , all ) . In the prednisolone-treated group , patients with grade 3 polyps and positive nasal endoscopy showed significantly less improvement in TNSS , PEFI and TNPS than patients with grade s 1 - 2 size and with negative nasal endoscopy . CONCLUSIONS A short course of oral steroids showed good clinical efficacy in the treatment of nasal polyposis , however , polyps size grade 3 and /or positive nasal endoscopy predispose to a poorer treatment outcome OBJECTIVES /HYPOTHESIS Although medical intervention is the first option for treatment of nasal polyps , surgery is still a therapeutic option for symptomatic cases that do not respond or partially respond to medical intervention . However , there is a need for high-level evidence for the preoperative use of steroids in nasal polyposis surgery . We aim ed to assess the perioperative effect of preoperative use of oral prednisolone for advanced-stage diffuse nasal polyposis . STUDY DESIGN Prospect i ve , double-blind , r and omized , placebo-controlled study . METHODS A visual analog scale ( VAS ) was evaluated for smell , nasal discharge , nasal obstruction , facial pressure , headache , butanol smell threshold , and peak nasal inspiratory flow ( PNIF ) before and after the use of study drug . Perioperative bleeding volume , visibility of operative field , operative time , hospital stay , and complication rate were also evaluated . RESULTS The improvement in the corticosteroid group ( CG ) in the VAS scores , butanol thresholds , and PNIF values showed statistically significant differences compared to the placebo group ( PG ) ( P < .05 ) . The perioperative bleeding volume , visibility score , operative time , and hospital stay for CG/PG were 141 mL/384 mL , 2.4/3.4 , 61 min/71.6 min , and 1.1 day/1.8 day , respectively ( P < .05 ) . The difference between the complication rates for the two groups did not show any statistically significant difference ( P = .214 ) . CONCLUSIONS Preoperative administration of systemic corticosteroids improves the perioperative visibility by reducing blood loss and shortens the operation time . We recommend the use of preoperative corticosteroid for the safety of the patients . The optimum dose and duration have not been established and require further studies . LEVEL OF EVIDENCE 1b BACKGROUND : The aim of this prospect i ve study was to evaluate the efficacy of a combined ( local and systemic ) steroid therapy on the extent of chronic polypoid rhinosinusitis and patient symptoms . METHODS AND PATIENTS : Subjects of this study were 20 patients with severe chronic polypoid rhinosinusitis with total or subtotal narrowing of the all sinuses . A nasal budesonide spray ( 2 × 0.1 mg/day ) and an oral fluocortolone medication with a daily reduction during a 12-day period ( total dose : 560 mg = group 1 ) and a 20-day period ( total dose : 715 mg = group 2 ) , respectively , were administered . Before and after the steroid treatment we evaluated the extent of the sinusitis with MRI and patient symptoms with symptom-related question naires . RESULTS : A significant reduction ( > 30 % ) of the chronic polypoid rhinosinusitis was observed in 50 % of MRI findings . The steroid effect on polypoid masses was heterogeneous in different anatomic areas ( maxillary sinus 40 % , anterior ethmoid 19 % , posterior ethmoid 33 % , sphenoidal sinus 61 % , frontal sinus 46 % ) . Most sinusitis-related symptoms were distinctly diminished in most patients ( 80 % ) . No major side effects were observed . CONCLUSIONS : A combined short-term steroid therapy is highly effective in chronic polypoid rhinosinusitis , reducing the mucosal inflammation mainly in the large sinuses and reducing the incidence of symptoms significantly . However , this therapy was insufficient in the anterior ethmoid and can not replace the current surgical treatment concept of the osteomeatal complex in CPR . The indication for such a short-term steroid therapy is the preoperative treatment . It facilitates functional endoscopic sinus surgery by reducing the extent of surgical procedures , the time , and thereby the risks of sinus surgery . ( Otolaryngol Head Neck Surg 1999;120:517 - 23 . BACKGROUND Nasal polyposis is an inflammatory disease of unknown etiology . This study aim ed to evaluate the effect of a short course of oral prednisone followed by intranasal budesonide on nasal symptoms , polyp size , nasal flow , and computed tomography scan . METHODS Eighty-four patients with severe nasal polyps were included . After a steroid washout period , patients were r and omized into two groups : group A ( n = 63 ) received oral prednisone for 2 weeks and group B ( n = 21 ) did not receive any steroid treatment . Patients from group A received intranasal budesonide for 12 weeks . RESULTS Atopy was positive in 36.8 % of patients . Blood eosinophilia was higher in asthmatic ( 7.2 + /- 0.7 % , P < .05 ) than in nonasthmatic ( 3.0 + /- 0.4 % ) patients . Asthmatic patients showed higher scores on nasal obstruction and loss of smell than nonasthmatics . Oral steroids caused a significant improvement in all nasal symptoms and improved polyp size ( 2.1 + /- 0.1 , P < .05 ) and nasal flow ( 560 + /- 35 cm/s , P < .05 ) compared with nontreated patients ( 2.8 + /- 0.1 and 270 + /- 34 cm/s , respectively ) . Intranasal budesonide maintained the improvement on nasal symptoms , polyp size , and nasal flow . Steroid treatment reduced the computed tomography scan score ( 15.4 + /- 1 , P < .05 ) compared with before treatment ( 18.2 + /- 0.8 ) . CONCLUSION A short course of oral steroids improved all nasal symptoms , polyp size , and nasal flow , whereas intranasal steroid maintain this effect Conclusion . Patients with severe nasal polyposis ( NP ) and a high steroid consumption have a high prevalence of glucocorticoid-induced osteoporosis and secondary adrenal insufficiency . Objectives . To evaluate the risk of complications of the medical treatment in patients presenting with the diagnosis of NP . Patients and methods . This was a prospect i ve study . A total of 46 consecutive patients with NP were included when the oral steroid consumption during the past year was greater than three short courses of systemic steroid treatment ( i.e. more than 21 days per year of treatment , prednisolone 1 mg/kg body weight per day , for 6–10 days ) . The nasal function was checked on the basis of five criteria : nasal obstruction , anterior rhinorrhea , posterior rhinorrhea , facial pain , and loss of sense of smell . Two tests were carried out for each patient : ( i ) a bone mineral density evaluation by dual energy X-ray absorptiometry ( DXA ) at three different sites in the lumbar spine and femur , and ( ii ) an evaluation of the hypothalamic-pituitary-adrenal ( HPA ) axis by the synacthen test . Results . Most of the patients had a severe NP associated with asthma ( 78.3 % of the population ) , and aspirin idiosyncrasy ( 28.3 % ) . In all , 10.9 % and 43.5 % of patients had osteoporosis and osteopenia at the lumbar spine site . Twenty patients ( 48.8 % of the tested patients ) had an asymptomatic adrenal insufficiency OBJECTIVES To conduct the first prospect i ve , r and omized , controlled trial evaluating and comparing the medical and surgical treatment of polypoid and nonpolypoid chronic rhinosinusitis ( CRS ) . MATERIAL S AND METHODS Ninety patients with CRS were equally r and omized either to medical or surgical therapy . All patients underwent pre- and posttreatment assessment s of visual analogue score ( VAS ) , the Sinonasal Outcome Test-20 ( SNOT-20 ) , the Short Form 36 Health Survey ( SF-36 ) , nitric oxide ( NO ) , acoustic rhinometry , saccharine clearance time ( SCT ) , and nasal endoscopy . Each patient had three assessment s : before starting the treatment , after 6 months , and , finally , after 1 year . RESULTS Both the medical and surgical treatment of CRS significantly improved almost all the subjective and objective parameters of CRS ( P < .01 ) , with no significant difference being found between the medical and surgical groups ( P > .05 ) , except for the total nasal volume in CRS ( P < .01 ) and CRS without polyposis ( P < .01 ) groups , in which the surgical treatment demonstrated greater changes . CONCLUSION CRS should be initially targeted with maximal medical therapy ( e.g. , a 3 month course of a macrolide antibiotic , douche , and topical steroid ) , with surgical treatment being reserved for cases refractory to medical therapy . The presence of nasal polyps is not a poor prognostic factor for the efficacy of CRS therapy , either surgical or medical Corticosteroids often induce a variety of psychiatric symptoms , such as alterations of mood , neuropsychological deficits and even psychotic states . To date , only a few studies have specifically addressed behaviour as well as cognitive functioning in patients under steroid treatment . Fifty ophthalmologic patients participated in this prospect i ve study . They received methylprednisolone or fluocortolone at doses of 119 + /- 41 mg/day in the beginning and 75 + /- 22 mg after 8 days of treatment . Psychopathology and neuropsychological functioning were examined before and after steroid therapy , mood was self-rated on days 0 , 3 , 5 and 8 . No marked psychopathological abnormalities such as psychosis , dementia or delirious states were observed . However , a significant proportion of patients suffered from an organic mood disorder , 26 - 34 % experienced a hypomanic syndrome , 10 - 12 % a depressive syndrome . Most neuropsychological tests did not reveal significant effects of steroid treatment . Performance of Word Fluency and Trail Making A improved , while the Auditory-Verbal-Learning and the Digit-Symbol showed a worsening . Psychopathological and neuropsychological effects were not significantly correlated OBJECTIVES Nasal polyposis is not a life-threatening disorder but has a great impact on the quality of life . Steroids constitute the first line of treatment of nasal polyps . The aims of this study were to evaluate the quality of life in nasal polyp patients after : ( 1 ) a short course of oral steroids ; and ( 2 ) a long-term treatment with intranasal steroids . METHODS Patients with severe nasal polyps received either oral prednisone ( n = 60 ) or no steroid treatment ( control group , n = 18 ) for 2 weeks . Patients treated with steroids were also followed-up and evaluated after 12 , 24 , and 48 additional weeks with intranasal budesonide treatment . RESULTS Patients with nasal polyps showed worse scores on all SF-36 domains , except for physical functioning , compared to the Spanish general population . After two weeks , patients treated with oral prednisone demonstrated a significant improvement ( p < 0.05 ) in all impaired QoL domains compared to both control group and baseline . The mental component summary ( 51.0 + /- 1.2 , p < 0.05 ) and physical component summary ( 51.0 + /- 0.9 , p < 0.05 ) were improved compared to both control group and baseline . The improvement of all SF-36 domains was sustained by intranasal budesonida ( p < 0.05 ) after 12 , 24 , and 48 weeks . Nasal obstruction , sense of smell , and polyp size also improved after both the oral short course and the intranasal long-term steroids treatment ( p < 0.05 ) . CONCLUSION These results suggest that the treatment with a short-course of oral steroids improves the quality of life of patients with severe nasal polyps and that this effect is maintained by a long-term treatment with intranasal steroids OBJECTIVE To document the response to steroids in patients remaining anosmic following endoscopic nasal and sinus polypectomy . STUDY DESIGN A prospect i ve study of 24 patients with nasal and sinus polyps who were anosmic prior to endoscopic nasal and sinus surgery . Those who remained anosmic after surgery were treated with steroids . Most patients had asthma , allergic rhinitis , or both . A few had aspirin sensitivity . METHODS All 24 patients had testing of their sense of smell before and after surgery . Those who remained anosmic postoperatively were first treated with topical nasal and then oral steroids and then tested again . RESULTS Twelve of the 24 remained anosmic after surgery and were found to be unresponsive to nasal steroids , but oral steroids were found to restore the sense of smell to normal in most patients . Few patients continued to take the medication for long periods of time mainly because of a fear of side effects . Recent studies have suggested the role of systemic steroids in olfactory secretion , which may explain the mechanism for this response . CONCLUSION Patients who remain anosmic after the removal of nasal and sinus polyps can be treated with oral steroids result ing in improvement of their sense of smell . Further research is needed on a molecular level to determine the reason for this and also why oral but not nasal steroids are helpful in these patients 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 BACKGROUND Nasal polyps are a common disease with in the majority of cases unknown origin . Both the medical and surgical treatment of nasal polyps present a challenge in Otorhinolaryngology . METHODS We developed a four-stage grading system for nasal polyps based on the endoscopic aspect of more than 300 patients . In a study of 37 patients , treated by systemically ( Methylprednisolon 64 mg p.o . , decreasing amounts for the first 11 days ) and locally ( Budesonid 400 micrograms intranasal ) applied steroids for 90 days , this staging-system was tested . RESULTS The mean stage of polyps decreased significantly ( p < 0.01 ) from 2.8 at day 0 to 1.7 at day 7 and further to 1.2 and to 0.7 at day 28 and day 90 respectively . The mean nasal symptom score decreased equally from 1.14 on day 1 to 0.19 and to 0.14 on day 7 and day 28 respectively . To summarize , we observed a significant ( p < 0.01 ) decrease in polyp stages of 75 % respectively a significant ( p < 0.01 ) reduction of symptom scores of 93 % . CONCLUSIONS Thus , we present a suitable new grading system for nasal polyps which we applied directly to assess the efficacy of combined local and systemic steroid therapy . It was shown that this treatment can reduce polyps and prevent their recurrence over the observed time BACKGROUND The management of nasal polyps is undoubtedly a controversial subject . The medical treatment remains the undisputed therapeutic mainstay but most of the publications are aim ed at the registration of new molecules from the pharmaceutical industry which explains why they are confined to a single agent . DESIGN The aim of this study is focused on the evaluation of a dual modality on a series of 152 subjects treated according to a st and ardized protocol combining a short-term administration of prednisolone and the daily intranasal spraying of beclomethasone . RESULTS Over the follow-up period of one year , this modality proved to be successful in 68.5 % of the subjects ; only 31.5 % had to undergo surgery after its failure . In the former group , after a six months period , the average symptom reduction reached an improvement rate varying from 35 to 80 % , according to the symptom type . During the ensuing six months follow-up period , the improvement was maintained . The average utilization of prednisolone and beclomethasone was assessed for each individual patient . CONCLUSION Management of nasal polyps should be primarily medical . Resorting to surgical procedures should not be envisaged before a six months trial of dual steroid therapy under strict compliance to treatment BACKGROUND In the majority of CRS patients suffering from primary or recurrent CRS , topical glucocorticoids are highly effective . A subset of CRS patients , however , does not respond to ( topical ) glucocorticoids and requires surgical intervention . Although surgery is highly effective in those individuals , recurrence of disease is observed in some . In this study we describe our search for one or more predictors predicting the response to surgery in combination with peri-operative oral glucocorticoids in CRS patients . METHODS Thirty-five inferior turbinate specimens were r and omly selected from a larger group of CRS patients requiring FESS for persistent disease that either responded favorably or demonstrated recurrent disease . Tissue biopsies were taken at the time of surgery and compared for inflammatory markers , endothelial cell markers , and various leukocyte subsets using immunohistochemistry . RESULTS Compared to non-responders , the baseline level of lamina propria activated eosinophils is significantly increased in CRS patients responding to surgery in combination with peri-operative oral glucocorticoids treated or not treated post-operatively with topical glucocorticoids . No significant differences were observed for all other studied parameters . Post-operative treatment with FPANS 100 μg q.i.d . was significantly associated with response to treatment . A trend towards association was observed for increased numbers of eosinophils at baseline . CONCLUSION Our data suggest that CRS patients with higher levels of eosinophils are less likely to suffer from post-operative recurrent sinonasal disease when treated post-operatively with FPANS 100 μg q.i.d Background : Nasal polyposis ( NP ) is not a life‐threatening disorder but may have a great impact on the quality of life ( QoL ) . The objective of this study : ( i ) to investigate the health burden incurred by NP compared with the Spanish general population using the Short Form‐36 Health Survey ( SF‐36 ) question naire ; ( ii ) to compare the QoL outcome after medical or surgical treatment ; and ( iii ) to assess and compare the effect of medical and surgical treatment on nasal symptoms INTRODUCTION Recently , we demonstrated that acoustic rhinometry ( AR ) measurements correlated with nasal cavity volumes in patients with nasal polyposis ( NP ) . The aim of the present study was to evaluate whether AR and nasal nitric oxide ( nNO ) are useful methods in monitoring and follow-up of medical treatment of NP . MATERIAL AND METHODS Patients with severe nasal polyps were r and omized into two groups after a 4-week steroid washout period ( w0 ) : a treatment group received oral prednisone for 2 weeks ( w2 ) and intranasal budesonide for 12 weeks ( w12 ) while the control group received no steroid treatment . Nasal volume ( Vol 0 - 6 ) , minimum cross-sectional area ( mCSA ) , nNO , peak nasal inspiratory flow ( PNIF ) , nasal obstruction , and smell loss were evaluated . RESULTS At w2 , the treatment group showed a significant increase of vol 0 - 6 compared to w0 and the control group . The mCSA area also increased compared to w0 and the control group . At w12 , the improvement in vol 0 - 6 and mCSA was maintained after intranasal steroids compared to w0 . At w2 , the treatment group showed a paradoxical increase of nNO compared to w0 and the control group . At w12 , this increase was maintained by intranasal steroids . CONCLUSION Both oral and intranasal steroid treatments improve nasal patency and paradoxically increase nNO , by opening the ostiomeatal complex . This suggests that AR and nNO are useful methods in the monitoring and follow-up of patients with NP |
13,757 | 19,214,698 | Studies indicated smaller peak knee flexion during weight acceptance and less knee flexion excursion in total knee arthroplasty subjects compared to controls .
Knee angle at foot strike was generally similar in arthroplasty groups compared to controls .
Maximum external knee flexion moment was generally lower in arthroplasty groups compared to controls .
Conflicting results were found for other knee moments .
Conclusions Peak knee flexion and knee flexion excursion during weight acceptance are smaller in the operated knee following total knee arthroplasty compared to healthy controls .
There may also be a smaller peak knee flexion moment after arthroplasty compared to controls .
Knee mechanics in the operated knee are not normal after total knee arthroplasty .
Abnormal gait mechanics may predispose the individual to further joint degeneration , particularly in the nonoperated knee . | Background Development or retention of abnormal gait patterns after total knee arthroplasty may be related to the predictable pattern of further deterioration of other lower extremity joints .
The purpose of this study was to determine whether gait mechanics are abnormal after total knee arthroplasty by conducting a systematic review of the literature . | Introduction Previous radiostereometric studies have revealed abnormal anterior-posterior translation of the femur in patients operated with AMK ( DePuy , Johnson and Johnson , Leeds , UK ) total knee arthroplasty ( TKA ) . Based on these observations , we hypothesized that patients with TKA have an abnormal gait pattern , and that there are differences in kinematics depending on the design of the tibial joint area . Method We used a gait analysis system to evaluate the influence of joint area design on the kinematics of the hip and knee during level walking . 39 TKA patients ( 42 knees ) and 18 healthy age-matched controls were studied . Patients with 5 ° varus/valgus alignment or less were r and omized to receive either a relatively flat or a concave tibial insert with retention of the posterior cruciate ligament . Patients who had more than 5 ° varus-valgus alignment and /or extension defect of 10 ° or more were r and omized to receive the concave or a posterior-stabilized tibial component with resection of the posterior cruciate ligament . Results Patients with TKA tended to have less hip and knee extension and decreased knee and hip extension moment than controls . They also tended to walk more slowly . TKA altered the gait pattern , but choice of implant design had little influence . Interpretation In patients with a similar degree of degenerative joint disease and within the limits of the constraints offered by the prostheses under study , the choice of joint area constraint has little influence on the gait pattern OBJECTIVE The aim of this study is to evaluate residual muscle function abnormalities after total knee replacement , with respect to gait kinematics and kinetics . DESIGN Longitudinal study on a follow-up of up to two years . BACKGROUND Gait usually presents an excellent improvement after total knee replacement . Nevertheless , some kinematics and kinetics abnormalities persist even after a long period of time and they might have implication s in long-term prosthesis failure . Additionally , lower limb muscle activity has not been sufficiently studied in the past directly by means of dynamic EMG . METHODS Nine patients who had a posterior cruciate sparing total knee replacement design were evaluated by means of clinical assessment and gait analysis at the end of rehabilitation trials at six , twelve and twenty four months . EMG from trunk and lower limb muscles was registered and elaborated through a statistical detector for the on-off timing . RESULTS Gait analysis showed a slow gait , with a " stiff knee gait pattern " and prolonged muscular co-contractions during stance . CONCLUSIONS Knee kinematics and kinetics abnormalities during loading acceptance after total knee replacement are associated with co-contractions in muscular activation pattern . RELEVANCE Gait pattern at two years after total knee replacement is deemed unphysiological , potentially dangerous for the implant duration in time and responsible for residual disability in patients . Muscular behavior during daily activities provides insight into the integration of the prosthetic biomechanics within the muscular-skeletal system . This information is of relevance to improve prosthetic design , rehabilitation programs and knee motor performance OBJECTIVE Patients with unilateral hip or knee replacements for end-stage osteoarthritis ( OA ) are at high risk for future progression of OA in other joints of the lower extremities , often requiring additional joint replacements . Although the risks of future surgery in the contralateral cognate joints ( i.e. , contralateral hip replacement after an initial hip replacement ) have been evaluated , the evolution of end-stage hip OA to OA involving the knee joints , and vice versa ( i.e. , noncognate progression ) has not been investigated . Because characterization of OA progression in noncognate joints may shed light on the pathogenesis of multijoint OA , we investigated the pattern of evolution of end-stage lower extremity OA in a large , clinical cohort . METHODS Total joint replacement ( TJR ) was selected as a marker of end-stage OA , and a data base comprising all lower extremity TJRs performed at a large referral center between 1981 and 2001 was accessed . Of the 5,894 patients identified , 486 patients with idiopathic OA who underwent hip replacement and 414 who underwent initial knee replacement were analyzed to determine the relative likelihood of subsequent TJRs . Patients with the systemic inflammatory arthropathy , rheumatoid arthritis ( RA ) , were evaluated as a control population because RA progression is not considered to be a primarily mechanically mediated process . RESULTS The contralateral cognate joint was the most common second joint to undergo replacement in both the OA and the RA groups . However , in OA patients for whom the second TJR was in a noncognate joint , that joint was > 2-fold more likely to be on the contralateral limb than on the ipsilateral limb ( hip to knee P < 0.001 ; knee to hip P = 0.013 ) . In contrast , among the RA cohort , the evolution was r and om and no laterality for noncognate TJR was observed at either the hip or the knee ( P = 0.782 ) . CONCLUSION This characterization of end-stage lower extremity OA demonstrates that the disease evolves nonr and omly ; after 1 joint is replaced , the contralateral limb is significantly more likely to show progression of OA than is the ipsilateral limb . Thus , OA in 1 weight-bearing joint appears to influence the evolution of OA in other joints . The absence of such laterality in RA suggests that OA progression may be mediated by extrinsic factors such as altered joint loading Abstract : The objective of this study was to measure three-dimensional knee motion during gait in patients with total knee replacements which either retained the posterior cruciate ligament ( n = 11 ) , or required sacrifice of the posterior cruciate ligament and replacement of its function with a posterior stabilizing articular surface ( n = 9 ) . Clinical ly meaningful translations ( anterior and posterior , medial and lateral , proximal and distal ) and rotations ( flexion and extension , internal and external rotation , abduction and adduction ) were measured using an instrumented spatial linkage . Although patients from both groups were able to achieve passive full extension and a minimum of 95 ° flexion , some of their translations and rotations during free speed walking were consistently less than those in a group of healthy controls . Motion during the swing phase of gait was similar for both knee replacement groups . However , abduction and adduction and proximal and distal translation were larger ( but neither difference was significant ) for the patients with implants with a posterior stabilizing surface , which suggests that the stabilizing surface may not reliably provide as much stability in these directions as does retention of the posterior cruciate ligament BACKGROUND Clarification of the indications for patellar resurfacing in total knee arthroplasty ( TKA ) is still necessary . Few studies of adequate power have evaluated functional differences between total knee arthroplasty with and without patellar resurfacing , in particular walking gait . This study aim ed to identify clinical ly relevant differences in knee kinematic or kinetic parameters during level walking between total knee arthroplasty with and without patellar resurfacing , after controlling for pre-surgery gait parameters . METHODS Kinematic and kinetic gait analysis of level walking was performed on 34 subjects ( 41 knees ) before and 12 - 18 months after total knee arthroplasty with patellar resurfacing performed r and omly . Linear regression analysis was used to examine the influence of patellar resurfacing upon gait variables whilst controlling for the corresponding pre-surgery measure . FINDINGS The pre-surgery value was a moderate to strong significant predictor of all post-surgery temporal-spatial and kinetic gait parameters ( p < 0.001 - 0.008 ) , and most kinematic parameters ( p < 0.001 - 0.066 ) . The addition of patellar resurfacing to the regression models did not improve the predictive power in any case . Only one parameter , knee flexion at heel-strike , displayed a difference near statistical significance between total knee arthroplasty with and without patellar resurfacing ( 10 degrees versus 7 degrees respectively , p = 0.023 ) . INTERPRETATION Pre-surgery gait patterns are an important determinant of post-surgery gait . There are no clinical ly relevant differences in walking gait between total knee arthroplasty performed with or without patellar resurfacing , using the Profix design |
13,758 | 17,296,876 | Short-term exposure to marijuana is associated with bronchodilation .
Physiologic data were inconclusive regarding an association between long-term marijuana smoking and airflow obstruction measures .
Long-term marijuana smoking is associated with increased respiratory symptoms suggestive of obstructive lung disease | BACKGROUND The relationship between marijuana smoking and pulmonary function or respiratory complications is poorly understood ; therefore , we conducted a systematic review of the impact of marijuana smoking on pulmonary function and respiratory complications . | After experimental induction of acute bronchospasm in 8 subjects with clinical ly stable bronchial asthma , effects of 500 mg of smoked marijuana ( 2.0 per cent delta9-tetrahydrocannabinol ) on specific airway conductance and thoracic gas volume were compared with those of 500 mg of smoked placebo marijuana ( 0.0 per cent delta9-tetrahydrocannabinol ) , 0.25 ml of aerosolized saline , and 0.25 ml of aerosolized isoproterenol ( 1,250 mug ) . Bronchospasm was induced on 4 separate occasions , by inhalation of methacholine and , on four other occasions , by exercise on a bicycle ergometer or treadmill . Methacholine and exercise caused average decreases in specific airway conductance of 40 to 55 per cent and 30 to 39 per cent , respectively , and average increases in thoracic gas volume of 35 to 43 per cent and 25 to 35 per cent , respectively . After methacholine-induced bronchospasm , placebo marijuana and saline inhalation produced minimal changes in specific airway conductance and thoracic gas volume , whereas 2.0 per cent marijuana and isoproterenol each caused a prompt correction of the bronchospasm and associated hyperinflation . After exercise-induced bronchospasm , placebo marijuana and saline were followed by gradual recovery during 30 to 60 min , whereas 2.0 per cent marijuana and isoproterenol caused an immediate reversal of exercise-induced asthma and hyperinflation 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 Abstract Normal volunteers with previous marihuana smoking experience inhaled the total smoke from 3.23 mg per kilogram of marihuana , using a bag-in-box technic . R and omly , nine received marihuana containing a high ( 2.6 per cent ) , and eight a low ( 1.0 per cent ) concentration of delta-9 tetrahydrocannabinol . Physiologic variables were monitored before and for 20 minutes after smoking . In the high-dose group the heart rate increased 28 per cent . Concomitantly , airway resistance , measured in a body plethysmograph , fell 38 per cent ; the functional residual capacity remained unchanged ( ± 50 ml ) throughout , and specific airway conductance increased 44 per cent . Flow-volume loops showed a 45 per cent increase in flow rate at 25 per cent of vital capacity . The low-dose group showed no increase in heart rate but significant , if lesser changes , in airways dynamics . Carbon dioxide sensitivity , measured by rebreathing remained unchanged in both groups . Marihuana smoke , unlike cigarette smoke , causes bronchodilatation Abstract Acute pulmonary physiologic effects of smoked marijuana and oral Δ9-tetrahydrocannabinol were investigated in 32 healthy , experienced male marijuana smokers . After smoking of marijuana ass Ten young , healthy male volunteers smoked a marihuana cigarette with 2.5 % δ9-THC and a THC-exhausted placebo cigarette . The marihuana administration was associated with an increase in heart rate , elevation of systolic blood pressure , conjunctival reddening and specific airway conductance increase ; time perception and Automated Digit Symbol Substitution Test performance were impaired . Diastolic blood pressure and attention measured by the Continuous Performance Task were not affected . The placebo preparation produced a subjective pleasant “ high ” but no physiologic effects nor performance change . The “ high ” induced by the active preparation was often rated as unpleasant Effects on airway dynamics , heart rate , and the central nervous system of various doses of delta9-tetrahydrocannabinol administered in a r and om , double blind fashion using a Freon-propelled , metered-dose nebulizer were evaluated in 11 healthy men and 5 asthmatic subjects . Effects of aerosolized delta9-tetrahydrocannabinol were compared with aerosolized placebo and isoproterenol and with 20 mg of oral and smoked delta9-tetrahydrocannabinol . In the normal subjects , after 5 to 20 mg of aerosolized delta9-tetrahydrocannabinol , specific airway conductance increased immediately , reached a maximum ( 33 to 41 per cent increase ) after 1 to 2 hours , and remained significantly greater than placebo values for 2 to 3 hours . The bronchodilator effect of aerosolized delta9-tetrahydrocannabinol was less than that of isoproterenol after 5 min , but significantly greater than that of isoproterenol after 1 to 3 hours . The magnitude of bronchodilatation after all doses of aerosolized delta9-tetrahydrocannabinol was comparable , but 5 mg of delta9-tetrahydrocannabinol caused a significantly smaller increase in heart rate and level of intoxication than the 20-mg dose . Smoked delta9-tetrahydrocannabinol produced greater cardiac and intoxicating effects than either aerosolized or oral delta9-tetrahydrocannabinol . Side effects of aerosolized delta9-tetrahydrocannabinol included slight cough and /or chest discomfort in 3 of the 11 normal subjects . Aerosolized delta9-tetrahydrocannabinol caused significant bronchodilatation in 3 of 5 asthmatic subjects , but caused moderate to severe bronchoconstriction associated with cough and chest discomfort in the other 2 . These findings indicate that aerosolized delat9-tetrahydrocannabinol , although capable of causing significant bronchodilatation with minimal systemic side effects , has a local irritating effect on the airways , which may make it unsuitable for therapeutic use To assess the possible role of daily smoking of marijuana in the development of chronic obstructive pulmonary disease ( COPD ) , we evaluated the effect of habitual use of marijuana with or without tobacco on the age-related change in lung function ( measured as FEV1 ) in comparison with the effect of nonsmoking and regular tobacco smoking . A convenience sample of 394 healthy young Caucasian adults ( 68 % men ; age : 33 + /- 6 yr ; mean + /- SD ) including , at study entry , 131 heavy , habitual smokers of marijuana alone , 112 smokers of marijuana plus tobacco , 65 regular smokers of tobacco alone , and 86 nonsmokers of either substance were recruited from the greater Los Angeles community . FEV1 was measured in all 394 participants at study entry and in 255 subjects ( 65 % ) on up to six additional occasions at intervals of > or = 1 yr ( 1.7 + /- 1.1 yr ) over a period of 8 yr . R and om-effects models were used to estimate mean rates of decline in FEV1 and to compare these rates between smoking groups . Although men showed a significant effect of tobacco on FEV1 decline ( p < 0.05 ) , in neither men nor women was marijuana smoking associated with greater declines in FEV1 than was nonsmoking , nor was an additive effect of marijuana and tobacco noted , or a significant relationship found between the number of marijuana cigarettes smoked per day and the rate of decline in FEV1 . We conclude that regular tobacco , but not marijuana , smoking is associated with greater annual rates of decline in lung function than is nonsmoking . These findings do not support an association between regular marijuana smoking and chronic COPD but do not exclude the possibility of other adverse respiratory effects |
13,759 | 26,343,314 | INTERPRETATION DOX has higher CE3 rates than NON does .
LD statistically trended to lower cardiac event rates than DOX .
Non-statistical significance among EPI , LD and DOX with regard to cardiac toxicity indicates that avoidance of CE3 should not motivate selection of a particular anthracycline in otherwise healthy women in whom total lifetime anthracycline exposure will likely be limited .
Overall low incidence of CE3 with any type of anthracycline indicates that we can safely use any anthracycline if cumulative dose limits are not exceeded .
While CE3 does not limit our choice of anthracycline LD appears to be the least cardiotoxic . | BACKGROUND Anthracyclines play a broad and important role in the care of patients with either operable or metastatic breast cancer .
However cardiotoxicity narrows the therapeutic index of this drug class leading to potentially clinical ly meaningful treatment delays or discontinuations .
We conducted a Bayesian network meta- analysis , a vali date d statistical methodology , allowing direct and indirect comparison of cardiotoxicity of different anthracycline and non-anthracycline regimens . | The National Surgical Adjuvant Breast and Bowel Project ( NSABP ) implemented protocol B-15 to compare 2 months of Adriamycin ( doxorubicin ; Adria Laboratories , Columbus , OH ) and cyclophosphamide ( AC ) with 6 months of conventional cyclophosphamide , methotrexate , and fluorouracil ( CMF ) in patients with breast cancer nonresponsive to tamoxifen ( TAM , T ) . A second aim was to determine whether AC followed in 6 months by intravenous ( IV ) CMF was more effective than AC without reinduction therapy . Through 3 years of follow-up , findings from 2,194 patients indicate no significant difference in disease-free survival ( DFS , P = .5 ) , distant disease-free survival ( DDFS , P = .5 ) or survival ( S , P = .8 ) among the three groups . Since the outcome from AC and CMF was almost identical , the issue arises concerning which regimen is more appropriate for the treatment of breast cancer patients . AC seems preferable since , following total mastectomy , AC was completed on day 63 versus day 154 for conventional CMF ; patients visited health professionals three times as often for conventional CMF as for AC ; women on AC received therapy on each of 4 days versus on each of 84 days for conventional CMF ; and nausea-control medication was given for about 84 days to conventional CMF patients versus for about 12 days to patients on AC . The difference in the amount of alopecia between the two treatment groups was less than anticipated . While alopecia was almost universally observed following AC therapy , 71 % of the CMF patients also had hair loss and , in 41 % , the loss was greater than 50 % . This study and NSABP B-16 , which evaluates the worth of AC therapy in TAM-responsive patients , indicate the merit of 2 months of AC therapy for all positive-node breast cancer patients PURPOSE We evaluated the efficacy of cyclophosphamide , methotrexate , and fluorouracil ( CMF ) versus cyclophosphamide , doxorubicin , and fluorouracil ( CAF ) in node-negative breast cancer patients with and without tamoxifen ( TAM ) , overall and by hormone receptor ( HR ) status . PATIENTS AND METHODS Node-negative patients identified by tumor size ( > 2 cm ) , negative HR , or high S-phase fraction ( n = 2,690 ) were r and omly assigned to CMF , CAF , CMF + TAM ( CMFT ) , or CAF + TAM ( CAFT ) . Cox regression evaluated overall survival ( OS ) and disease-free survival ( DFS ) for CAF versus CMF and TAM versus no TAM separately . Two-sided CIs and one-sided P values for planned comparisons were calculated . RESULTS Ten-year estimates indicated that CAF was not significantly better than CMF ( P = .13 ) for the primary outcome of DFS ( 77 % v 75 % ; HR = 1.09 ; 95 % CI , 0.94 to 1.27 ) . CAF had slightly better OS than CMF ( 85 % v 82 % , HR = 1.19 for CMF v CAF ; 95 % CI , 0.99 to 1.43 ) ; values were statistically significant in the planned one-sided test ( P = .03 ) . Toxicity was greater with CAF and did not increase with TAM . Overall , TAM had no benefit ( DFS , P = .16 ; OS , P = .37 ) , but the TAM effect differed by HR groups . For HR-positive patients , TAM was beneficial ( DFS , HR = 1.32 for no TAM v TAM ; 95 % CI , 1.09 to 1.61 ; P = .003 ; OS , HR = 1.26 ; 95 % CI , 0.99 to 1.61 ; P = .03 ) , but not for HR-negative patients ( DFS , HR = 0.81 for no TAM v TAM ; 95 % CI , 0.64 to 1.03 ; OS , HR = 0.79 ; 95 % CI , 0.60 to 1.05 ) . CONCLUSION CAF did not improve DFS compared with CMF ; there was a slight effect on OS . Given greater toxicity , we can not conclude CAF to be superior to CMF . TAM is effective in HR-positive disease , but not in HR-negative disease 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 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 To evaluate activity and tolerability of two anthracycline-containing regimens as first-line treatment for anthracycline-naïve relapsed breast cancer patients . Methods Patients with relapsed breast cancer not previously treated with adjuvant anthracyclines were r and omly assigned to epirubicin/vinorelbine ( arm A : EPI/VNB , EPI 90 mg/m2 on day 1 , VNB 25 mg/m2 on days 1,5 plus G-CSF subcutaneously on days 7 - 12 , with cycles repeated every 21 days ) , or to pegylated liposomal doxorubicin/VNB ( arm B : PLD/VNB , PLD 40 mg/m2 on day 1 , VNB 30 mg/m2 on days 1 , 15 , with cycles repeated every 4 weeks ) . Primary objective was to evaluate the efficacy of the two regimens in terms of response rate , secondarily toxicity , progression free survival and overall survival . Results One hundred and four patients have been enrolled ( arm A 54 , arm B 50 ) : characteristics were well balanced between the 2 arms . Responses were as follows : arm A , 3 ( 5.6 % ) CR , 20 ( 37 % ) PR , ( ORR 42.6 % , 95%CI 29.3%-55.9 % ) ; arm B , 8 ( 16 % ) CR , 18 ( 36 % ) PR , ( ORR 52 % , 95%CI 38.2%-65.8 % ) . Median progression free survival was 10.7 months in arm A ( 95 % CI , 8.7 - 12.6 ) , and 8.8 months in arm B ( 95 % CI , 7.1 - 10.5 ) . Median overall survival was 34.6 months in arm A ( 95%CI , 19.5 - 49.8 ) and 24.8 months in arm B ( 95%CI , 15.7 - 33.9 ) . As toxicity concerns , both treatment regimens were well tolerated ; myelosuppression was the dose-limiting toxicity , with G3 - 4 neutropenia occurring in 18.5 % and 22 % of the patients of arm A and B , respectively . No relevant differences in main toxic effects have been observed between the two arms , except for alopecia , more common in arm A , and cutaneous toxicity , observed only in arm B. No clinical congestive heart failures have been observed , one case of tachyarrhythmia was reported after the last EPI/VNB cycle , and two reversible ≥ 20 % LVEF decreases have been observed in arm A. Conclusions Both anthracycline- containing regimens evaluated in the present study seem to be active and with a satisfactory tolerability in anthracycline-naïve relapsed breast cancer patients The EORTC Breast Cancer Cooperative Group carried out a r and omized trial to compare doxorubicin with epirubicin as second-line chemotherapy in patients with metastatic breast cancer . Two hundred and fifty-nine patients with at least one site of metastatic disease entered this trial , of whom 232 patients were eligible . Treatment consisted of doxorubicin 75 mg m(-2 ) or epirubicin 90 mg m(-2 ) i.v . every 3 weeks . The overall response rates for doxorubicin and epirubicin were 36 % and 28 % respectively ( P = 0.173 ) . The median time to progression was 23 weeks for doxorubicin and 19 weeks for epirubicin ( P = 0.063 ) and the median duration of response was 40 weeks for doxorubicin and 32 weeks for epirubicin ( P = 0.059 ) . The median survival was 47 weeks for doxorubicin and 44 weeks for epirubicin ( P = 0.196 ) . Leucocyte count on retreatment day ( P = 0.011 ) and platelet nadir ( P = 0.031 ) were significantly lower in the doxorubicin-treated group . Also mucositis ( P < 0.001 ) , diarrhoea ( P = 0.005 ) and haemorrhage ( P = 0.048 ) were significantly worse in the doxorubicin arm . Nine patients on doxorubicin and two patients on epirubicin experienced congestive heart failure ( CHF ) . At the dose levels used in this study , no statistical differences in response rate and survival were found between the two treatment arms . Treatment with doxorubicin tended to result in a slightly longer duration of response and time to progression but doxorubicin was more toxic than epirubicin PURPOSE To compare a full-dose epirubicin-cyclophosphamide ( HEC ) regimen with classical cyclophosphamide , methotrexate , and fluorouracil ( CMF ) therapy and with a moderate-dose epirubicin-cyclophosphamide regimen ( EC ) in the adjuvant therapy of node-positive breast cancer . PATIENTS AND METHODS Node-positive breast cancer patients who were aged 70 years or younger were r and omly allocated to one of the following treatments : CMF for six cycles ( oral cyclophosphamide ) ; EC for eight cycles ( epirubicin 60 mg/m(2 ) , cyclophosphamide 500 mg/m(2 ) ; day 1 every 3 weeks ) ; and HEC for eight cycles ( epirubicin 100 mg/m(2 ) , cyclophosphamide 830 mg/m(2 ) ; day 1 every 3 weeks ) . RESULTS Two hundred fifty-five , 267 , and 255 eligible patients were treated with CMF , EC , and HEC , respectively . Patient characteristics were well balanced among the three arms . One and three cases of congestive heart failure were reported in the EC and HEC arms , respectively . Three cases of acute myeloid leukemia were reported in the HEC arm . After 4 years of median follow-up , no statistically significant differences were observed between HEC and CMF ( event-free survival [ EFS ] : hazards ratio [ HR ] = 0.96 , 95 % confidence interval [ CI ] , 0.70 to 1.31 , P = .80 ; distant-EFS : HR = 0.97 , 95 % CI , 0.70 to 1.34 , P = .87 ; overall survival [ OS ] : HR = 0.97 , 95 % CI , 0.65 to 1.44 , P = .87 ) . HEC is more effective than EC ( EFS : HR = 0.73 , 95 % CI , 0.54 to 0.99 , P = .04 ; distant-EFS : HR = 0.75 , 95 % CI , 0.55 to 1.02 , P = .06 ; OS HR = 0.69 , 95 % CI , 0.47 to 1.00 , P = .05 ) . CONCLUSION This three-arm study does not show an advantage in favor of an adequately dosed epirubicin-based regimen over classical CMF in the adjuvant therapy of node-positive pre- and postmenopausal women with breast cancer . Moreover , this study confirms that there is a dose-response curve for epirubicin in breast cancer adjuvant therapy PURPOSE To evaluate the efficacy and safety of vinorelbine combined with doxorubicin or continuous infusion of fluorouracil as initial therapy for advanced breast cancer . AUBJECTS AND METHODS : A total of 118 women who had not received chemotherapy for advanced breast cancer were enrolled and included in the intent-to-treat analysis . Subjects were stratified into two treatment groups . If subjects were c and i date s for anthracycline therapy , they received doxorubicin 50 mg/m(2 ) on day 1 and vinorelbine 25 mg/m(2 ) on days 1 and 8 ( n = 62 ) . If subjects had received adjuvant anthracycline therapy or had cardiac disease , they received fluorouracil 750 mg/m(2)/day by continuous infusion on days 1 through 5 and vinorelbine 30 mg/m(2 ) on days 1 and 5 ( n = 56 ) . The regimens were repeated every 21 days until evidence of progression of disease or severe toxicity . RESULTS For doxorubicin and vinorelbine , the objective response rate was 55 % ( 95 % confidence interval [ CI ] : 42 % to 68 % ) , median time to disease progression was 34 weeks , median time to treatment failure was 32 weeks , and median survival was 92 weeks ( 95 % CI : 72 to 128 weeks ) . For fluorouracil and vinorelbine , the objective response rate was 45 % ( 95 % CI : 31 % to 59 % ) , median time to disease progression was 32 weeks , median time to treatment failure was 30 weeks , and median survival was 53 weeks ( 95 % CI : 47 to 64 weeks ) . The most common adverse event was grade 3 or 4 granulocytopenia , which occurred in 95 % of subjects in the doxorubicin-vinorelbine group and in 88 % of those in the fluorouracil-vinorelbine group . The most common nonhematologic adverse event was grade 3 or 4 stomatitis , which occurred in 9 % and 32 % of subjects in the two groups , respectively . CONCLUSION Both vinorelbine-containing regimens appear to offer useful options as initial therapy for advanced breast cancer . Both regimens were active , and any efficacy differences between the two may have been related to differences in prognosis for the anthracycline-pretreated group ( i.e. , selection for prior aggressive adjuvant therapy ) and or comorbid cardiac conditions . Both regimens were associated with predictable but manageable toxicity , but a lower dose of fluorouracil ( e.g. , 600 mg/m(2)/day ) should be used to reduce the risk of stomatitis PURPOSE To assess whether the addition of epirubicin ( EPI ) therapy to prolonged treatment with tamoxifen ( TAM ) improves relapse-free and overall survival in postmenopausal women with node-positive primary breast cancer . PATIENTS AND METHODS Six hundred four patients entered onto a r and omized clinical trial were allocated to receive TAM 20 mg/d for 4 years or TAM 20 mg/d for 4 years plus EPI 50 mg/m(2 ) intravenously on days 1 and 8 every 4 weeks for six cycles . Analysis was performed according to allocated treatment , with all r and omized patients included ( intention to treat ) , irrespective of eligibility status . RESULTS After a median follow-up period of 5.7 years , an improvement in relapse-free survival ( RFS ) was observed for the TAM and EPI-treated patients , compared with those who received TAM alone . The unadjusted hazard ratio was 0.72 ( 95 % confidence interval , 0.54 to 0.96 ) , with a corresponding reduction in the odds of recurrence of 27.9 % ( SD , 12 . 3 ) , which was statistically significant ( P = .023 ) . Adjustment for prognostic and /or predictive factors did not material ly affect the hazard ratio . No difference was observed in terms of overall survival ( reduction in odds of death , 11.9 % [ SD , 16.3 ] ; P = .46 ) . Combined chemohormonal treatment was associated with a higher incidence of acute side effects but without a clear increase in long-term cardiotoxicity . Twelve nonbreast second malignancies , including five hematologic malignancies ( two of which were cases of acute myelogenous leukemia ) , were observed . CONCLUSION The data show that combined chemohormonal treatment reduces the risk of relapse in postmenopausal patients with node-positive breast cancer . No evidence was found , however , for an improvement in overall survival . The size of benefit observed for both outcomes was consistent with that reported in the Early Breast Cancer Trialists ' Collaborative Group overview . The trial presented here , however , provides the first report of an improvement in RFS associated with the provision of a single cytotoxic drug in addition to prolonged TAM Doxorubicin is a highly effective and widely used cytotoxic agent with application that is limited by cardiotoxicity related to the cumulative dose of the drug . A large‐scale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an estimated 7 % of patients developed doxorubicin‐related congestive heart failure ( CHF ) after a cumulative dose of 550 mg/m2 . To assess whether this estimate is reflective of the incidence in the broader clinical oncology setting , the authors evaluated data from three prospect i ve studies to determine both the incidence of doxorubicin‐related CHF and the accumulated dose of doxorubicin at which CHF occurs One hundred forty-one patients with advanced breast cancer who had not received prior chemotherapy were r and omly assigned to receive doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 every 3 weeks . These doses were selected to produce equivalent toxicities . All patients were assessed for toxicity , and 138 patients were assessable for response . After a median of five treatment cycles , 47 % ( 32 of 68 ) of doxorubicin-treated patients achieved a partial or complete response . Response duration and survival were 10 and 12 months for doxorubicin and 8 and 10 months for epirubicin , respectively . Noncardiac toxicities were similar for both drugs . Of 41 patients receiving doxorubicin who had serial left ventricular ejection fraction assessment s , seven sustained a fall of 10 % or more , and one patient developed congestive cardiac failure at a cumulative doxorubicin dose of 489 mg/m2 . Of 39 patients receiving epirubicin who had serial cardiac assessment s , five sustained left ventricular ejection fraction falls of 10 % or more and two patients developed congestive cardiac failure at cumulative doses of 178 mg/m2 and 833 mg/m2 . These data indicate that an epirubicin dose of 90 mg/m2 produces toxicity equivalent to doxorubicin 60 mg/m2 but does not improve response rates , response duration , or survival in advanced breast cancer |
13,760 | 28,849,277 | Synthesis of the review ed studies provided evidence of the usefulness of PROs in facilitating patient-clinician communication on a variety of topics .
We identified mechanisms though which PROs influenced patient-clinician communication to include increasing symptom awareness , prompting discussion , streamlining consultations , and facilitating inter-professional communication .
Barriers to PRO use in communication improvement include technical problems impeding its administration and completion , compliance issues due to lack of incentive or forgetfulness , and use of PROs that do not appropriately assess issues relevant to the patient .
Facilitators include increased education on PRO use , using PRO tools that patients find more acceptable , and providing patient data summaries in an easily accessible format for clinicians .
Conclusions Our review suggests that PROs facilitate patient-clinician communication through various mechanisms that could perhaps contribute to improvements in symptom management and survival . | Purpose Patient-reported outcomes ( PROs ) are an increasingly popular tool to optimize care and bridge the gap between patient experience and clinician underst and ing .
The aim of this review was to identify mechanisms through which PROs facilitate patient-clinician communication in the adult oncology population . | Purpose Computer-based , patient-reported symptom survey tools have been described for patients undergoing chemotherapy . We hypothesized that patients undergoing radiotherapy might also benefit , so we developed a computer application to acquire symptom ratings from patients and generate summaries for use at point of care office visits and conducted a r and omized , controlled pilot trial to test its feasibility . Methods Subjects were r and omized prior to beginning radiotherapy . Both control and intervention group subjects completed the computerized symptom assessment , but only for the intervention group were printed symptom summaries made available before each weekly office visit . Metrics compared included the Global Distress Index ( GDI ) , concordance of patient-reported symptoms and symptoms discussed by the physician and numbers of new and /or adjusted symptom management medications prescribed . Results One hundred twelve patients completed the study : 54 in the control and 58 in the intervention arms . There were no differences in GDI over time between the control and intervention groups . In the intervention group , more patient-reported symptoms were actually discussed in radiotherapy office visits : 46/202 vs. 19/230 . A sensitivity analysis to account for within-subjects correlation yielded 23.2 vs. 10.3 % ( p = 0.03 ) . Medications were started or adjusted at 15.4 % ( 43/280 ) of control visits compared to 20.4 % ( 65/319 ) of intervention visits ( p = 0.07 ) . Conclusions This computer application is easy to use and makes extensive patient-reported outcome data available at the point of care . Although no differences were seen in symptom trajectory , patients who had printed symptom summaries had improved communication during office visits and a trend towards a more active symptom management during radiotherapy Background The electronic self report assessment - cancer ( ESRA-C ) , has been shown to reduce symptom distress during cancer therapy The purpose of this analysis was to evaluate aspects of how the ESRA-C intervention may have result ed in lower symptom distress ( SD ) . Methods Patients at two cancer centers were r and omized to ESRA-C assessment only ( control ) or the Web-based ESRA-C intervention delivered to patients ’ homes or to a tablet in clinic . The intervention allowed patients to self-monitor symptom and quality of life ( SxQOL ) between visits , receive self-care education and coaching to report SxQOL to clinicians . Summaries of assessment s were delivered to clinicians in both groups . Audio-recordings of clinic visits made 6 weeks after treatment initiation were coded for discussion s of 26 SxQOL issues , focusing on patients ’ /caregivers ’ coached verbal reports of SxQOL severity , pattern , alleviating/aggravating factors and requests for help . Among issues identified as problematic , two measures were defined for each patient : the percent SxQOL reported that included a coached statement , and an index of verbalized coached statements per SxQOL . The Wilcoxon rank test was used to compare measures between groups . Clinician responses to problematic SxQOL were compared . A mediation analysis was conducted , exploring the effect of verbal reports on SD outcomes . Results 517 ( 256 intervention ) clinic visits were audio-recorded . General discussion of problematic SxQOL was similar in both groups . Control group patients reported a median 75 % of problematic SxQOL using any specific coached statement compared to a median 85 % in the intervention group ( p = .0009 ) . The median report index of coached statements was 0.25 for the control group and 0.31 for the intervention group ( p = 0.008 ) . Fatigue , pain and physical function issues were reported significantly more often in the intervention group ( all p < .05 ) . Clinicians ' verbalized responses did not differ between groups . Patients ' verbal reports did not mediate final SD outcomes ( p = .41 ) . Conclusions Adding electronically-delivered , self-care instructions and communication coaching to ESRA-C promoted specific patient descriptions of problematic SxQOL issues compared with ESRA-C assessment alone . However , clinician verbal responses were no different and subsequent symptom distress group differences were not mediated by the patients ' reports . Trial registration NCT00852852 ; 26 Feb PURPOSE Although patient-reported cancer symptoms and quality -of-life issues ( SQLIs ) have been promoted as essential to a comprehensive assessment , efficient and efficacious methods have not been widely tested in clinical setting s. The purpose of this trial was to determine the effect of the Electronic Self-Report Assessment -Cancer ( ESRA-C ) on the likelihood of SQLIs discussed between clinicians and patients with cancer in ambulatory clinic visits . Secondary objectives included comparison of visit duration between groups and usefulness of the ESRA-C as reported by clinicians . PATIENTS AND METHODS This r and omized controlled trial was conducted in 660 patients with various cancer diagnoses and stages at two institutions of a comprehensive cancer center . Patient-reported SQLIs were automatically displayed on a graphical summary and provided to the clinical team before an on-treatment visit ( n = 327 ) ; in the control group , no summary was provided ( n = 333 ) . SQLIs were scored for level of severity or distress . One on-treatment clinic visit was audio recorded for each participant and then scored for discussion of each SQLI . We hypothesized that problematic SQLIs would be discussed more often when the intervention was delivered to the clinicians . RESULTS The likelihood of SQLIs being discussed differed by r and omized group and depended on whether an SQLI was first reported as problematic ( P = .032 ) . Clinic visits were similar with regard to duration between groups , and clinicians reported the summary as useful . CONCLUSION The ESRA-C is the first electronic self-report application to increase discussion of SQLIs in a US r and omized clinical trial PURPOSE This study aim ed to determine whether feeding back patient-reported outcomes ( PROs ) to providers and families of children with advanced cancer improves symptom distress and health-related quality of life ( HRQoL ) . PATIENTS AND METHODS This study was a parallel , multicentered pilot r and omized controlled trial . At most once per week , children age ≥ 2 years old with advanced cancer or their parent completed the computer-based Pediatric Quality of Life and Evaluation of Symptoms Technology ( PediQUEST ) survey consisting of age- and respondent-adapted versions of the Memorial Symptom Assessment Scale ( MSAS ) , Pediatric Quality of Life Inventory 4.0 Generic Core Scales ( PedsQL4.0 ) , and an overall Sickness question . In the intervention group ( n = 51 ) , oncologists and families received printed reports summarizing PROs ; e-mails were sent to oncologists and subspecialists when predetermined scores were exceeded . No feedback was provided in the control group ( n = 53 ) . Primary outcomes included linear trends of MSAS , PedsQL4.0 total and subscale scores , and Sickness scores during 20 weeks of follow-up , along with child , parent , and provider satisfaction with PediQUEST feedback . RESULTS Feedback did not significantly affect average MSAS , PedsQL4.0 , or Sickness score trends . Post hoc subgroup analyses among children age ≥ 8 years who survived 20 weeks showed that feedback improved PedsQL4.0 emotional ( + 8.1 ; 95 % CI , 1.8 to 14.4 ) and Sickness ( -8.2 ; 95 % CI , -14.2 to -2.2 ) scores . PediQUEST reports were valued by children , parents , and providers and contributed at least sometimes to physician initiation of a psychosocial consult ( 56 % ) . CONCLUSION Although routine feedback of PROs did not significantly affect the child 's symptoms or HRQoL , changes were in expected directions and improvements observed in emotional HRQoL through exploratory analyses were encouraging . Importantly , children , parents , and providers value PRO feedback The potential benefits of health-related quality of life ( HRQL ) assessment in oncology clinical practice include better detection of problems , enhanced disease and treatment monitoring and improved care . However , few empirical studies have investigated the effects of incorporating such assessment s into routine clinical care . Recent r and omized studies have reported improved detection of and communication about patients ' concerns , but few have found effects on patient HRQL or satisfaction . This study examined whether offering interpretive assistance of HRQL results would improve these patient outcomes . Two hundred and thirteen participants with metastatic breast , lung or colorectal cancer were r and omly assigned to one of three conditions : usual care ; HRQL assessment or HRQL assessment followed by a structured interview and discussion . Interviews about patients ' assessment responses were conducted by a research nurse , who then presented HRQL information to the treating nurse . HRQL and treatment satisfaction outcomes were assessed at 3 and 6 months . No significant differences were found between study conditions in HRQL or satisfaction . Results suggest that routine HRQL assessment , even with description of results , is insufficient to improve patient HRQL and satisfaction . It is suggested that positive effects may require supplementing assessment results with specific suggestions for clinical management changes PURPOSE There is growing interest to enhance symptom monitoring during routine cancer care using patient-reported outcomes , but evidence of impact on clinical outcomes is limited . METHODS We r and omly assigned patients receiving routine outpatient chemotherapy for advanced solid tumors at Memorial Sloan Kettering Cancer Center to report 12 common symptoms via tablet computers or to receive usual care consisting of symptom monitoring at the discretion of clinicians . Those with home computers received weekly e-mail prompts to report between visits . Treating physicians received symptom printouts at visits , and nurses received e-mail alerts when participants reported severe or worsening symptoms . The primary outcome was change in health-related quality of life ( HRQL ) at 6 months compared with baseline , measured by the EuroQol EQ-5D Index . Secondary endpoints included emergency room ( ER ) visits , hospitalizations , and survival . RESULTS Among 766 patients allocated , HRQL improved among more participants in the intervention group than usual care ( 34 % v 18 % ) and worsened among fewer ( 38 % v 53 % ; P < .001 ) . Overall , mean HRQL declined by less in the intervention group than usual care ( 1.4- v 7.1-point drop ; P < .001 ) . Patients receiving intervention were less frequently admitted to the ER ( 34 % v 41 % ; P = .02 ) or hospitalized ( 45 % v 49 % ; P = .08 ) and remained on chemotherapy longer ( mean , 8.2 v 6.3 months ; P = .002 ) . Although 75 % of the intervention group was alive at 1 year , 69 % with usual care survived the year ( P = .05 ) , with differences also seen in quality -adjusted survival ( mean of 8.7 v. 8.0 months ; P = .004 ) . Benefits were greater for participants lacking prior computer experience . Most patients receiving intervention ( 63 % ) reported severe symptoms during the study . Nurses frequently initiated clinical actions in response to e-mail alerts . CONCLUSION Clinical benefits were associated with symptom self-reporting during cancer care Purpose Monitoring patient-reported symptoms is necessary to adjust and improve supportive care during chemotherapy . Continuing advances in computerized approaches to symptom monitoring can enhance communication about unrelieved symptoms between patients and oncology providers and may facilitate intensified symptom treatment . Methods An automated IT-based telephone monitoring system was developed to enable oncology providers to receive and act on alert reports from patients about unrelieved symptoms during chemotherapy treatment . Daily , 250 participants ( r and omized to treatment or attentional control ) were asked to call the automated system to report presence , severity , and distress for common chemotherapy-related symptoms ( 1–10 scale if present ) . For the treatment group , symptoms exceeding preset thresholds for moderate-to-severe intensity levels generated emailed alert reports to both the patient ’s oncologist and oncology nurse . Results Patients reported high satisfaction and ease of use of the automated system . Over 80 % of providers reported usefulness of the symptom alert reports . Ten monitored symptoms result ed in , on average , nine moderate-to-severe intensity alerts per patient over 45 study days . However , providers rarely contacted patients after receiving alerts . There were no significant differences in change of symptom severity between the two groups ( mean difference = 0.06 , p = 0.58 ) . Conclusion Despite patients ’ use of a daily symptom monitoring system and providers ’ receipt of information about unrelieved symptoms of moderate-to-severe intensity , oncology physicians and nurses did not contact patients to intensify symptom treatment nor did symptoms improve . Further research is indicated to determine if oncology providers initiated follow-up to intensify symptom treatment , whether symptom outcomes would improve This r and omized controlled trial investigated the effect of reporting physical symptoms by using a systematic symptom monitoring instrument , the Symptom Monitor , on symptom prevalence and severity among patients with cancer in the palliative phase . The overall objective was to achieve symptom relief through systematic and regular symptom reporting by patients themselves . One hundred forty-six patients with cancer in the palliative phase were r and omized to either the intervention group ( n = 69 with Symptom Monitor ) or the control group ( n = 77 without Symptom Monitor ) . Ten physical symptoms with regard to prevalence and severity were monitored . After 2 months , the prevalence of symptoms was lower in the intervention group compared to the control group ( prevalent differences 2.1 - 24.3 % ) for 9 out of 10 symptoms ( except coughing ) . The intervention group scored a statistically significantly lower prevalence in constipation and vomiting ( prevalence differences 24.3 % and 18.0 % , respectively ) . In four symptoms ( fatigue , lack of appetite , shortness of breath , and nausea ) , the intervention group had a lower , although not statistically significant , severity score ( median differences 0.5 - 1 ) . In four symptoms ( pain , coughing , sleeplessness , and diarrhea ) , the severity score was the same in both groups ( medians 2 - 4 ) . In two symptoms ( constipation and vomiting ) , the severity score was lower in the control group ( median differences -1 and -2 ) . A comparison between the study groups on improved , deteriorated , or steady-state cases showed that the severity score had deteriorated less for 8 out of 10 symptoms in a larger proportion of patients in the intervention group . Although statistical significance was not reached , the prevalence as well as severity of symptoms in the palliative phase of cancer can be influenced by using the Symptom Monitor PURPOSE Patients with cancer experience considerable symptom burden , psychological morbidity , and unmet psychosocial needs . Research suggests that feedback of patient-reported outcomes to clinicians or caseworkers , alongside management strategies , may result in improved patient functioning . Two intervention models were developed to test this effect in a r and omized , controlled trial against usual care ( UC ) : a telephone caseworker ( TCW ) model and an oncologist/general practitioner ( O/GP ) model . Primary end points included anxiety , depression , physical/emotional functioning , and unmet supportive care needs . PATIENTS AND METHODS Participants with nonlocalized breast or colorectal cancers were surveyed by computer-assisted telephone interview ( CATI ) at three time points : baseline , 3 months , and 6 months . Data collected from participant CATIs in the supportive care models were used to generate feedback to either each participant 's design ated TCW , or their nominated O/GPs . Data obtained from participants in the UC model were used only to assess the impact of supportive care models . In total , 356 participants consented to study participation , completed the baseline CATI , and were r and omly assigned to the UC , TCW , or O/GP groups . RESULTS No overall intervention effect was observed . Physical functioning was significantly improved at the third CATI for participants in the TCW model ( P = .01 ) , and there was a trend toward fewer participants with unmet needs ( P = .07 ) . TCW group participants also were more likely to have the following : identified issues of need discussed ( P < .0001 ) ; referrals made ( P < .0001 ) ; and strong agreement that the intervention improved communication with their health care team ( P = .0005 ) . CONCLUSION The TCW model holds some promise ; however , additional work in at-risk population s is required before we recommend implementation PURPOSE Regularly collecting patient-reported outcomes ( PROs ) of health-related quality of life with feedback to oncologists may assist in eliciting and monitoring patients ' problems during cancer treatment . This study examined how PRO feedback had an impact on patient-physician communication over time to gain a better underst and ing of how it may influence patient care . PATIENTS AND METHODS Exploratory analyses were performed on a data set from a previous study . Patients were r and omly assigned to intervention ( regular completion of European Organisation for Research and Treatment of Cancer Quality of Life Question naire-Core 30 and Hospital Anxiety and Depression Scale with feedback to oncologists ) , attention-control ( completion of same question naires without feedback ) , and control ( st and ard care ) arms . The content of consultation audio recordings between 28 oncologists and 198 patients over four consecutive visits ( 792 consultations ) was analyzed . Mixed-effects models and multivariate regressions were used to examine the longitudinal impact of the intervention on patient-physician communication , dynamics of patient-physician interaction , and the association between PROs and the content of clinic discussion . RESULTS Patients in the intervention arm discussed more symptoms over time compared with patients in the attention-control ( P = .008 ) and control ( P = .04 ) arms . No study arm effect was observed for function discussion s. Discussion topics were predominantly raised by patients /relatives , regardless of arm allocation . Clinic discussion s were associated with severity of patient-reported symptoms but not with patient-reported functional concerns . CONCLUSION A positive longitudinal impact of the intervention on symptom discussion was observed , but not for function discussion , suggesting that potentially serious problems may remain unaddressed . Training oncologists in responding to patient-reported functional concerns may increase the impact of this intervention Purpose We conducted a secondary qualitative analysis of consultations between oncologists and their patients to explore how patient-reported outcome measures ( PROMs ) data were referred to in the process of ( 1 ) eliciting and exploring patients ’ concerns ; ( 2 ) making decisions about supportive treatment and ( 3 ) making decisions about chemotherapy and other systemic treatments . Methods We purposively sample d audio recordings of 18 consultations from the intervention arm and 4 from the attention control arm of a previous UK r and omised controlled trial of the feedback of PROMs data to doctors ( Velikova et al. in J Clin Oncol 22(4):714–724 [ 1 ] ) . We used a combination of content and conversation analysis to examine how opportunities for discussion of health-related quality of life issues are opened up or closed down within the consultation and explore why this may or may not lead to changes in patient management . Findings Explicit reference to the PROMs data provided an opportunity for the patient to clarify and further elaborate on the side effects of chemotherapy . High scores on the PROMs data were not explored further if the patient indicated they were not a problem or were not related to the cancer or chemotherapy . Symptomatic treatment was more often offered for problems like nausea , constipation , pain and depression but much less so for fatigue . Doctors discussed fatigue by providing a cause for the fatigue ( e.g. the chemotherapy ) , presenting this as ‘ something to be expected ’ , minimising its impact or moving on to another topic . Chemotherapy regimens were not changed on the basis of the PROMs data alone , but PROMs data were sometimes used to legitimise changes . Conclusions Explicit mention of PROMs data in the consultation may strengthen opportunities for patients to elaborate on their problems , but doctors may not always know how to do this . Our findings have informed the development of a training package to enable doctors to optimise their use of PROMs data within the consultation BACKGROUND Routine symptom and health-related quality of life ( HRQOL ) assessment s can engage patients , give provider feedback , and improve doctor/patient communication . OBJECTIVE We compared the impact of a technology-assisted symptom monitoring system versus usual care on HRQOL and doctor/patient communication in early-stage prostate cancer ( PCa ) survivors . METHODS Men ( N = 94 ) were on average 62-years old , mostly African American ( AA ; 61.7 % ) , and 10 - 19 months post-treatment . They were r and omized to symptom monitoring plus feedback ( SM + F ; n = 49 ) or usual care ( UC ; n = 45 ) . SM+F participants completed a 12-item telephoneassisted monitoring intervention . All participants completed a baseline and 2 follow-up interviews . RESULTS Among the SM+F participants , perceptions of the monitoring system were positive : 97.1 % endorsed it as easy/very easy to use and 85 % felt all patients could benefit from it . At baseline , men reported favorable general and cancer-specific HRQOL and doctor/patient communication , but poorer urinary and sexual function . Although there was no overall impact of the intervention , post hoc exploratory analyses indicated that among AA men , those who received SM+F improved relative to UC on doctor/patient communication ( P < .05 ) , general HRQOL ( P < .06 ) , and sexual function ( P < .05 ) . LIMITATIONS Variability in survivor follow-up care , limited access to eligible participants , and minimal physician training in the use of reports likely decreased physician investment . CONCLUSION Overall , PCa survivors were receptive to this monitoring system . Exploratory analyses suggest that this technology-assisted monitoring system may be of particular benefit to African American men . Additional studies with larger sample s , more intervention time-points , and increased physician training are needed to strengthen the intervention 's impact INTRODUCTION AND AIM In a r and omised trial investigating the effects of regular use of health-related quality of life ( HRQOL ) in oncology practice , we previously reported an improvement in communication ( objective analysis of recorded encounters ) and patient well-being . The secondary aims of the trial were to measure any impact on patient satisfaction and patients ' perspectives on continuity and coordination of their care . METHODS In a prospect i ve trial involving 28 oncologists , 286 cancer patients were r and omised to : ( 1 ) intervention arm : regular touch-screen completion of HRQOL with feedback to physicians ; ( 2 ) attention-control arm : completion of HRQOL without feedback ; and ( 3 ) control arm : no HRQOL assessment . Secondary outcomes were patients ' experience of continuity of care ( Medical Care Question naire , MCQ ) including ' Communication ' , ' Coordination ' and ' Preferences to see usual doctor ' subscales , patients ' satisfaction , and patients ' and physicians ' evaluation of the intervention . Analysis employed mixed-effects modelling , multiple regression and descriptive statistics . RESULTS Patients in the intervention arm rated their continuity of care as better than the control group for ' Communication ' subscale ( p=0.03 ) . No significant effects were found for ' Coordination ' or ' Preferences to see usual doctor ' . Patients ' evaluation of the intervention was positive . More patients in the intervention group rated the HRQOL assessment as useful compared to the attention-control group ( 86 % versus 29 % ) , and reported their doctors considered daily activities , emotions and quality of life . CONCLUSION Regular use of HRQOL measures in oncology practice brought changes to doctor-patient communication of sufficient magnitude and importance to be reported by patients . HRQOL data may improve care through facilitating rapport and building inter-personal relationships BACKGROUND The PatientViewpoint website collects patient-reported outcomes and links them with the electronic health record to aid patient management . This pilot test evaluated PatientViewpoint 's use , usefulness , and acceptability to patients and clinicians . METHODS This was a single-arm prospect i ve study that enrolled breast and prostate cancer patients undergoing treatment and the clinicians who managed them . Patients completed patient-reported outcomes every 2 weeks , and clinicians could access the results for patient visits . Scores that were poor relative to norms or substantially worse than the previous assessment were highlighted . After three on- study visits , we assessed patient and clinician perspectives on PatientViewpoint using close-ended and open-ended questions . RESULTS Eleven out of 12 eligible clinicians ( 92 % ) and 52/76 eligible patients ( 68 % ) enrolled . Patients completed a median of 71 % of assigned question naires ; clinicians reported using the information for 79 % of patients , most commonly as a source of additional information ( 51 % ) . At the median , score reports identified three potential issues , of which 1 was discussed during the visit . Patients reported the system was easy to use ( 92 % ) , useful ( 70 % ) , aided recall of symptoms/side effects ( 72 % ) , helped them feel more in control of their care ( 60 % ) , improved discussion s with their provider ( 49 % ) , and improved care quality ( 39 % ) . Patients and clinicians desired more information on score interpretation and minor adjustments to site navigation . CONCLUSIONS These results support the feasibility and value of PatientViewpoint . An ongoing study is using a continuous quality improvement approach to further refine PatientViewpoint . Future studies will evaluate its impact on patient care and outcomes PURPOSE To examine the effects on process of care and patient well-being , of the regular collection and use of health-related quality -of-life ( HRQL ) data in oncology practice . PATIENTS AND METHODS In a prospect i ve study with repeated measures involving 28 oncologists , 286 cancer patients were r and omly assigned to either the intervention group ( regular completion of European Organization for Research and Treatment of Cancer-Core Quality of Life Question naire version 3.0 , and Hospital Anxiety and Depression Scale on touch-screen computers in clinic and feedback of results to physicians ) ; attention-control group ( completion of question naires , but no feedback ) ; or control group ( no HRQL measurement in clinic before encounters ) . Primary outcomes were patient HRQL over time , measured by the Functional Assessment of Cancer Therapy-General question naire , physician-patient communication , and clinical management , measured by content analysis of tape-recorded encounters . Analysis employed mixed-effects modeling and multiple regression . RESULTS Patients in the intervention and attention-control groups had better HRQL than the control group ( P = .006 and P = .01 , respectively ) , but the intervention and attention-control groups were not significantly different ( P = .80 ) . A positive effect on emotional well-being was associated with feedback of data ( P = .008 ) , but not with instrument completion ( P = .12 ) . A larger proportion of intervention patients showed clinical ly meaningful improvement in HRQL . More frequent discussion of chronic nonspecific symptoms ( P = .03 ) was found in the intervention group , without prolonging encounters . There was no detectable effect on patient management ( P = .60 ) . In the intervention patients , HRQL improvement was associated with explicit use of HRQL data ( P = .016 ) , discussion of pain , and role function ( P = .046 ) . CONCLUSION Routine assessment of cancer patients ' HRQL had an impact on physician-patient communication and result ed in benefits for some patients , who had better HRQL and emotional functioning The current study evaluated the efficacy of incorporating st and ardized health‐related quality of life ( HRQL ) assessment s as a routine part of the outpatient chemotherapy treatment of cancer patients in a community hospital in terms of : 1 ) facilitating nurse‐patient communication , 2 ) increasing nurses ' awareness of patients ' HRQL , 3 ) patient management , 4 ) patients ' satisfaction , and 5 ) patients ' HRQL CONTEXT There has been increasing interest in the use of health-related quality -of-life ( HRQL ) assessment s in daily clinical practice , yet few empirical studies have been conducted to evaluate the usefulness of such assessment s. OBJECTIVE To evaluate the efficacy of st and ardized HRQL assessment s in facilitating patient-physician communication and increasing physicians ' awareness of their patients ' HRQL-related problems . DESIGN Prospect i ve , r and omized crossover trial . SETTING Outpatient clinic of a cancer hospital in the Netherl and s. PARTICIPANTS Ten physicians and 214 patients ( 76 % women ; mean age , 57 years ) undergoing palliative chemotherapy who were invited to participate between June 1996 and June 1998 . INTERVENTION At 3 successive outpatient visits , patients completed an HRQL question naire ( European Organization for Research and Treatment of Cancer Quality of Life Question naire-Core 30 ) . The responses were computer scored and transformed into a graphic summary . Physicians and patients received a copy of the summary before the consultation . MAIN OUTCOME MEASURES Audiotapes of the consultations were content analyzed to evaluate patient-physician communication . Physicians ' awareness of their patients ' health problems was assessed by comparing physicians ' and patients ' ratings on the Dartmouth Primary Care Cooperative Information Functional Health Assessment ( COOP ) and the World Organisation Project of National Colleges and Academics ( WONCA ) charts . RESULTS The HRQL-related issues were discussed significantly more frequently in the intervention than in the control group ( mean [ SD ] communication composite scores : 4.5 [ 2.3 ] vs 3.7 [ 1.9 ] , respectively ( P = .01 ) . Physicians in the intervention group identified a greater percentage of patients with moderate-to-severe health problems in several HRQL domains than did those in the control group . All physicians and 87 % of the patients believed that the intervention facilitated communication and expressed interest in its continued use . CONCLUSION Incorporating st and ardized HRQL assessment s in daily clinical oncology practice facilitates the discussion of HRQL issues and can heighten physicians ' awareness of their patients ' HRQL The purpose of this paper was to determine if providing patient specific Quality of Life ( QL ) information to clinic staff before a clinic appointment improved patient care in a lung cancer outpatient clinic . Patients were sequentially assigned to either a usual care control group or the experimental group , which completed a computerized version of the European Organization for Research and Treatment of Cancer ( EORTC ) QLQ-C30 question naire in order to provide the clinic staff with QL information prior to the clinic appointment . The control group completed the EORTC QLQ-C30 paper version after the clinic appointment . Outcome measures were patient satisfaction , the degree to which issues identified on the QL question naire were addressed in the appointment , and a chart audit , which measured charting of QL issues and actions taken by the clincian relating to QL . In the experimental group , more QL issues identified by the patient on the EORTC QLQ-C30 were addressed during the clinic appointment than in the control group . As well , marginally more categories were charted and a trend towards more actions being taken was seen in the experimental group . Patients reported being equally and highly satisfied with the treatment in both groups . The clinical implication is that the computerized administration of the EORTC QLQ-C30 question naire and providing staff with a report highlighting patient-specific QL deficits is a simple , time-effective and acceptable means of improving patient-provider communication in a busy outpatient clinic . Large trials study ing its effectiveness in different patient population s and regions would further eluci date the nature of this effect and potentially improve the overall quality of care that patients receive PURPOSE Routinely collected patient-reported outcomes ( PROs ) could provide invaluable data to a patient-centered learning health system but are often highly missing in clinical trials . We analyzed our experience with PROs to underst and patterns of missing data using electronic collection as part of routine clinical care . METHODS This is an analysis of a prospect ively collected observational data base of electronic PROs captured as part of routine clinical care in four different outpatient oncology clinics at an academic referral center . RESULTS More than 24,000 clinical encounters from 7,655 unique patients are included . Data were collected via an electronic tablet-based survey instrument ( Patient Care Monitor , version 2.0 ) , at the time of clinical care , as part of routine care processes . Missing instruments ( ie , no items completed ) were su bmi tted for 6.8 % of clinical encounters , and 15.8 % of encounters had missing items . Nearly 90 % of all encounters involved < 10 % missing items . In multivariable analyses , younger age , private health insurance , being seen in the breast oncology clinic , less time spent on the instrument , and longitudinal care were significantly associated with less missingness . CONCLUSION Embedding collection of electronic PRO data into routine clinical care yielded low rates of missing data in this real-world , prospect ively collected data base . In contrast to clinical trial experience , missingness improve with longitudinal care . This approach may be a solution to minimizing missingness of PROs in research or clinical care setting s in support of learning health care systems |
13,761 | 29,637,172 | Conclusions Findings of this review show that implementation of NRT improves neonatal and perinatal mortality . | Background Training of birth attendants in neonatal resuscitation is likely to reduce birth asphyxia and neonatal mortality .
We performed a systematic review and meta- analysis to assess the impact of neonatal resuscitation training ( NRT ) programme in reducing stillbirths , neonatal mortality , and perinatal mortality . | Background Maternal and newborn mortality rates remain unacceptably high , especially where the majority of births occur in home setting s or in facilities with inadequate re sources . The introduction of emergency obstetric and newborn care services has been proposed by several organizations in order to improve pregnancy outcomes . However , the effectiveness of emergency obstetric and neonatal care services has never been proven . Also unproven is the effectiveness of community mobilization and community birth attendant training to improve pregnancy outcomes . Methods / Design We have developed a cluster-r and omized controlled trial to evaluate the impact of a comprehensive intervention of community mobilization , birth attendant training and improvement of quality of care in health facilities on perinatal mortality in low and middle-income countries where the majority of births take place in homes or first level care facilities . This trial will take place in 106 clusters ( 300 - 500 deliveries per year each ) across 7 sites of the Global Network for Women 's and Children 's Health Research in Argentina , Guatemala , India , Kenya , Pakistan and Zambia . The trial intervention has three key elements , community mobilization , home-based life saving skills for communities and birth attendants , and training of providers at obstetric facilities to improve quality of care . The primary outcome of the trial is perinatal mortality . Secondary outcomes include rates of stillbirth , 7-day neonatal mortality , maternal death or severe morbidity ( including obstetric fistula , eclampsia and obstetrical sepsis ) and 28-day neonatal mortality . Discussion In this trial , we are evaluating a combination of interventions including community mobilization and facility training in an attempt to improve pregnancy outcomes . If successful , the results of this trial will provide important information for policy makers and clinicians as they attempt to improve delivery services for pregnant women and newborns in low-income countries . Trial Registration Clinical Trials.gov BACKGROUND Neonatal deaths in developing countries make the largest contribution to global mortality in children younger than 5 years . 90 % of deliveries in the poorest quintile of households happen at home . We postulated that a community-based participatory intervention could significantly reduce neonatal mortality rates . METHODS We pair-matched 42 geopolitical clusters in Makwanpur district , Nepal , selected 12 pairs r and omly , and r and omly assigned one of each pair to intervention or control . In each intervention cluster ( average population 7000 ) , a female facilitator convened nine women 's group meetings every month . The facilitator supported groups through an action-learning cycle in which they identified local perinatal problems and formulated strategies to address them . We monitored birth outcomes in a cohort of 28?931 women , of whom 8 % joined the groups . The primary outcome was neonatal mortality rate . Other outcomes included stillbirths and maternal deaths , uptake of antenatal and delivery services , home care practice s , infant morbidity , and health-care seeking . Analysis was by intention to treat . The study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N31137309 . FINDINGS From 2001 to 2003 , the neonatal mortality rate was 26.2 per 1000 ( 76 deaths per 2899 livebirths ) in intervention clusters compared with 36.9 per 1000 ( 119 deaths per 3226 livebirths ) in controls ( adjusted odds ratio 0.70 [ 95 % CI 0.53 - 0.94 ] ) . Stillbirth rates were similar in both groups . The maternal mortality ratio was 69 per 100000 ( two deaths per 2899 livebirths ) in intervention clusters compared with 341 per 100000 ( 11 deaths per 3226 livebirths ) in control clusters ( 0.22 [ 0.05 - 0.90 ] ) . Women in intervention clusters were more likely to have antenatal care , institutional delivery , trained birth attendance , and hygienic care than were controls . INTERPRETATION Birth outcomes in a poor rural population improved greatly through a low cost , potentially sustainable and scalable , participatory intervention with women 's groups Background Fetal and neonatal mortality rates in low-income countries are at least 10-fold greater than in high-income countries . These differences have been related to poor access to and poor quality of obstetric and neonatal care . Methods This trial tested the hypothesis that teams of health care providers , administrators and local residents can address the problem of limited access to quality obstetric and neonatal care and lead to a reduction in perinatal mortality in intervention compared to control locations . In seven geographic areas in five low-income and one middle-income country , most with high perinatal mortality rates and substantial numbers of home deliveries , we performed a cluster r and omized non-masked trial of a package of interventions that included community mobilization focusing on birth planning and hospital transport , community birth attendant training in problem recognition , and facility staff training in the management of obstetric and neonatal emergencies . The primary outcome was perinatal mortality at ≥28 weeks gestation or birth weight ≥1000 g. Results Despite extensive effort in all sites in each of the three intervention areas , no differences emerged in the primary or any secondary outcome between the intervention and control clusters . In both groups , the mean perinatal mortality was 40.1/1,000 births ( P = 0.9996 ) . Neither were there differences between the two groups in outcomes in the last six months of the project , in the year following intervention cessation , nor in the clusters that best implemented the intervention . Conclusions This cluster r and omized comprehensive , large-scale , multi-sector intervention did not result in detectable impact on the proposed outcomes . While this does not negate the importance of these interventions , we expect that achieving improvement in pregnancy outcomes in these setting s will require substantially more obstetric and neonatal care infrastructure than was available at the sites during this trial , and without them provider training and community mobilization will not be sufficient . Our results highlight the critical importance of evaluating outcomes in r and omized trials , as interventions that should be effective may not be . Trial registration Clinical Trials.gov OBJECTIVE : Poor communication and teamwork may contribute to errors during neonatal resuscitation . Our objective was to evaluate whether interns who received a 2-hour teamwork training intervention with the Neonatal Resuscitation Program ( NRP ) demonstrated more teamwork and higher quality resuscitations than control subjects . METHODS : Participants were noncertified 2007 and 2008 incoming interns for pediatrics , combined pediatrics and internal medicine , family medicine , emergency medicine , and obstetrics and gynecology ( n = 98 ) . Pediatrics and combined pediatrics/internal medicine interns were eligible for 6-month follow-up ( n = 34 ) . A r and omized trial was conducted in which half of the participants in the team training arm practice d NRP skills by using high-fidelity simulators ; the remaining practice d with low-fidelity simulators , as did control subjects . Blinded , trained observers viewed video recordings of high-fidelity – simulated resuscitations for teamwork and resuscitation quality . RESULTS : High-fidelity training ( HFT ) group had higher teamwork frequency than did control subjects ( 12.8 vs 9.0 behaviors per minute ; P < .001 ) . Intervention groups maintained more workload management ( control subjects : 89.3 % ; low-fidelity training [ LFT ] group : 98.0 % [ P < .001 ] ; HFT group : 98.8 % ; HFT group versus control subjects [ P < .001 ] ) and completed resuscitations faster ( control subjects : 10.6 minutes ; LFT group : 8.6 minutes [ P = .040 ] ; HFT group : 7.4 minutes ; HFT group versus control subjects [ P < .001 ] ) . Overall , intervention teams completed the resuscitation an average of 2.6 minutes faster than did control subjects , a time reduction of 24 % ( 95 % confidence interval : 12%–37 % ) . Intervention groups demonstrated more frequent teamwork during 6-month follow-up resuscitations ( 11.8 vs 10.0 behaviors per minute ; P = .030 ) . CONCLUSIONS : Trained participants exhibited more frequent teamwork behaviors ( especially the HFT group ) and better workload management and completed the resuscitation more quickly than did control subjects . The impact on team behaviors persisted for at least 6 months . Incorporating team training into the NRP curriculum is a feasible and effective way to teach interns teamwork skills . It also improves simulated resuscitation quality by shortening the duration BACKGROUND Two recent trials have shown that women 's groups can reduce neonatal mortality in poor communities . We assessed the effectiveness of a scaled-up development programme with women 's groups to address maternal and neonatal care in three rural districts of Bangladesh . METHODS 18 clusters ( with a mean population of 27 953 [ SD 5953 ] ) in three districts were r and omly assigned to either intervention or control ( nine clusters each ) by use of stratified r and omisation . For each district , cluster names were written on pieces of paper , which were folded and placed in a bottle . The first three cluster names drawn from the bottle were allocated to the intervention group and the remaining three to control . All clusters received health services strengthening and basic training of traditional birth attendants . In intervention clusters , a facilitator convened 18 groups every month to support participatory action and learning for women , and to develop and implement strategies to address maternal and neonatal health problems . Women were eligible to participate if they were aged 15 - 49 years , residing in the project area , and had given birth during the study period ( Feb 1 , 2005 , to Dec 31 , 2007 ) . Neither study investigators nor participants were masked to treatment assignment . In a population of 229 195 people ( intervention clusters only ) , 162 women 's groups provided coverage of one group per 1414 population . The primary outcome was neonatal mortality rate ( NMR ) . Analysis was by intention to treat . This trial is registered as an International St and ard R and omised Controlled Trial , number IS RCT N54792066 . FINDINGS We monitored outcomes for 36 113 births ( intervention clusters , n=17 514 ; control clusters , n=18 599 ) in a population of 503 163 over 3 years . From 2005 to 2007 , there were 570 neonatal deaths in the intervention clusters and 656 in the control clusters . Cluster-level mean NMR ( adjusted for stratification and clustering ) was 33.9 deaths per 1000 livebirths in the intervention clusters compared with 36.5 per 1000 in the control clusters ( risk ratio 0.93 , 95 % CI 0.80 - 1.09 ) . INTERPRETATION For participatory women 's groups to have a significant effect on neonatal mortality in rural Bangladesh , detailed attention to programme design and context ual factors , enhanced population coverage , and increased enrolment of newly pregnant women might be needed . FUNDING Women and Children First , the UK Big Lottery Fund , Saving Newborn Lives , and the UK Department for International Development OBJECTIVE To evaluate the effectiveness of an educational intervention on pediatric residents ' resuscitation fund of knowledge , technical skills , confidence , and overall performance . DESIGN Prospect i ve , nonconcurrent , controlled interventional trial . SETTING Urban pediatric tertiary care hospital . PARTICIPANTS An intervention group ( IG ) of 28 pediatric residents graduating in 1997 , and a control group ( CG ) of 30 pediatric residents graduating in 1996 . INTERVENTIONS Resuscitation course with didactic lectures and skills practice stations , as well as a minimum of 3 practice mock resuscitations with immediate feedback throughout postgraduate year 3 . MAIN OUTCOME MEASURES Fund of knowledge , using the Pediatric Advanced Life Support test and short answer test ; technical skills , using the Airway and Vascular Access Skills Assessment ; experience and confidence , using an anonymous survey ; and overall performance , evaluated using a videotaped mock resuscitation test . RESULTS The IG scored better on the short answer test ( P<.001 ) . A larger number of IG residents were successful in the completion of ancillary airway maneuvers and femoral vascular access ( P = .02 ) , as well as endotracheal intubation ( P = .004 ) and intraosseous access ( P = .002 ) . The IG was more confident in their leadership role ( P = .0001 ) and technical skills ( P = .05 ) . Trends toward improved overall performance were noted for the IG mock resuscitations . Residents in the IG were more likely to assess the airway in fewer than 2 minutes ( P = .02 ) , recognize the threat to life in fewer than 5 minutes ( P = .02 ) , and complete the primary survey in a timely fashion ( P = .05 ) . They required fewer prompts ( P = .04 ) and made fewer mistakes ( P = .07 ) . CONCLUSIONS A structured , formal curriculum can improve the necessary fund of knowledge , skills , confidence , and leadership required for resuscitation Objective : To add a team training and human error curriculum to the Neonatal Resuscitation Program ( NRP ) and measure its effect on teamwork . We hypothesized that teams that received the new course would exhibit more teamwork behaviors than those in the st and ard NRP course . Study design : Interns were r and omized to receive NRP with team training or st and ard NRP , then video recorded when they performed simulated resuscitations at the end of the day-long course . Outcomes were assessed by observers blinded to study arm allocation and included the frequency or duration of six team behaviors : inquiry , information sharing , assertion , evaluation of plans , workload management and vigilance . Result : The interns in the NRP with team training group exhibited more frequent team behaviors ( number of episodes per minute ( 95 % CI ) ) than interns in the control group : information sharing 1.06 ( 0.24 , 1.17 ) vs 0.13 ( 0.00 , 0.43 ) ; inquiry 0.35 ( 0.11 , 0.42 ) vs 0.09 ( 0.00 , 0.10 ) ; assertion 1.80 ( 1.21 , 2.25 ) vs 0.64 ( 0.26 , 0.91 ) ; and any team behavior 3.34 ( 2.26 , 4.11 ) vs 1.03 ( 0.48 , 1.30 ) ( P-values < 0.008 for all comparisons ) . Vigilance and workload management were practice d throughout the entire simulated code by nearly all the teams in the NRP with team training group ( 100 % for vigilance and 88 % for workload management ) vs only 53 and 20 % of the teams in the st and ard NRP . No difference was detected in the frequency of evaluation of plans . Conclusion : Compared with the st and ard NRP , NRP with a teamwork and human error curriculum led interns to exhibit more team behaviors during simulated resuscitations Background Neonatal deaths account for over 40 % of all under-5 year deaths ; their reduction is increasingly critical for achieving Millennium Development Goal 4 . An estimated 3 million newborns die annually during their first month of life ; half of these deaths occur during delivery or within 24 hours . Every year , 6 million babies require help to breathe immediately after birth . Resuscitation training to help babies breathe and prevent/manage birth asphyxia is not routine in low-middle income facility setting s. Helping Babies Breathe ( HBB ) , a simulation-training program for babies wherever they are born , was developed for use in low-middle income countries . We evaluated whether HBB training of facility birth attendants reduces perinatal mortality in the Eunice Kennedy Shriver National Institute of Child Health and Human Development ’s Global Network research sites . Methods / design We hypothesize that a two-year prospect i ve pre-post study to evaluate the impact of a facility-based training package , including HBB and essential newborn care , will reduce all perinatal mortality ( fresh stillbirth or neonatal death prior to 7 days ) among the Global Network ’s Maternal Neonatal Health Registry births ≥1500 grams in the study clusters served by the facilities . We will also evaluate the effectiveness of the HBB training program changing on facility-based perinatal mortality and resuscitation practice s. Seventy-one health facilities serving 52 geographically-defined study clusters in Belgaum and Nagpur , India , and Eldoret , Kenya , and 30,000 women will be included . Primary outcome data will be collected by staff not involved in the HBB intervention . Additional data on resuscitations , resuscitation debriefings , death audits , quality monitoring and improvement will be collected . HBB training will include training of MTs , facility level birth attendants , and quality monitoring and improvement activities . Discussion Our study will evaluate the effect of a HBB/ENC training and quality monitoring and improvement package on perinatal mortality using a large multicenter design and approach in 71 re source -limited health facilities , leveraging an existing birth registry to provide neonatal outcomes through day 7 . The study will provide the evidence base , lessons learned , and best practice s that will be essential to guiding future policy and investment in neonatal resuscitation . Trial registration Trial registration Clinical Trials.gov Identifier : OBJECTIVE : This study evaluated the effectiveness of Helping Babies Breathe ( HBB ) newborn care and resuscitation training for birth attendants in reducing stillbirth ( SB ) , and predischarge and neonatal mortality ( NMR ) . India contributes to a large proportion of the worlds annual 3.1 million neonatal deaths and 2.6 million SBs . METHODS : This prospect i ve study included 4187 births at > 28 weeks ’ gestation before and 5411 births after HBB training in Karnataka . A total of 599 birth attendants from rural primary health centers and district and urban hospitals received HBB training developed by the American Academy of Pediatrics , using a train-the-trainer cascade . Pre-post written trainee knowledge , posttraining provider performance and skills , SB , predischarge mortality , and NMR before and after HBB training were assessed by using χ2 and t-tests for categorical and continuous variables , respectively . Backward stepwise logistic regression analysis adjusted for potential confounding . RESULTS : Provider knowledge and performance systematic ally improved with HBB training . HBB training reduced resuscitation but increased assisted bag and mask ventilation incidence . SB declined from 3.0 % to 2.3 % ( odds ratio [ OR ] 0.76 , 95 % confidence interval [ CI ] 0.59–0.98 ) and fresh SB from 1.7 % to 0.9 % ( OR 0.54 , 95 % CI 0.37–0.78 ) after HBB training . Predischarge mortality was 0.1 % in both periods . NMR was 1.8 % before and 1.9 % after HBB training ( OR 1.09 , 95 % CI 0.80–1.47 , P = .59 ) but unknown status at 28 days was 2 % greater after HBB training ( P = .007 ) . CONCLUSIONS : HBB training reduced SB without increasing NMR , indicating that resuscitated infants survived the neonatal period . Monitoring and community-based assessment are recommended Background Whether facility-based implementation of Helping Babies Breathe ( HBB ) reduces neonatal mortality at a population level in low and middle income countries ( LMIC ) has not been studied . Therefore , we evaluated HBB implementation in this context where our study team has ongoing prospect i ve outcome data on all pregnancies regardless of place of delivery . Methods We compared outcomes of birth cohorts in three sites in India and Kenya pre-post implementation of a facility-based intervention , using a prospect i ve , population -based registry in 52 geographic clusters . Our hypothesis was that HBB implementation would result in a 20 % decrease in the perinatal mortality rate ( PMR ) among births ≥1500 g. Results We enrolled 70,704 births during two 12-month study periods . Births within each site did not differ pre-post intervention , except for an increased proportion of < 2500 g newborns and deliveries by caesarean section in the post period . There were no significant differences in PMR among all registry births ; however , a post-hoc analysis stratified by birthweight documented improvement in < 2500 g mortality in Belgaum in both registry and in HBB-trained facility births . No improvement in < 2500 g mortality measures was noted in Nagpur or Kenya and there was no improvement in normal birth weight survival . Conclusions Rapid scale up of HBB training of facility birth attendants in three diverse sites in India and Kenya was not associated with consistent improvements in mortality among all neonates ≥1500 g ; however , differential improvements in < 2500 g survival in Belgaum suggest the need for careful implementation of HBB training with attention to the target population , data collection , and ongoing quality monitoring activities . Trial registration The study was registered at Clinical Trials.gov : NCT01681017 BACKGROUND In rural India , most births take place in the home , where high-risk care practice s are common . We developed an intervention of behaviour change management , with a focus on prevention of hypothermia , aim ed at modifying practice s and reducing neonatal mortality . METHODS We did a cluster-r and omised controlled efficacy trial in Shivgarh , a rural area in Uttar Pradesh . 39 village administrative units ( population 104,123 ) were allocated to one of three groups : a control group , which received the usual services of governmental and non-governmental organisations in the area ; an intervention group , which received a preventive package of interventions for essential newborn care ( birth preparedness , clean delivery and cord care , thermal care [ including skin-to-skin care ] , breastfeeding promotion , and danger sign recognition ) ; or another intervention group , which received the package of essential newborn care plus use of a liquid crystal hypothermia indicator ( ThermoSpot ) . In the intervention clusters , community health workers delivered the packages via collective meetings and two antenatal and two postnatal household visitations . Outcome measures included changes in newborn-care practice s and neonatal mortality rate compared with the control group . Analysis was by intention to treat . This study is registered as International St and ard R and omised Control Trial , number NCT00198653 . FINDINGS Improvements in birth preparedness , hygienic delivery , thermal care ( including skin-to-skin care ) , umbilical cord care , skin care , and breastfeeding were seen in intervention arms . There was little change in care-seeking . Compared with controls , neonatal mortality rate was reduced by 54 % in the essential newborn-care intervention ( rate ratio 0.46 [ 95 % CI 0.35 - 0.60 ] , p<0.0001 ) and by 52 % in the essential newborn care plus ThermoSpot arm ( 0.48 [ 95 % CI 0.35 - 0.66 ] , p<0.0001 ) . INTERPRETATION A socioculturally context ualised , community-based intervention , targeted at high-risk newborn-care practice s , can lead to substantial behavioural modification and reduction in neonatal mortality . This approach can be applied to behaviour change along the continuum of care , harmonise vertical interventions , and build community capacity for sustained development . FUNDING USAID and Save the Children-US through a grant from the Bill & Melinda Gates Foundation OBJECTIVE : The goal was to determine the effect of training in newborn care and resuscitation on 7-day ( early ) neonatal mortality rates for very low birth weight ( VLBW ) infants . The study was design ed to test the hypothesis that these training programs would reduce neonatal mortality rates for VLBW infants . METHODS : Local instructors trained birth attendants from 96 rural communities in 6 developing countries in protocol and data collection , the World Health Organization Essential Newborn Care ( ENC ) course , and a modified version of the American Academy of Pediatrics Neonatal Resuscitation Program ( NRP ) , by using a train-the-trainer model . To test the impact of ENC training , data on infants of 500 to 1499 g were collected by using a before/after , active baseline , controlled study design . A cluster-r and omized , controlled trial design was used to test the impact of the NRP . RESULTS : A total of 1096 VLBW ( 500–1499 g ) infants were enrolled , and 98.5 % of live-born infants were monitored to 7 days . All-cause , 7-day neonatal mortality , stillbirth , and perinatal mortality rates were not affected by ENC or NRP training . CONCLUSIONS : Neither ENC nor NRP training of birth attendants decreased 7-day neonatal , stillbirth , or perinatal mortality rates for VLBW infants born at home or at first-level facilities . Encouragement of delivery in a facility where a higher level of care is available may be preferable when delivery of a VLBW infant is expected BACKGROUND Newborn deaths account for 57 % of deaths in children younger than 5 years in Pakistan . Although a large programme of trained lady health workers ( LHWs ) exists , the effectiveness of this training on newborn outcomes has not been studied . We aim ed to evaluate the effectiveness of a community-based intervention package , principally delivered through LHWs working with traditional birth attendants and community health committees , for reduction of perinatal and neonatal mortality in a rural district of Pakistan . METHODS We undertook a cluster r and omised trial between February , 2006 , and March , 2008 , in Hala and Matiari subdistricts , Pakistan . Catchment areas of primary care facilities and all affiliated LHWs were used to define clusters , which were allocated to intervention and control groups by restricted , stratified r and omisation . The intervention package delivered by LHWs through group sessions consisted of promotion of antenatal care and maternal health education , use of clean delivery kits , facility births , immediate newborn care , identification of danger signs , and promotion of careseeking ; control clusters received routine care . Independent data collectors undertook quarterly household surveillance to capture data for births , deaths , and household practice s related to maternal and newborn care . Data collectors were masked to cluster allocation ; those analysing data were not . The primary outcome was perinatal and all-cause neonatal mortality . Analysis was by intention to treat . This trial is registered , IS RCT N16247511 . FINDINGS 16 clusters were assigned to intervention ( 23,353 households , 12,391 total births ) and control groups ( 23,768 households , 11,443 total births ) . LHWs in the intervention clusters were able to undertake 4428 ( 63 % ) of 7084 planned group sessions , but were only able to visit 2943 neonates ( 24 % ) of a total 12,028 livebirths in their catchment villages . Stillbirths were reduced in intervention clusters ( 39·1 stillbirths per 1000 total births ) compared with control ( 48·7 per 1000 ; risk ratio [ RR ] 0·79 , 95 % CI 0·68 - 0·92 ; p=0·006 ) . The neonatal mortality rate was 43·0 deaths per 1000 livebirths in intervention clusters compared with 49·1 per 1000 in control groups ( RR 0·85 , 0·76 - 0·96 ; p=0·02 ) . INTERPRETATION Our results support the scale-up of preventive and promotive maternal and newborn interventions through community health workers and emphasise the need for attention to issues of programme management and coverage for such initiatives to achieve maximum potential . FUNDING WHO ; Saving Newborn Lives Program of Save the Children USA , funded by the Bill & Melinda Gates Foundation BACKGROUND Community mobilisation through participatory women 's groups might improve birth outcomes in poor rural communities . We therefore assessed this approach in a largely tribal and rural population in three districts in eastern India . METHODS From 36 clusters in Jharkh and and Orissa , with an estimated population of 228 186 , we assigned 18 clusters to intervention or control using stratified r and omisation . Women were eligible to participate if they were aged 15 - 49 years , residing in the project area , and had given birth during the study . In intervention clusters , a facilitator convened 13 groups every month to support participatory action and learning for women , and facilitated the development and implementation of strategies to address maternal and newborn health problems . The primary outcomes were reductions in neonatal mortality rate ( NMR ) and maternal depression scores . Analysis was by intention to treat . This trial is registered as an International St and ard R and omised Controlled Trial , number IS RCT N21817853 . FINDINGS After baseline surveillance of 4692 births , we monitored outcomes for 19 030 births during 3 years ( 2005 - 08 ) . NMRs per 1000 were 55.6 , 37.1 , and 36.3 during the first , second , and third years , respectively , in intervention clusters , and 53.4 , 59.6 , and 64.3 , respectively , in control clusters . NMR was 32 % lower in intervention clusters adjusted for clustering , stratification , and baseline differences ( odds ratio 0.68 , 95 % CI 0.59 - 0.78 ) during the 3 years , and 45 % lower in years 2 and 3 ( 0.55 , 0.46 - 0.66 ) . Although we did not note a significant effect on maternal depression overall , reduction in moderate depression was 57 % in year 3 ( 0.43 , 0.23 - 0.80 ) . INTERPRETATION This intervention could be used with or as a potential alternative to health-worker-led interventions , and presents new opportunities for policy makers to improve maternal and newborn health outcomes in poor population s. FUNDING Health Foundation , UK Department for International Development , Wellcome Trust , and the Big Lottery Fund ( UK ) Background Birth asphyxia kills 0.7 to 1.6 million newborns a year globally with 99 % of deaths in developing countries . Effective newborn resuscitation could reduce this burden of disease but the training of health-care providers in low income setting s is often out date d. Our aim was to determine if a simple one day newborn resuscitation training ( NRT ) alters health worker resuscitation practice s in a public hospital setting in Kenya . Methods /Principal Findings We conducted a r and omised , controlled trial with health workers receiving early training with NRT ( n = 28 ) or late training ( the control group , n = 55 ) . The training was adapted locally from the approach of the UK Resuscitation Council . The primary outcome was the proportion of appropriate initial resuscitation steps with the frequency of inappropriate practice s as a secondary outcome . Data were collected on 97 and 115 resuscitation episodes over 7 weeks after early training in the intervention and control groups respectively . Trained providers demonstrated a higher proportion of adequate initial resuscitation steps compared to the control group ( trained 66 % vs control 27 % ; risk ratio 2.45 , [ 95 % CI 1.75–3.42 ] , p<0.001 , adjusted for clustering ) . In addition , there was a statistically significant reduction in the frequency of inappropriate and potentially harmful practice s per resuscitation in the trained group ( trained 0.53 vs control 0.92 ; mean difference 0.40 , [ 95 % CI 0.13–0.66 ] , p = 0.004 ) . Conclusions / Significance Implementation of a simple , one day newborn resuscitation training can be followed immediately by significant improvement in health workers ' practice s. However , evidence of the effects on long term performance or clinical outcomes can only be established by larger cluster r and omised trials . Trial Registration Controlled-Trials.com IS RCT Background In many developing countries , the majority of births are attended by traditional birth attendants , who lack formal training in neonatal resuscitation and other essential care required by the newly born infant . In these countries , the major causes of neonatal mortality are birth asphyxia , infection , and low-birth-weight/prematurity . Death from these causes is potentially modifiable using low-cost interventions , including neonatal resuscitation training . The purpose of this study was to evaluate the effect on perinatal mortality of training birth attendants in a rural area of the Democratic Republic of Congo ( DRC ) using two established programs . Methods This study , a secondary analysis of DRC-specific data collected during a multi-country study , was conducted in two phases . The effect of training using the WHO Essential Newborn Care ( ENC ) program was evaluated using an active baseline design , followed by a cluster r and omized trial of training using an adaptation of a neonatal resuscitation program ( NRP ) . The perinatal mortality rates before ENC , after ENC training , and after r and omization to additional NRP training or continued care were compared . In addition , the influence of time following resuscitation training was investigated by examining change in perinatal mortality during sequential three-month increments following ENC training . Results More than two-thirds of deliveries were attended by traditional birth attendants and occurred in homes ; these proportions decreased after ENC training . There was no apparent decline in perinatal mortality when the outcome of all deliveries prior to ENC training was compared to those after ENC but before NRP training . However , there was a gradual but significant decline in perinatal mortality during the year following ENC training ( RR 0.73 ; 95 % CI : 0.56 - 0.96 ) , which was independently associated with time following training . The decline was attributable to a decline in early neonatal mortality . NRP training had no demonstrable effect on early neonatal mortality . Conclusion Training DRC birth attendants using the ENC program reduces perinatal mortality . However , a period of utilization and re-enforcement of training may be necessary before a decline in mortality occurs . ENC training has the potential to be a low cost , high impact intervention in developing countries . Trial registration This trial has been registered at http://www . clinical trials.gov ( identifier NCT00136708 ) Objective To determine whether training traditional birth attendants to manage several common perinatal conditions could reduce neonatal mortality in the setting of a re source poor country with limited access to healthcare . Design Prospect i ve , cluster r and omised and controlled effectiveness study . Setting Lufwanyama , an agrarian , poorly developed district located in the Copperbelt province , Zambia . All births carried out by study birth attendants occurred at mothers ’ homes , in rural village setting s. Participants 127 traditional birth attendants and mothers and their newborns ( 3559 infants delivered regardless of vital status ) from Lufwanyama district . Interventions Using an unblinded design , birth attendants were cluster r and omised to intervention or control groups . The intervention had two components : training in a modified version of the neonatal resuscitation protocol , and single dose amoxicillin coupled with facilitated referral of infants to a health centre . Control birth attendants continued their existing st and ard of care ( basic obstetric skills and use of clean delivery kits ) . Main outcome measures The primary outcome was the proportion of liveborn infants who died by day 28 after birth , with rate ratios statistically adjusted for clustering . Secondary outcomes were mortality at different time points ; and comparison of causes of death based on verbal autopsy data . Results Among 3497 deliveries with reliable information , mortality at day 28 after birth was 45 % lower among liveborn infants delivered by intervention birth attendants than control birth attendants ( rate ratio 0.55 , 95 % confidence interval 0.33 to 0.90 ) . The greatest reductions in mortality were in the first 24 hours after birth : 7.8 deaths per 1000 live births for infants delivered by intervention birth attendants compared with 19.9 per 1000 for infants delivered by control birth attendants ( 0.40 , 0.19 to 0.83 ) . Deaths due to birth asphyxia were reduced by 63 % among infants delivered by intervention birth attendants ( 0.37 , 0.17 to 0.81 ) and by 81 % within the first two days after birth ( 0.19 , 0.07 to 0.52 ) . Stillbirths and deaths from serious infection occurred at similar rates in both groups . Conclusions Training traditional birth attendants to manage common perinatal conditions significantly reduced neonatal mortality in a rural African setting . This approach has high potential to be applied to similar setting s with dispersed rural population s. Trial registration Clinical trials.gov NCT00518856 OBJECTIVE To evaluate an intervention package promoting effective neonatal resuscitation training at county level hospitals across China . METHODS The intervention package was implemented across 4 counties and included expert seminars , training workshops , establishment of hospital-based resuscitation teams , and supervision of training by national and provincial instructors . Upon completing the activities , a survey was conducted in all county hospitals in the 4 intervention counties and 4 r and omly selected control counties . Data on healthcare providers ' knowledge and self-confidence , and incidence of deaths from birth asphyxia from 2009 to 2011 in all hospitals were collected and compared between the two groups . RESULTS Eleven intervention and eleven control hospitals participated in the evaluation , with 97 and 87 health providers , respectively , completing the question naire survey . Over 90 % of intervention hospitals had implemented neonatal resuscitation related practice protocol s , while in control hospitals the proportion was less than 55 % . The average knowledge scores of health providers in the intervention and control counties taking a written exam were 9.2±1.2 and 8.4±1.5 , respectively ( P<0.001 ) out of maximum possible score of 10 , and the average self-confidence scores were 57.3±2.5 and 54.1±8.2 , respectively ( P<0.001 ) . Incidence of birth asphyxia ( defined as 1-min Apgar score≤7 ) decreased from 8.8 % to 6.0 % ( P<0.001 ) in the intervention counties , and asphyxia-related deaths in the delivery room decreased from 27.6 to 5.0 per 100,000 ( P=0.076 ) . There was no difference over time in asphyxia rates for the control counties . CONCLUSIONS The intervention has not only improved skills of health providers , decreased the mortality and morbidity of birth asphyxia , but also result ed in effective implementation of guidelines and protocol s within hospitals The neonatal resuscitation program ( NRP ) has been developed to educate physicians and other health care providers about newborn resuscitation and has been shown to improve neonatal resuscitation skills . Simulation-based training is recommended as an effective modality for instructing neonatal resuscitation and both low and high-fidelity manikin simulators are used . There is limited research that has compared the effect of low and high-fidelity manikin simulators for NRP learning outcomes , and more specifically on teamwork performance and confidence . The purpose of this study was to examine the effect of using low versus high-fidelity manikin simulators in NRP instruction . A r and omized posttest-only control group study design was conducted . Third year undergraduate medical students participated in NRP instruction and were assigned to an experimental group ( high-fidelity manikin simulator ) or control group ( low-fidelity manikin simulator ) . Integrated skills station ( megacode ) performance , participant satisfaction , confidence and teamwork behaviour scores were compared between the study groups . Participants in the high-fidelity manikin simulator instructional group reported significantly higher total scores in overall satisfaction ( p = 0.001 ) and confidence ( p = 0.001 ) . There were no significant differences in teamwork behaviour scores , as observed by two independent raters , nor differences on m and atory integrated skills station performance items at the p < 0.05 level . Medical students ’ reported greater satisfaction and confidence with high-fidelity manikin simulators , but did not demonstrate overall significantly improved teamwork or integrated skills station performance . Low and high-fidelity manikin simulators facilitate similar levels of objective ly measured NRP outcomes for integrated skills station and teamwork performance OBJECTIVE To evaluate the management of prolonged labor and neonatal care before and after Advanced Life Support in Obstetrics ( ALSO ) training . METHODS Staff involved in childbirth at Kagera Regional Hospital , Tanzania , attended a 2-day ALSO provider course . In this prospect i ve intervention study conducted between July and November 2008 , the management and outcomes of 558 deliveries before and 550 after the training were observed . RESULTS There was no significant difference in the rate of cesarean deliveries owing to prolonged labor , and vacuum delivery was not practice d after the intervention . During prolonged labor , action was delayed for more than 3 hours in half of the cases . The stillbirth rate , Apgar scores , and frequency of neonatal resuscitation did not change significantly . After the intervention , there was a significant increase in newborns given to their mothers within 10 minutes , from 5.6 % to 71.5 % ( RR 12.71 ; 95 % CI , 9.04 - 17.88 ) . There was a significant decrease from 6 to 0 neonatal deaths before discharge among those born with an Apgar score after 1 minute of 4 or more ( P=0.03 ) . CONCLUSION ALSO training had no effect on the management of prolonged labor . Early contact between newborn and mother was more frequently practice d after ALSO training and the immediate neonatal mortality decreased INTRODUCTION The neonatal resuscitation programme ( NRP ) published by the American Academy of Paediatrics and American Heart Association was launched in Malaysia in 1996 . This study aim ed to review the outcome of NRP in Malaysia during the first eight years . METHODS Information on basic demographical data and training activities of NRP providers were collected prospect ively from NRP instructors from all over Malaysia during the eight years following the inception of the NRP . The national perinatal and neonatal mortality data during the five-year period before and eight years following implementation of the NRP were compared . RESULTS During the eight years following the launch , 14,575 personnel were trained . 40 percent of NRP-certified personnel worked in areas where delivery services were provided , viz . labour room , operation theatre , obstetric ward , emergency department and maternal and child health clinic . There were very few NRP-certified providers working in emergency departments and most of them were medical assistants . Most of the providers working in neonatal intensive care units ( NICUs ) and labour rooms were nurses while those in paediatric wards were doctors . All NRP-certified doctors working in NICUs and labour rooms obtained full certificates . Only 80 percent of NRP-certified nurses in these two areas obtained full certificates . There was further serial decrease in perinatal mortality and neonatal mortality rates in Malaysia during the years following the launch of the NRP programme . CONCLUSION The launch of the Malaysian NRP was associated with further improvement in perinatal and neonatal mortality rates BACKGROUND In previous studies , it has been demonstrated that Neonatal Resuscitation Program ( NRP ) courses improve the early outcomes of infants with perinatal asphyxia , but there has been no evidence to demonstrate the effect of NRP on long-term outcomes of perinatal asphyxia . The goal of the present study was to determine the effect of NRP courses on the long-term neurodevelopmental outcome of perinatal asphyxia . METHODS This prospect i ve study included infants referred to the Neonatal Unit during the years 2003 - 2005 . Those patients who were referred before NRP courses ( pretraining period ) were design ated as group 1 , those who were referred after the first NRP course ( transition period ) as group 2 , and those who were referred after the second NRP course ( post-training period ) as group 3 . Neurodevelopmental outcomes were assessed and compared at 4 - 6 years of age . RESULTS The study involved 40 patients : 23 in group 1 , nine in group 2 and eight in group 3 . The number of patients who had been diagnosed with cerebral palsy was 13 in group 1 , two in group 2 , and one in group 3 , which was a significant decrease . The number of patients with seizures and electroencephalography abnormality was 12 and 14 in group 1 , three and two in group 2 , and one and one in group 3 , respectively , which was also a significant decrease . CONCLUSIONS NRP courses have positive effects on short-term as well as long-term neurodevelopmental outcomes of infants with perinatal asphyxia . Further studies are required to determine the effects of NRP courses on minor deficits , such as cognitive and behavioral disturbances BACKGROUND Of the 3.7 million neonatal deaths and 3.3 million stillbirths each year , 98 % occur in developing countries . An evaluation of community-based interventions design ed to reduce the number of these deaths is needed . METHODS With the use of a train-the-trainer model , local instructors trained birth attendants from rural communities in six countries ( Argentina , Democratic Republic of Congo , Guatemala , India , Pakistan , and Zambia ) in the World Health Organization Essential Newborn Care course ( which focuses on routine neonatal care , resuscitation , thermoregulation , breast-feeding , " kangaroo " [ skin-to-skin ] care , care of the small baby , and common illnesses ) and ( except in Argentina ) in a modified version of the American Academy of Pediatrics Neonatal Resuscitation Program ( which teaches basic resuscitation in depth ) . The Essential Newborn Care intervention was assessed among 57,643 infants with the use of a before- and -after design . The Neonatal Resuscitation Program intervention was assessed as a cluster-r and omized , controlled trial involving 62,366 infants . The primary outcome was neonatal death in the first 7 days after birth . RESULTS The 7-day follow-up rate was 99.2 % . After birth attendants were trained in the Essential Newborn Care course , there was no significant reduction from baseline in the rate of neonatal death from all causes in the 7 days after birth ( relative risk with training , 0.99 ; 95 % confidence interval [ CI ] , 0.81 to 1.22 ) or in the rate of perinatal death ; there was a significant reduction in the rate of stillbirth ( relative risk with training , 0.69 ; 95 % CI , 0.54 to 0.88 ; P=0.003 ) . In clusters of births in which attendants had been r and omly assigned to receive training in the Neonatal Resuscitation Program , as compared with control clusters , there was no reduction in the rates of neonatal death in the 7 days after birth , stillbirth , or perinatal death . CONCLUSIONS The rate of neonatal death in the 7 days after birth did not decrease after the introduction of Essential Newborn Care training of community-based birth attendants , although the rate of stillbirths was reduced . Subsequent training in the Neonatal Resuscitation Program did not significantly reduce the mortality rates . ( Clinical Trials.gov number , NCT00136708 . BACKGROUND In 2009 , on the basis of promising evidence from trials in south Asia , WHO and UNICEF issued a joint statement about home visits as a strategy to improve newborn survival . In the Newhints trial , we aim ed to test this home-visits strategy in sub-Saharan Africa by assessing the effect on all-cause neonatal mortality rate ( NMR ) and essential newborn-care practice s. METHODS The Newhints cluster r and omised trial was undertaken in 98 zones in seven districts in the Brong Ahafo Region , Ghana . 49 zones were r and omly assigned to the Newhints intervention and 49 to the control intervention by use of restricted r and omisation with stratification to ensure comparability between interventions . Community-based surveillance volunteers ( CBSVs ) in Newhints zones were trained to identify pregnant women in their community and to make two home visits during pregnancy and three in the first week of life to promote essential newborn-care practice s , weigh and assess babies for danger signs , and refer as necessary . Primary outcomes were NMR and coverage of key essential newborn-care practice s. Analyses were by intention to treat . This study is registered with Clinical Trials.gov , number NCT00623337 . FINDINGS 16,168 ( 99 % ) of 16,329 deliveries between November , 2008 , and December , 2009 , were livebirths ; the status at 1 month was known for 15,619 ( 97 % ) livebirths . 482 neonatal deaths were recorded . Coverage data were available from 6029 women in Newhints zones ; of these 4358 ( 72 % ) reported having CBSV visits during pregnancy and 3815 ( 63 % ) reported having postnatal visits . This coverage increased substantially from June , 2009 , after the introduction of new implementation strategies and reached almost 90 % for pregnancy visits by the end of the trial and 75 % for postnatal visits . The Newhints intervention significantly increased coverage of key essential newborn-care behaviours , except for four or more antenatal-care visits ( 5975 [ 76 % ] of 7859 vs 5988 [ 74 % ] of 8121 , respectively ; relative risk 1·02 , 95 % CI 0·96 - 1·09 ; p=0·52 ) and baby delivered in a facility ( 5373 [ 68 % ] vs 5539 [ 68 % ] , respectively ; 0·97 , 0·81 - 1·14 ; p=0·69 ) . The largest increase was for care-seeking , with 102 ( 77 % ) of 132 sick babies in Newhints zones taken to a hospital or clinic compared with 77 ( 55 % ) of 139 in control zones ( 1·43 , 1·17 - 1·76 ; p=0·001 ) . Increases were also noted in bednet use during pregnancy ( 5398 [ 69 % ] of 7859 vs 5135 [ 63 % ] of 8121 , respectively ; 1·12 , 1·03 - 1·21 ; p=0·005 ) , money saved for delivery or emergency ( 5730 [ 86 % ] of 6681 vs 5525 [ 80 % ] of 6941 , respectively ; 1·09 , 1·05 - 1·12 ; p<0·0001 ) , transport arranged in advance for facility ( 2496 [ 37 % ] vs 2061 [ 30 % ] , respectively ; 1·30 , 1·12 - 1·49 ; p=0·0004 ) , birth assistant for home delivery washed h and s with soap ( 1853 [ 93 % ] of 1992 vs 1817 [ 87 % ] of 2091 , respectively ; 1·05 , 1·02 - 1·09 ; p=0·001 ) , initiation of breastfeeding in less than 1 h of birth ( 3743 [ 49 % ] of 7673 vs 3280 [ 41 % ] of 7921 , respectively ; 1·22 , 1·07 - 1·40 ; p=0·004 ) , skin to skin contact ( 3355 [ 44 % ] vs 1931 [ 24 % ] , respectively ; 2·30 , 1·85 - 2·87 ; p=0·0002 ) , first bath delayed for longer than 6 h ( 3131 [ 41 % ] vs 2269 [ 29 % ] , respectively ; 1·65 , 1·27 - 2·13 ; p<0·0001 ) , exclusive breastfeeding for 26 - 32 days ( 1217 [ 86 % ] of 1414 vs 1091 [ 80 % ] of 1371 ; 1·10 , 1·04 - 1·16 ; p=0·001 ) , and baby sleeping under bednet for 8 - 56 days ( 4548 [ 79 % ] of 5756 vs 4291 [ 73 % ] of 5846 ; 1·09 , 1·03 - 1·15 ; p=0·002 ) . There were 230 neonatal deaths in the Newhints zones compared with 252 in the control zones . The overall NMRs per 1000 livebirths were 29·8 and 31·9 , respectively ( 0·92 , 0·75 - 1·12 ; p=0·405 ) . INTERPRETATION The reduction in NMR with Newhints is consistent with the reductions achieved in three trials undertaken in programme setting s in south Asia . Because there is no suggestion of any heterogeneity ( p=0·850 ) between these trials and Newhints , the meta- analysis summary estimate of a reduction of 12 % ( 95 % CI 5 - 18 ) provides the best evidence for the likely effect of the home-visits strategy delivered within programmes in sub-Saharan Africa and in south Asia . Improvements in the quality of delivery and neonatal care in health facilities and development of innovative , effective strategies to increase coverage of home visits on the day of birth could lead to the achievement of more substantial reductions . FUNDING WHO , Bill & Melinda Gates Foundation , and UK Department for International Development OBJECTIVE To assess the effect on maternal health outcomes of a community-based behavior change management intervention for essential newborn care leading to a reduction in neonatal mortality . METHODS A cluster-r and omized controlled trial involving 1 control and 2 intervention arms was conducted in Shivgarh , India , between January 2004 and May 2005 . Risk-enhancing domiciliary newborn care behaviors , including those posing a concomitant risk to maternal health , were targeted through home visits and community meetings . Secondary outcomes included knowledge of maternal danger signs , self-reported complications , maternal care practice s , care-seeking from trained providers , and maternal mortality ratio ( MMR ) . The intervention arms were combined for analysis , which was done by intention to treat . RESULTS Significant improvements were observed in maternal health equity and outcomes including knowledge of danger signs , care practice s , self-reported complications , and timely care-seeking from trained providers . The difference in adjusted MMR was not significant ( relative risk 0.44 ; 95 % confidence interval , 0.14 - 1.43 ; P=0.11 ) owing to the inadequate sample size for this outcome , but may suggest a decline in MMR given improvements in other outcomes in the causal pathway to mortality . CONCLUSION Community-based strategies focused on prevention and care-seeking effectively complemented facility-based strategies toward improving maternal health , while synergizing with newborn care interventions BACKGROUND Neonatal mortality accounts for a high proportion of deaths in children under the age of 5 years in Bangladesh . Therefore the project for advancing the health of newborns and mothers ( Projahnmo ) implemented a community-based intervention package through government and non-government organisation infrastructures to reduce neonatal mortality . METHODS In Sylhet district , 24 clusters ( with a population of about 20 000 each ) were r and omly assigned in equal numbers to one of two intervention arms or to the comparison arm . Because of the study design , masking was not feasible . All married women of reproductive age ( 15 - 49 years ) were eligible to participate . In the home-care arm , female community health workers ( one per 4000 population ) identified pregnant women , made two antenatal home visits to promote birth and newborn-care preparedness , made postnatal home visits to assess newborns on the first , third , and seventh days of birth , and referred or treated sick neonates . In the community-care arm , birth and newborn-care preparedness and careseeking from qualified providers were promoted solely through group sessions held by female and male community mobilisers . The primary outcome was reduction in neonatal mortality . Analysis was by intention to treat . The study is registered with Clinical Trials.gov , number 00198705 . FINDINGS The number of clusters per arm was eight . The number of participants was 36059 , 40159 , and 37598 in the home-care , community-care , and comparison arms , respectively , with 14 769 , 16 325 , and 15 350 livebirths , respectively . In the last 6 months of the 30-month intervention , neonatal mortality rates were 29.2 per 1000 , 45.2 per 1000 , and 43.5 per 1000 in the home-care , community-care , and comparison arms , respectively . Neonatal mortality was reduced in the home-care arm by 34 % ( adjusted relative risk 0.66 ; 95 % CI 0.47 - 0.93 ) during the last 6 months versus that in the comparison arm . No mortality reduction was noted in the community-care arm ( 0.95 ; 0.69 - 1.31 ) . INTERPRETATION A home-care strategy to promote an integrated package of preventive and curative newborn care is effective in reducing neonatal mortality in communities with a weak health system , low health-care use , and high neonatal mortality Objective : Recent evidence shows poor retention of Pediatric Advanced Life Support provider skills . Frequent refresher training and in situ simulation are promising interventions . We developed a “ Pediatric Advanced Life Support – reconstructed ” recertification course by deconstructing the training into six 30-minute in situ simulation scenario sessions delivered over 6 months . We hypothesized that in situ Pediatric Advanced Life Support – reconstructed implementation is feasible and as effective as st and ard Pediatric Advanced Life Support recertification . Design : A prospect i ve r and omized , single-blinded trial . Setting : Single-center , large , tertiary PICU in a university-affiliated children ’s hospital . Subjects : Nurses and respiratory therapists in PICU . Interventions : Simulation-based modular Pediatric Advanced Life Support recertification training . Measurements and Main Results : Simulation-based pre- and post assessment sessions were conducted to evaluate participants ’ performance . Video-recorded sessions were rated by trained raters blinded to allocation . The primary outcome was skill performance measured by a vali date d Clinical Performance Tool , and secondary outcome was behavioral performance measured by a Behavioral Assessment Tool . A mixed-effect model was used to account for baseline differences . Forty participants were prospect ively r and omized to Pediatric Advanced Life Support reconstructed versus st and ard Pediatric Advanced Life Support with no significant difference in demographics . Clinical Performance Tool score was similar at baseline in both groups and improved after Pediatric Advanced Life Support reconstructed ( pre , 16.3 ± 4.1 vs post , 22.4 ± 3.9 ; p < 0.001 ) , but not after st and ard Pediatric Advanced Life Support ( pre , 14.3 ± 4.7 vs post , 14.9 ± 4.4 ; p = 0.59 ) . Improvement of Clinical Performance Tool was significantly higher in Pediatric Advanced Life Support reconstructed compared with st and ard Pediatric Advanced Life Support ( p = 0.006 ) . Behavioral Assessment Tool improved in both groups : Pediatric Advanced Life Support reconstructed ( pre , 33.3 ± 4.5 vs post , 35.9 ± 5.0 ; p = 0.008 ) and st and ard Pediatric Advanced Life Support ( pre , 30.5 ± 4.7 vs post , 33.6 ± 4.9 ; p = 0.02 ) , with no significant difference of improvement between both groups ( p = 0.49 ) . Conclusions : For PICU-based nurses and respiratory therapists , simulation-based “ Pediatric Advanced Life Support – reconstructed ” in situ training is feasible and more effective than st and ard Pediatric Advanced Life Support recertification training for skill performance . Both Pediatric Advanced Life Support recertification training courses improved behavioral performance In a community-based intervention trial to reduce childhood mortality from pneumonia the intervention area included 58 villages ( 6176 children aged 0 - 4 years ) and the control area 44 villages ( 3947 children ) in Gadchiroli , India . The interventions included mass education about childhood pneumonia and case-management of pneumonia by paramedics , village health workers , and traditional birth attendants ( TBAs ) who were trained to recognise childhood pneumonia and treat it with co-trimoxazole . Parents sought treatment , and coverage was 76 % without active case-detection efforts . The case-fatality rate among the 612 cases treated by health workers was 0.8 % , compared with 13.5 % in the control area . After a year of intervention pneumonia-specific childhood mortality was significantly lower in the intervention than in the control area ( 8.1 vs 17.5 deaths per 1000 children under 5 years ) ; the difference between the areas was greatest in children under 1 year . The differences in infant mortality ( 89 vs 121 per 1000 ) and total under-5 mortality ( 28.5 vs 40.7 per 1000 ) were highly significant . Mortality from other causes remained similar in the two areas but neonatal mortality due to birth injury and prematurity was significantly lower in the intervention area , presumably owing to the combination of better maternal and neonatal care by the TBAs trained in the project and the availability of treatment for pneumonia . The cost of co-trimoxazole was US $ 0.025 per child per year ( $ 2.64 per child saved ) |
13,762 | 29,084,794 | Similar change was observed across most other effectiveness outcomes reported . | null | null |
13,763 | 18,708,737 | Considering implant success rates and peri-implant parameters early loading protocol produces equal outcomes as with conventional loading . | OBJECTIVES Implant loading time is considered to influence the treatment outcomes .
Number of experimental studies have shown that implant loading up to 3 months can produce equally satisfactory results .
However , research results in this area are not consistent .
The purpose of the study was to investigate the influence of conventional and early loading of two-implant supported m and ibular overdentures on treatment outcomes . | In order for clinicians to effectively manage their practice s , they need to know how much time they spent in carrying out procedures . The provision of two-implant overdentures for edentulous patients is becoming more prevalent as increasing evidence demonstrates their great benefit to patients . The aim of this study was to measure the number of visits and the time required during the surgical phase ( from pre-op examination to preliminary impressions ) of m and ibular two-implant overdenture treatment . Thirty edentulous patients were assigned to receive two root-form implants in the m and ible between the mental foramen , as part of a r and omized controlled clinical trial . All visits and time spent by the oral surgeon , the surgical assistant and the prosthodontist were measured individually . The mean number of scheduled visits with the oral surgeon was four , and the mean time taken was 104 min . The mean time taken by the surgical assistant was 122 min . On average , the prosthodontist was required for two visits , with a total mean time of 36 min . In addition to the scheduled visits , 14 patients solicited additional appointments ( unscheduled visits ) for various problems ( e.g. loose healing cap ) . The average time taken for unscheduled visits was 32 min . Combining scheduled and unscheduled visits , the mean total time taken by the oral surgeon was 109 min . The surgical assistant was needed for a mean total of 125 min , and the prosthodontist spent , on average , 46 min in this phase of treatment . Results from this study will assist clinicians in establishing the total time and number of visits needed for the surgical phase of two-implant m and ibular overdenture treatment Purpose : The aim of this study was to evaluate and compare immediate-loaded implant-retained m and ibular overdentures and delayed-loaded implant-retained m and ibular overdentures . Material s : Ten completely edentulous male patients received 40 dental implants . Patients were r and omly divided into 2 equal groups , 5 patients each . Patients of both groups received conventional maxillary complete denture and had stage 1 surgery for placing 4 dental implant fixtures , 2 on each side anterior to the mental foramina . Group A : One-stage surgical procedure and immediate loading . Patients in this group received m and ibular bar-retained overdenture supported by 4 endosseous implants loaded immediately after implant placement . Group B : The original 2-stage concept and delayed loading . Patients in this group received m and ibular bar-retained overdenture supported by 4 endosseous implants that remained submerged for a period of 4 months before loading . The patients were evaluated clinical ly and radiographically immediately after overdenture delivery and after 6 months , 12 months , 18 months , and 24 months . Results : The results of clinical evaluation showed no statistical significant difference between the 2 groups regarding the effect of treatment . The radiographic assessment showed no statistical significant difference in mesial and distal alveolar bone loss at the different intervals of the follow-up period , except at the 12-month period , where immediately loaded implants showed a decrease in the amount of alveolar bone loss mesially and distally compared to delayed loaded implants . Conclusions : The results suggest that immediate-loaded implants provide promising results compared to delayed-loaded implants and can be a possible alternative procedure in implant dentistry This study was design ed to compare the results of immediate and delayed loading of implants with implant-retained m and ibular overdentures . Ten patients ( test group ) received 40 Brånemark System MKII implants ( 4 per patient ) placed in the interforaminal area of the m and ible . St and ard abutments were immediately screwed to the implants , rigidly connected with a bar , and immediately loaded with an overdenture . Ten patients ( control group ) received the same type and number of implants in the same area , but the implants were left to heal submerged . Four to 8 months later , st and ard abutments were screwed to the implants and the same prosthetic procedure was applied . Each implant was evaluated at the time of prosthetic loading and at 6 , 12 , and 24 months after the initial prosthetic load with the following parameters : modified Plaque Index ( MPI ) , modified Bleeding Index ( MBI ) , probing depth ( PD ) , and Periotest . Peri-implant bone resorption was evaluated on panoramic radiographs taken 12 and 24 months after initial prosthetic loading . No significant differences were found between the 2 groups regarding MPI , MBI , Periotest , peri-implant bone resorption , and PD at 6 and 24 months ( P > .05 ) . The only difference was found regarding PD values on the mesial and lingual sites at 12 months ( P < .05 ) . The cumulative success rate of implants was 97.5 % in both groups . Results from this study showed that immediate loading of endosseous implants rigidly connected with a U-shaped bar does not seem to have any detrimental effect on osseointegration . Conversely , this method significantly shortens the duration of treatment with relevant satisfaction for the patients The aim of this study was to determine the influence of age on peri-implant tissues in patients treated with implant-supported overdentures in the m and ible . A prospect i ve study was carried out with 2 groups of healthy edentulous patients . The mean age of the younger group ( n = 32 ) was 46 years ( range 35 to 50 years ) ; the mean age of the older group ( n = 26 ) was 68 years ( range 60 to 80 years ) . 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 , after 1 year , and after 3 years . The evaluated clinical parameters were implant loss , Plaque Index , Gingival Index , Bleeding Index , and probing depth . Radiographic evaluation was performed using a st and ardized long-cone technique with a direction device . Statistical analysis was carried out with SPSS software . One implant in the older group was lost during the healing period . After 3 years , the mean scores for Plaque Index , Gingival Index , and Bleeding Index were between 0 and 1 for both groups ( out of possible scores of 0 to 3 ) , and the mean probing depth was 3 mm in both groups . The mean bone loss after 3 years was 1.2 mm in the younger group and 0.8 mm in the older group , but this difference was not significant . It was concluded from this study population that the clinical performance of implant-supported overdentures in the m and ible is equally successful in younger and older patients PURPOSE This r and omized controlled clinical trial aim ed to evaluate the efficacy of splinted implants versus unsplinted implants in overdenture therapy over a 10-year period . MATERIAL S AND METHODS The study sample comprised 36 completely edentulous patients , 17 men and 19 women ( mean age 63.7 years ) . In each patient , 2 implants ( Brånemark System , Nobel Biocare , Göteborg , Sweden ) were placed in the interforaminal area . Three to 5 months after placement , they were connected to st and ard abutments . The patients were then rehabilitated with ball-retained overdentures , magnet-retained overdentures , or bar-retained overdentures ( the control group ) . Patients were followed for 4 , 12 , 60 , and 120 months post-abutment connection . Group means as well as linear regression models were fitted with attachment type and time as classification variables and corrected for simultaneous testing ( Tukey ) . RESULTS After 10 years , 9 patients had died and 1 was severely ill . Over 10 years , no implants failed . Mean Plaque Index , Bleeding Index , change in attachment level , Periotest values , and marginal bone level at the end of the follow-up period were not significantly different among the groups . DISCUSSION The annual marginal bone loss , excluding the first months of remodeling , was comparable with that found around healthy natural teeth . CONCLUSION The fact that no implants failed and that overall marginal bone loss after the first year of bone remodeling was limited suggested that implants in a 2-implant m and ibular overdenture concept have an excellent prognosis in this patient population , irrespective of the attachment system used The aim of this study was to compare the success rates after 1 and 2 years of conventionally and early loaded pairs of unsplinted ITI implants supporting m and ibular overdentures in edentulous patients . Twenty-four participants ( age range 55 - 80 years ) were r and omly allocated with maximum concealment to two treatment groups . In the first group , the implants were allowed to heal for 12 weeks before being functionally loaded ( control ) and the second group had 6 weeks of healing with identical loading . All participants had new conventional complete maxillary and m and ibular dentures prior to the study . Two s and blasted large-grit acid-etched ( SLA ) surface ITI implants were placed in the m and ibular interforaminal area , following a st and ardized nonsubmerged surgical protocol . After 6 or 12 weeks of healing , matrices were processed into the fitting surface of the pre-existing m and ibular dentures and the implants loaded . Implant success was determined using mobility tests and radiographs taken at baseline and 52 and 104 weeks after surgery . Clinical peri-implant parameters were also documented . Results showed all implants successfully osseointegrated , according to accepted criteria , after 2 years . Mean loss of crestal bone height after 1 year was 0.35 + /- 0.22 mm ( control ) vs. 0.27 + /- 0.18 mm ( test ) . After 2 years this reduced to 0.09 + /- 0.06 mm ( control ) vs. 0.12 + /- 0.17 mm ( test ) . The mean Periotest value after 1 year was -4.9 ( control ) vs.-3.78 ( test ) . After 2 years , the mean resonance frequency value for the control implants was 6797 Hz [ mean implant stability quotient ( ISQ ) = 64.77 ] and for the test implants 6670 Hz ( mean ISQ = 62.0 ) . Shortened loading periods for these ITI implants did not cause any statistically significant differences in osseointegration or peri-implant parameters . We conclude that pairs of unsplinted SLA-surface ITI implants can be successfully loaded with m and ibular overdentures 6 weeks after surgery BACKGROUND Step-wise reduction in loading protocol s is necessary to evaluate early loading of implants with m and ibular overdentures . PURPOSE To compare the success rates of two different dental implant systems following conventional or early loading protocol s in patients being rehabilitated with m and ibular overdentures . MATERIAL S AND METHODS Forty-eight edentulous participants were r and omly allocated to two different implant systems : one with a machined titanium implant surface ( Sterioss , Nobel Biocare , Yorba Linda , California , USA ) and the other with a roughened titanium surface ( Southern Implants , Irene , South Africa ) . For each system , the participants were further divided into control groups , in whom m and ibular implant overdentures and their respective matrices were inserted following a st and ard 12-week healing period , and test groups , in whom a 6-week healing period was followed prior to identical loading . Two unsplinted implants to support implant overdentures were placed in the anterior m and ible of all participants , using a st and ardized one-stage surgical procedure . Mobility tests and marginal bone levels , as well as peri-implant parameters , were evaluated at each baseline and 52 and 104 weeks after surgery . RESULTS There was no statistically significant difference in the success rates of the two systems in either control or test groups . At the 2-year evaluation , a success rate was found of 87.5 % and 70.8 % for the control and test Sterioss groups , respectively , and 83.3 % and 100 % for the control and test Southern Implants groups were observed . For the Sterioss groups , eight implants were lost at an early stage : seven in the test group and one in the control group . For the Southern Implants control and test groups , no failures were seen at any time interval . There were no significant differences in marginal bone loss , Periotest values , and peri-implant parameters between implant systems or between any of the control or test groups . CONCLUSIONS Early loading , with step-wise reductions in loading protocol s , of unsplinted machined Sterioss and roughened Southern Implants fixtures with m and ibular overdentures is possible for up to 2 years It is unclear whether m and ibular implant overdentures improve the nutritional state of edentulous patients better than conventional dentures . In a r and omized clinical trial , we tested for post-treatment differences in nutritional status between patients with m and ibular two-implant retained overdentures and those with conventional complete dentures . Edentulous subjects ( ages 65–75 yrs ) received two-implant m and ibular overdentures ( IOD , n = 30 ) or conventional dentures ( CD , n = 30 ) . Measures of nutritional state were gathered before and 6 mos after treatment . Significant improvements in anthropometric parameters were detected in the IOD but not in the CD group , for percent body fat ( p = 0.011 ) and skin-fold thickness at the biceps , subscapularis , and abdomen ( p < 0.05 ) , with significant decreases in waist circumference ( p < 0.0001 ) and waist-hip ratio ( p = 0.001 ) . Significant increases were seen in concentrations of serum albumin ( p = 0.015 ) , hemoglobin ( p = 0.01 ) , and B12 ( p = 0.01 ) . No significant between-group differences were found . These results suggest that low-cost IOD treatment may improve the nutritional state of edentulous people OBJECTIVES The aim of this study was to compare the performance of two non-splinted implants used as retention for a m and ibular overdenture when applying conventional or early loading protocol s. MATERIAL AND METHODS Twenty edentulous patients were treated with two unsplinted and non-submerged implants ( 15 mm long , TiUnite RP , Brånemark System ) in the anterior m and ible . The patients were r and omly allotted into two groups : ( i ) test group ( Group A ) , in which the overdenture was connected 1 week after surgery , and ( ii ) control group ( Group B ) , in which the overdenture was connected after 12 weeks of healing . Resonance frequency analyses ( RFA ) for implant stability measurements were performed at implant surgery and after 1 , 3 , 6 , 9 and 12 months . Marginal bone levels were evaluated at implant surgery and after 6 and 12 months . RESULTS No implant from either group was lost and all implants showed less than 1 mm of marginal bone resorption during the first year . The mean implant stability quotient ( ISQ ) values at implant surgery were 76.2+/-2.8 for Group A and 75.6+/-4.5 for Group B. The 12-month measurements showed 76.4+/-2.5 ISQ and 76.4+/-2.8 ISQ for Groups A and B , respectively . There were no statistically significant changes between or within the groups with time . There were no differences in marginal bone loss , which was on average 0.3 mm for both groups after 1 year . CONCLUSION Although a limited number of patients were followed for 1 year only , the results of the present study indicate that early loading of two unsplinted 15 mm long implants with an overdenture does not negatively affect implant stability or marginal bone conditions when compared with implants subjected to 12 weeks of healing before loading BACKGROUND The purpose of this prospect i ve study is to compare the long-term outcome of immediately loaded implant-retained m and ibular overdentures supported by four screw-type one-piece transmucosal implants with that of four screw-type two-piece implants inserted in the interforaminal area of the m and ible and rigidly connected by a U-shaped curved MATERIAL S AND METHODS A prospect i ve pilot study was conducted with 10 patients receiving an implant-supported overdenture in the m and ible . The patients were r and omly assigned to two groups . In the control group ( five patients ) , four st and ard Brånemark implants ( MK II ; Nobel Biocare AB , Gothenburg , Sweden ) , 3.75 mm large and at least 10 mm long , were sited anterior to the mental foramina , and four st and ard abutments ( Nobel Biocare AB ) for bar construction were immediately screwed to the implants . In the test group ( five patients ) , four conical transmucosal implants ( Nobel Biocare AB ) , 3.75 mm large and at least 9 mm long in the threaded part , were sited anterior to the mental foramina . Immediately after implant placement , a U-shaped gold or titanium bar was fabricated and implants were immediately loaded ( within 24 h ) in both groups with an implant-retained overdenture . The patients were followed up for a minimum of 24 months . Implants were evaluated at the time of immediate loading and at 12 and 24 months after prosthetic loading , with the following parameters : modified plaque index ( MPI ) , modified bleeding index ( MBI ) , and probing depth ( PD ) . Periimplant bone resorption was evaluated on panoramic radiographs taken 12 and 24 months after the beginning of prosthetic loading . RESULTS No significant differences were found between the two groups with regard to MPI , MBI , PD , and periimplant bone resorption at 12 and 24 months . The cumulative success rate of implants according to the criteria proposed by Albrektsson and colleagues was 100 % in both groups after 2 years of functional loading . CONCLUSIONS Results from this study demonstrated that the success rate for immediately loaded m and ibular implants is similar to that obtained in cases of delayed loading and that there are no significant differences between results with two-piece implants and one-piece transmucosal implants BACKGROUND The original Brånemark protocol for dental implant treatment was based on submerged healing prior to loading . In recent years , immediate/early functional loading has been reported to be possible with high success for various indications including two splinted m and ibular implants supporting an overdenture . However , there are a limited number of studies regarding the early loading protocol for two unsplinted m and ibular implants supporting an overdenture . METHODS A total of 26 edentulous patients were treated with two unsplinted dental implants supporting m and ibular overdentures . All implants were placed in the canine regions of each m and ible according to the one-stage surgery . For the test group , overdentures were connected 1 week after surgery , and for the control group , overdentures were connected 3 months after surgery . Peri-implant parameters were recorded 1 , 6 , 12 , 18 , and 24 months after surgery . Marginal bone levels were evaluated at implant placement and after 6 , 12 , 18 , and 24 months . Clinical stability measurements were performed at surgery , and after 3 , 6 , 12 , 18 , and 24 months . RESULTS No implant from either group was lost during 2 years . Clinical peri-implant parameters , clinical implant stability measurements , and marginal bone resorptions showed no statistically significant differences between the two groups during 24 months . CONCLUSION The results of this clinical trial suggest that the early loading approach of two dental implants supporting a m and ibular overdenture does not jeopardize peri-implant soft tissue health , marginal bone resorption , and implant stability PURPOSE The aim of this report is to present the implant and clinical outcomes of an immediate-loading protocol of TiUnite implants with m and ibular overdentures in edentulous patients . MATERIAL S AND METHODS Two groups of edentulous patients were selected . Thirty-five consecutively treated patients received 70 immediately loaded TiUnite implants and 69 Brånemark implants as backup ( 1 patient received 1 Brånemark implant ) . The control group was a historical cohort that comprised 42 patients who received 111 Brånemark implants . All overdentures were supported by a resilient bar mechanism . Implant and clinical outcomes , including maintenance events for the first year , were recorded . RESULTS Implant success rates were in excess of 95 % with both protocol s. Immediately loaded implants had less bone loss than did implants loaded with the conventional protocol ( Mann-Whitney U test ; P = .001 ) . Patients in the immediate-loading group required more prosthodontic maintenance , consisting of overdenture remakes and laboratory relining of prostheses ( Chi-square test ; P < .05 ) . Of note , 74 % of patients in the immediate-loading group needed a reline to improve the denture seal around the bar housing ( Chi-square test ; P < .05 ) . CONCLUSION The favorable implant and bone level outcomes with immediate loading attest to its biologic success . The prosthetic maintenance encountered in the immediate-loading group does not negate the clinical potential of the treatment but rather suggests that the protocol may benefit from modifications The purpose of this prospect i ve clinical study was to evaluate the efficacy of early loading of implants and to provide evidence to support simplified treatment of m and ibular edentulism by using an implant design ed for 1-stage surgery , combined with ball abutments to circumvent the need for a fixed prosthodontic superstructure . Historically , the recommended time between the placement and functional loading of dental implants has been 3 months in the m and ible . This recommendation is the result of a systematic ally chosen healing time during development of implant treatment . In recent years , histologic and experimental studies have shown that specially design ed implants can result in increased bone-to-implant contact at earlier healing times . Accordingly , these implants can be placed into function faster than previously recommended . In this study , 21 patients aged between 61 and 85 years with edentulous m and ibles were included . All received 2 titanium plasma-sprayed , solid-screw dental implants in the interforaminal region . Ten patients had the implants loaded with an overdenture connected with ball abutments after 3 months ( control group ) . The other 11 patients ( test group ) had prostheses connected to the ball abutments after a maximum of 3 weeks . Marginal bone resorption , Periotest values , and patient satisfaction were evaluated . The cumulative post-loading implant survival rate was 100 % for both groups after 24 months . Marginal bone resorption after 1 year around all implants ranged from 0 to 2 mm ( no significant differences between groups ; P < .05 ) . Periotest values for all implants 1 year after loading were below zero ( range -1 to -6 ) . The results of this clinical trial suggest that successful early loading of 2 implants is possible provided there is uncomplicated implant placement In this prospect i ve multicenter study , non-submerged ITI implants were followed in order to evaluate their long-term prognosis in fully edentulous jaws . A total of 1286 implants were inserted in 233 consecutive patients and , after a healing period of three to six months , the successfully integrated implants were restored with 163 overdentures and 95 fixed full-arch bridges . This prospect i ve study not only calculated the 10-year cumulative survival and success rates for the 1286 implants by life table analysis , but also evaluated the actual survival and success rates for 498 implants after at least five years of functional loading . In addition , cumulative success rates were calculated for implant subgroups according to implant length and location . Additional analyses were performed to evaluate the estimated and actual survival and success rates of the implants in relation to various prosthetic rehabilitation techniques . The 10-year cumulative survival and success rates were 95.9 % and 92.7 % , respectively . The actual 5-year survival and success rates of the first 498 implants that were inserted were 97.7 % and 95.0 % , respectively . The analysis of implant subgroups showed slightly more favourable cumulative success rates for 12 mm long implants ( 93 % ) , in comparison to 10 mm and 8 mm long implants ( 91.6 % and 89.6 % , respectively ) . The cumulative success rate for m and ibular implants ( approximately 94 % ) was also more favourable than that for maxillary implants ( approximately 91 % ) . Patients who were loaded with both maxillary and m and ibular prostheses maintained success rates well above 90 % ; while only implants that were inserted to support maxillary overdentures that were retained by Dolder bars showed a success rate below 90 % Studies have shown that m and ibular implant overdentures significantly increase satisfaction and quality of life of edentulous elders . Improved chewing ability appears to have a positive impact on nutritional state . Therefore , it is important to determine the best design of this prosthesis over the long term . In this r and omized controlled trial , three groups of edentulous participants with atrophic m and ibles wore 3 types of implant overdentures . During an eight-year follow-up , only seven of the 110 participants had dropped out of this study . Almost all participants were still satisfied with their overdentures . Participant satisfaction concerning retention and stability of the m and ibular overdenture had decreased significantly in the two-implant ball attachment group , whereas the opinion of participants in the single- and triple-bar groups was still at the same level . The long-term results suggest that a m and ibular overdenture retained by 2 implants with a single bar may be the best treatment strategy for edentulous people with atrophic ridges BACKGROUND A prospect i ve clinical study was conducted to evaluate clinical ly and radiographically the performance of two implants immediately loaded supporting a ball attachment-retained m and ibular overdenture . MATERIAL S AND METHODS Seventeen completely edentulous patients were included in the study . Each patient received two implants inserted after a minimal flap reflection and no vestibular extension in order to reduce the postoperative swelling and facilitate immediate prosthesis connection . After implant placement , a m and ibular complete denture was connected to the implants using ball attachments of appropriate height according to the depth of the peri-implant tissue . Patients were asked not to remove the denture for 1 week . No limitations to chewing function were given . At implant placement , the maximum value of insertion torque was recorded . Patients were examined at 1 , 2 , 4 , 12 , and 52 weeks postsurgery . At postoperative visit , occlusion was checked and the need for any prosthesis maintenance was recorded . The radiographic bone level ( RBL ) change was measured on periapical radiographs at baseline and 12 months after loading . RESULTS After 12 months of loading , no implant failure was reported and the survival rate was 100 % . Average RBL change was 0.7 mm + /- 0.5 mm . Of the 17 cases , two had major prosthetic complications and five patients required minor extra maintenance appointments . CONCLUSIONS The immediate loading of two implants by means of ball attachment-retained m and ibular complete denture may be a predictable treatment option . This clinical approach offers increased stability and comfort , while keeping a high implant success rate PURPOSE The aim of this prospect i ve r and omized clinical trial was to evaluate 10 years of treatment of patients receiving a m and ibular implant-retained overdenture ( IRO ) or a conventional complete denture ( CD ) . MATERIAL S AND METHODS One hundred twenty-one edentulous patients were treated with an IRO ( 2 endosseous implants , n = 61 ) or a conventional CD ( n = 60 ) . Clinical aspects and patient satisfaction were evaluated . One year after placement of the denture , unsatisfied patients of the CD group were given the opportunity to receive implants . RESULTS In the IRO group , 4 implants were lost during the first year and 4 implants were lost during the next 4 years . Between 5 and 10 years , no implants were lost ( survival rate : 93 % ) . In the CD group , 24 patients ( 40 % ) chose an IRO between 1 and 10 years . DISCUSSION Patients in the IRO group were significantly more satisfied than patients in the CD group after 1 year ( satisfaction score 8.3 versus 6.6 on a scale of 1 to 10 ) , after 5 years ( 7.4 versus 6.4 ) , and after 10 years ( 7.7 versus 6.8 ) . CONCLUSION The mean satisfaction score of the CD group ( including patients who later received implants ) was still lower than that of the IRO group , in spite of the opportunity for retreatment with IROs . Endosseous implants had a high survival rate after 10 years of follow-up This prospect i ve study has been design ed to compare the results of immediate and delayed loading of implant-retained m and ibular overdentures after a 2-year follow-up . Twenty patients have been r and omly divided into two groups . Group 1 patients ( test group ) received four ITI implants in the intraforaminal area of the m and ible . Octa abutments were immediately screwed on implants ; 2 days after surgery , the implants were rigidly connected with a U-shaped Dolder gold bar and loaded with an overdenture . Group 2 patients ( control group ) received , in the same area , the same type and number of implants , which were left to heal according to the st and ard protocol . At 3 - 4 months , Octa abutments were screwed on the implants and the same prosthetic procedure of the test group was applied . The minimum follow-up period lasted 2 years , with recall appointments at 2 weeks , 1 , 3 , 6 months , 1 year and every following year postoperatively , evaluating : MPI , MBI , PD , Periotest and radiographic peri-implant bone resorption . Success criteria according to Albrektsson et al. were used . Only one implant out of the 40 of group 2 failed , whereas none failed in group 1 . No statistical difference of the clinical parameters evaluated was noticed in the two groups . Therefore , immediate loading of implants , if connected with a U-shaped bar , can provide the same results of the ' traditional ' technique as far as osseointegration and short-term survival rates of implants are concerned . Moreover , this method significantly shortens the treatment period , thus increasing patient satisfaction PURPOSE The purpose of this study is to evaluate prospect ively survival and success rates of implants placed in the interforaminal area of edentulous m and ibles and immediately loaded with an implant-supported overdenture . MATERIAL S AND METHODS Eighty-two patients , 33 males and 49 females , aged between 42 and 87 years ( mean age 58.6 yr ) , presenting edentulous m and ibles were rehabilitated with an implant-supported overdenture in the m and ible . Three hundred twenty-eight screw-type osseointegrated implants ( 164 Ha-Ti , Mathys Dental , Bettlach , Switzerl and ; 84 ITI Dental Implant System , Straumann Institute , Waldenburg , Switzerl and ; 40 Brånemark Conical , Nobel Biocare AB , Gothenburg , Sweden ; 40 Frialoc , Friatec , AG Mannheiti , Germany ) , were placed in the intraforaminal area of the mental symphysis ( 4 implants per patient ) . Immediately after implant placement , a U-shaped gold or titanium bar was fabricated and implants were rigidly connected with the bar and immediately loaded with an implant-retained overdenture . Success rate of implants was evaluated clinical ly and radiographically every year after the loading of the prostheses according to the following parameters : ( 1 ) absence of clinical mobility of implants tested individually after bar removal , ( 2 ) absence of periimplant radiolucency evaluated on panoramic radiographs , ( 3 ) absence of pain and radiologic or clinical signs of neural lesion , and ( 4 ) periimplant bone resorption mesial and distal to each implant less than 0.2 mm after the first year of prosthetic load . RESULTS Of 328 implants placed , 296 were followed up from a minimum of 36 months to a maximum of 96 months , with a mean follow-up of 62 months . Seven implants in 6 different patients were removed owing to loss of osseointegration , whereas 18 implants , although still osseointegrated , did not fulfill success criteria due to bone resorption > 0.2 mm/year after the first year of loading . Despite implant losses , all patients maintained their bars supporting overdentures , although in 6 patients they were supported by 3 instead of 4 implants . The only patient who lost 2 implants received 2 new implants , which survived normally . Therefore , the absolute success and survival rates were 91.6 % and 97.6 % , respectively , whereas the cumulative survival and success rates of implants obtained with a life table analysis were 96.1 % and 88.2 % , respectively . CONCLUSIONS Results of this study seem to demonstrate that survival and success rates of immediately loaded implants placed in the intraforaminal area of the m and ible and rigidly connected with a bar through an implant-supported overdenture are consistent with those reported in the international literature as far as delayed loading is concerned after 3 years of loading . After longer observation times , this study demonstrated that , while survival rates of implants and bar-supported overdentures are still consistent with results published in the international literature pertaining to delayed loading , a moderate decrease in success rates of implants was found . Nevertheless , it must be stressed that this decrease ( 88.8 and 90.4 % after a 7- to 8-year observation period for Ha-Ti and ITI implants ) is related only to two implant systems ; no data are available for the other two implant systems because of the shorter follow-up period BACKGROUND Before early functional loading of unsplinted implants with m and ibular overdentures can become widespread , more clinical studies are needed to investigate the success of the approach . PURPOSE To evaluate the success rates of two types of roughened titanium surface implants with early 2-week functional loading of paired m and ibular interforaminal implants with overdentures . MATERIAL S AND METHODS R and om allocation divided 24 strictly selected edentulous participants into two groups , with each group to receive a different implant system ( ITI Dental Implant System , Straumann AG , Waldenburg , Switzerl and ; or Southern Implant System , Southern Implants , Irene , South Africa ) . Two implants were placed in the anterior m and ible of all participants using one-stage st and ardized surgical procedures . Previously constructed conventional m and ibular dentures ( opposing maxillary complete dentures ) were temporarily relined and worn by the participants for the first 2 weeks ; participants used a soft diet . Two weeks after implant surgery and following some mucosal healing , the m and ibular dentures had the tissue conditioner removed and the appropriate matrices included for an unsplinted prosthodontic design . RESULTS No implant from either group was lost . Resonance frequency analysis ( RFA ) indicated higher primary stability at surgery for the Southern group than for the ITI group , with a statistically significant difference between the groups throughout the study period . The drop in RF values between surgery and 6 weeks was significant and was greater for the Southern group . RFA also indicated stabilized osseointegration between 6 to 12 and 12 to 52 weeks , with no participant showing any decrease in those values over time . Participants with type 3 bone showed a significant improvement in RF values between 12 and 52 weeks , eventually matching those of participants with type 2 bone . There were no significant differences in marginal bone loss , periimplant parameters , or prosthodontic maintenance between the groups over the study period . CONCLUSIONS Using only strict patient selection criteria , 1-year follow-up data indicate that early functional loading of ITI and Southern implants with m and ibular two-implant overdentures is possible as early as 2 weeks after implant surgery PURPOSE To report on the implant outcome of delayed , early , and immediate loading of implants in the edentulous m and ible in a prospect i ve controlled study . MATERIAL S AND METHODS On a consecutive basis , the first 10 patients received an overdenture retained by 2 ball attachments 4 months after implant insertion ( delayed ) , and the next 10 patients received an overdenture 1 week after implant surgery ( early ) . The next 10 patients were treated with a fixed prosthesis on 3 implants ( Br6nemark Novum ) either the day of or the day after surgery ( immediate ) . All patients were followed for 1 year ; half were followed for 2 years . Measures of assessment for this prospect i ve clinical trial included monitoring of loading at prosthesis level ( bite fork ) as well as at the abutment level ( strain gauges ) , 3-dimensional imaging of marginal bone remodeling , and implant stability . RESULTS AND DISCUSSION One patient in each OD group lost both implants . The losses occurred 6 months after loading in the delayed group and 1 month after loading in the early group . In the immediate group , 1 patient lost both distal implants 5 months after loading . In 2 other patients , 1 distal implant failed after 1 year of loading . Maximal bite forces increased over time for all groups . Marginal bone loss was the highest for the immediate group , while no differences in implants stability were observed between the 3 groups after 1 year of loading . CONCLUSIONS According to this prospect i ve controlled clinical trial , the results achieved with implants loaded early were comparable to those achieved with implants loaded after a delay . Distal implants are at higher risk for failure in the immediate loaded protocol PURPOSE The goal of this multicenter prospect i ve clinical trial was to compare clinical outcome and post-treatment care and patient satisfaction with different implant systems used for m and ibular overdenture treatment during a 6-year follow-up period . PATIENTS AND METHODS A total of 87 edentulous patients with a severely resorbed m and ible ( bone height , 8 to 15 mm ) received treatment involving either 2 Intra Mobiele Zylinder implants ( IMZ group , n = 41 ) ( Friedrichsfeld AG , Mannheim , Germany ) , 2 Brånemark implants ( Brå group , n = 17 ) ( Nobel Biocare AB , Gothenburg , Sweden ) or a Transm and ibular Implant ( TMI ; Krijnen Medical , Beesd , The Netherl and s ) ( TMI group , n = 29 ) . The evaluation involved clinical parameters , radiographs , surgical and prosthetic post-treatment care , clinical implant performance ( CIP scale ) , and patient satisfaction . RESULTS After 6 years , there was a significant difference in the mean plaque index : the mean plaque index of the TMI group was significantly higher than that of the IMZ and Brå groups . Other clinical parameters showed no significant differences . The implant survival rate of 97.5 % was noted in the IMZ group , 97.1 % in the Brå group , and 72.0 % in the TMI group . The CIP scale were significantly worse for the TMI group . CONCLUSION It was concluded that the IMZ and the Brånemark implant systems have a better survival rate and clinical implant performance than the TMI system . Based on these data , these systems should be the choice for the edentulous m and ible with a height between 8 and 15 mm |
13,764 | 26,744,335 | Conclusion The effects of massage on performance recovery are rather small and partly unclear , but can be relevant under appropriate circumstances ( short-term recovery after intensive mixed training ) .
However , it remains question able if the limited effects justify the widespread use of massage as a recovery intervention in competitive athletes | Background Post-exercise massage is one of the most frequently applied interventions to enhance recovery of athletes .
However , evidence to support the efficacy of massage for performance recovery is scarce .
Moreover , it has not yet been concluded under which conditions massage is effective .
Objective The objective of this study was to perform a systematic review and meta- analysis of the available literature on massage for performance recovery . | OBJECTIVES The purpose of this study was to investigate the physiological and psychological effects of massage on delayed onset muscle soreness ( DOMS ) . METHODS Eighteen volunteers were r and omly assigned to either a massage or control group . DOMS was induced with six sets of eight maximal eccentric contractions of the right hamstring , which were followed 2 h later by 20 min of massage or sham massage ( control ) . Peak torque and mood were assessed at 2 , 6 , 24 , and 48 h postexercise . Range of motion ( ROM ) and intensity and unpleasantness of soreness were assessed at 6 , 24 , and 48 h postexercise . Neutrophil count was assessed at 6 and 24 h postexercise . RESULTS A two factor ANOVA ( treatment v time ) with repeated measures on the second factor showed no significant treatment differences for peak torque , ROM , neutrophils , unpleasantness of soreness , and mood ( p > 0.05 ) . The intensity of soreness , however , was significantly lower in the massage group relative to the control group at 48 h postexercise ( p < 0.05 ) . CONCLUSIONS Massage administered 2 h after exercise induced muscle injury did not improve hamstring function but did reduce the intensity of soreness 48 h after muscle insult Massage therapy is commonly used following endurance running races with the expectation that it will enhance post-run recovery of muscle function and reduce soreness . A limited number of studies have reported little or no influence of massage therapy on post-exercise muscle recovery . However , no studies have been conducted in a field setting to assess the potential for massage to influence muscle recovery following an actual endurance running race . To evaluate the potential for repeated massage therapy interventions to influence recovery of quadriceps and hamstring muscle soreness , recovery of quadriceps and hamstring muscle strength and reduction of upper leg muscle swelling over a two week recovery period following an actual road running race . Twelve adult recreational runners ( 8 male , 4 female ) completed a half marathon ( 21.1 km ) road race . On days 1,4 , 8 , and 11 post-race , subjects received 30 minutes of st and ardized massage therapy performed by a registered massage therapist on a r and omly assigned massage treatment leg , while the other ( control ) leg received no massage treatment . Two days prior to the race ( baseline ) and preceding the treatments on post-race days 1 , 4 , 8 , and 11 the following measures were conducted on each of the massage and control legs : strength of quadriceps and hamstring muscles , leg swelling , and soreness perception . At day 1 , post-race quadriceps peak torque was significantly reduced ( p < 0.05 ) , and soreness and leg circumference significantly elevated ( p < 0.05 ) relative to pre-race values with no difference between legs . This suggested that exercise-induced muscle disruption did occur . Comparing the rate of return to baseline measures between the massaged and control legs , revealed no significant differences ( p > 0.05 ) . All measures had returned to baseline at day 11 . Massage did not affect the recovery of muscles in terms of physiological measures of strength , swelling , or soreness . However , question naires revealed that 7 of the 12 participants perceived that the massaged leg felt better upon recovery . Key PointsMassage does not appear to affect physiological indices of muscle recovery post exercise . Massage does appear to positively influence perceptions of recovery . More research needs to be completed on the purported benefits of massage PURPOSE The intention of this study was to assess the effectiveness of massage on muscle recovery as a function of therapist education in participants who completed a 10-km running race . METHODS Race participants were offered a 12- to 15-min massage immediately post-event . Participants were r and omly assigned to a student therapist with either 450 , 700 , or 950 h of didactic training in massage . Muscle soreness was recorded by question naire using a 0- to 10-point visual scale at time points immediately before and after massage , and 24 and 48 h post-event . Eight hundred ninety-five subjects were recruited , with 317 subjects returning question naires from all time points . RESULTS Race participants who received massage from student therapists with 950 h of didactic training reported significantly greater improvement in muscle soreness across time compared with those who received massage from therapists with 700 or 450 h of education in massage ( P < 0.01 ) . On study entry , there was no difference in muscle soreness ( P = 0.99 ) , with a group mean of 4.4 + /- 0.4 ; at the 24-h measurement , soreness was 2.4 + /- 0.6 , 3.7 + /- 0.5 , and 3.6 + /- 0.9 for the 950- , 700- , and 450-h groups , respectively ( P < 0.01 ) . CONCLUSION Level of therapist training was shown to impact effectiveness of massage as a post-race recovery tool ; greater reduction in muscle soreness was achieved by therapists with 950 h of training as opposed to those with 700 or 450 The physiological adaptations to sauna bathing could enhance endurance performance . We have therefore performed a cross-over study in which six male distance runners completed 3 wk of post-training sauna bathing and 3 wk of control training , with a 3 wk washout . During the sauna period , subjects sat in a humid sauna at 89.9+/-2.0 degrees C ( mean+/-st and ard deviation ) immediately post-exercise for 31+/-5 min on 12.7+/-2.1 occasions . The performance test was a approximately 15 min treadmill run to exhaustion at the runner 's current best speed over 5 km . The test was performed on the 1st and 2nd day following completion of the sauna and control periods , and the times were averaged . Plasma , red-cell and total blood volume were measured via Evans blue dye dilution immediately prior to the first run to exhaustion for each period . Relative to control , sauna bathing increased run time to exhaustion by 32 % ( 90 % confidence limits 21 - 43 % ) , which is equivalent to an enhancement of approximately 1.9 % ( 1.3 - 2.4 % ) in an endurance time trial . Plasma and red-cell volumes increased by 7.1 % ( 5.6 - 8.7 % ) and 3.5 % ( -0.8 % to 8.1 % ) respectively , after sauna relative to control . Change in performance had high correlations with change in plasma volume ( 0.96 , 0.76 - 0.99 ) and total blood volume ( 0.94 , 0.66 - 0.99 ) , but the correlation with change in red cell volume was unclear ( 0.48 , -0.40 to 0.90 ) . We conclude that 3 wk of post-exercise sauna bathing produced a worthwhile enhancement of endurance running performance , probably by increasing blood volume Delayed onset muscle soreness is a common problem that can interfere with rehabilitation as well as activities of daily living . The purpose of this study was to test the impact of therapeutic massage , upper body ergometry , or microcurrent electrical stimulation on muscle soreness and force deficits evident following a high-intensity eccentric exercise bout . Forty untrained , volunteer female subjects were r and omly assigned to one of three treatment groups or to a control group . Exercise consisted of high-intensity eccentric contractions of the elbow flexors . Resistance was reduced as subjects fatigued , until they reached exhaustion . Soreness rating was determined using a visual analog scale . Force deficits were determined by measures of maximal voluntary isometric contraction at 90 degrees of elbow flexion and peak torque for elbow flexion at 60 degrees/sec on a Cybex II isokinetic dynamometer . Maximal voluntary isometric contraction and peak torque were determined at the 0 hour ( before exercise ) and again at 24 and 48 hours postexercise . Treatments were applied immediately following exercise and again at 24 hours after exercise . The control group subjects rested following their exercise bout . Statistical analysis showed significant increases in soreness rating and significant decreases in force generated when the 0 hour was compared with 24- and 48-hour measures . Further analysis indicated no statistically significant differences between massage , microcurrent electrical stimulation , upper body ergometry , and control groups Abstract Objective To evaluate the effectiveness of acupressure in terms of disability , pain scores , and functional status . Design R and omised controlled trial . Setting Orthopaedic clinic in Kaohsiung , Taiwan . Participants 129 patients with chronic low back pain . Intervention Acupressure or physical therapy for one month . Main outcome measures Self administered Chinese versions of st and ard outcome measures for low back pain ( primary outcome : Rol and and Morris disability question naire ) at baseline , after treatment , and at six month follow-up . Results The mean total Rol and and Morris disability question naire score after treatment was significantly lower in the acupressure group than in the physical therapy group regardless of the difference in absolute score ( - 3.8 , 95 % confidence interval - 5.7 to - 1.9 ) or mean change from the baseline ( - 4.64 , - 6.39 to - 2.89 ) . Acupressure conferred an 89 % ( 95 % confidence interval 61 % to 97 % ) reduction in significant disability compared with physical therapy . The improvement in disability score in the acupressure group compared with the physical group remained at six month follow-up . Statistically significant differences also occurred between the two groups for all six domains of the core outcome , pain visual scale , and modified Oswestry disability question naire after treatment and at six month follow-up . Conclusions Acupressure was effective in reducing low back pain in terms of disability , pain scores , and functional status . The benefit was sustained for six months PURPOSE The purpose of the present study was to determine whether activity would affect the recovery of muscle function after high-force eccentric exercise of the elbow flexors . METHODS Twenty-six male volunteers were r and omly assigned to one of three groups for a 4-d treatment period : immobilization ( N = 9 ) , control ( N = 8) , and light exercise ( N = 9 ) . Relaxed arm angle ( RANG ) , flexed arm angle ( FANG ) , maximal isometric force ( MIF ) , and perceived muscle soreness ( SOR ) were obtained for 3 consecutive days pre-exercise ( baseline ) , immediately post-exercise , and for 8 consecutive days after the 4-d treatment period ( recovery ) . During the treatment period , the immobilization group had their arm placed in a cast and supported in a sling at 90 degrees . The control group had no restriction of their arm activity . The light exercise group performed a daily exercise regimen of 50 biceps curls with a 5-lb dumbbell . RESULTS All subjects showed a prolonged decrease in RANG , increase in FANG , loss in MIF , and increase in SOR in the days after eccentric exercise . During recovery , there was no significant interaction observed among groups over time in RANG ( P > 0.05 ) or FANG ( P > 0.05 ) , but there was a significant interaction observed among groups over time in both MIF ( P < 0.01 ) and SOR ( P < 0.01 ) . Recovery of MIF was facilitated by light exercise and immobilization , whereas recovery from SOR was facilitated by light exercise and delayed by immobilization . CONCLUSIONS The recovery of MIF in both the light exercise and immobilization groups suggests that more than one mechanism may be involved in the recovery of isometric force after eccentric exercise Thirteen males and 7 females completed their maximum number of leg extensions against a half maximum load . In a r and omised , crossover study they were exercised to fatigue using an ergonometer , ski-squats and leg extensions followed either by a 6 min massage or rest after which they again completed their maximum number of leg extensions against half maximum load . The process was repeated a few days later with the alternative condition ( rest or massage ) . The results showed that massage after exercise fatigue significantly improved quadriceps performance compared to rest ( p = 0.001 ) . The data was further analysed in relation to age and gender The aim of this study was to examine the acute effects of pre- performance lower limb massage after warm-up on explosive and high-speed motor capacities and flexibility . Twenty-four physically active healthy Caucasian male subjects volunteered to participate in this study . All subjects were from a Physical Education and Sport Department in a large university in Turkey . The study had a counterbalanced crossover design . Each of the subjects applied the following intervention protocol s in a r and omised order ; ( a ) massage , ( b ) stretching , and ( c ) rest . Before ( pre ) and after ( post ) each of the interventions , the 10 meter acceleration ( AS ) , flying start 20 meter sprint ( FS ) , 30 meter sprint from st and ing position ( TS ) , leg reaction time ( LR ) , vertical jump ( VJ ) and sit & reach ( SR ) tests were performed . A Wilcoxon 's signed rank test was used to compare before and after test values within the three interventions ( massage , stretching and rest ) . The data showed a significant worsening , after massage and stretching interventions , in the VJ , LR ( only in stretching intervention ) , AS and TS tests ( p < 0.05 ) , and significant improvement in the SR test ( p < 0.05 ) . In contrast , the rest intervention led only to a significant decrement in TS performance ( p < 0.05 ) . In conclusion , the present findings suggest that performing 10 minute posterior and 5 minute anterior lower limb Swedish massage has an adverse effect on vertical jump , speed , and reaction time , and a positive effect on sit and reach test results . Key pointsPerforming 10 minute posterior and 5 minute anterior lower limb Swedish massages has an adverse affect on vertical jump , speed , and reaction time and a positive effect on sit and reach test results .According to the present results , long duration massage should not be recommended for warm-ups . Larger subject pools are needed to verify these events The effects of warm underwater water-jet massage on neuromuscular functioning , selected biochemical parameters ( serum creatine kinase , lactic dehydrogenase , serum carbonic anhydrase , myoglobin , urine urea and creatinine ) and muscle soreness were studied among 14 junior track and field athletes . Each subject spent , in a r and omized order , two identical training weeks engaged in five strength/power training sessions lasting 3 days . The training weeks differed from each other only in respect of underwater water jet massage treatments . These were used three times ( 20 min each ) during the treatment week and not used during the control week . During the treatment week continuous jumping power decreased and ground contact time increased significantly less ( P < 0.05 ) and serum myoglobin increased more than during the control week . It is suggested that underwater water-jet massage in connection with intense strength/power training increases the release of proteins from muscle tissue into the blood and enhances the maintenance of neuro-muscular performance capacity The effect of a combination of a warm-up , stretching exercises and massage on subjective scores for delayed onset muscle soreness ( DOMS ) and objective functional and biochemical measures was studied . Fifty people , r and omly divided in a treatment and a control group , performed eccentric exercise with the forearm flexors for 30 min . The treatment group additionally performed a warm-up and underwent a stretching protocol before the eccentric exercise and massage afterwards . Functional and biochemical measures were obtained before , and 1 , 24 , 48 , 72 and 96h after exercise . The median values at the five post-exercise time points differed significantly for DOMS measured when the arm was extended ( p = 0.043 ) . Significant main effects for treatment were found on the maximal force ( p = 0.026 ) , the flexion angle of the elbow ( p = 0.014 ) and the creatine kinase activity in blood ( p = 0.006 ) . No time-by-treatment interactions were found . DOMS on pressure , extension angle and myoglobin concentration in blood did not differ between the groups . This combination of a warm-up , stretching and massage reduces some negative effects of eccentric exercise , but the results are inconsistent , since some parameters were significantly affected by the treatment whereas others were not , despite the expected efficacy of a combination of treatments . The objective measures did not yield more unequivocal results than the subjective DOMS scores OBJECTIVE The aim of this study was to investigate the effect of local effleurage massage on the recovery from fatigue in the small h and muscles . METHODS This study was a within-subject repeated measure design . Twelve healthy , right-h and ed volunteer male subjects with a mean age of 25 + /- 2.8 years were recruited into the study from a university population . Subjects were r and omly allocated to a rest or massage protocol . Subjects undertook the alternate protocol at a subsequent session . All subjects underwent baseline dynamometry testing of isometric thumb adduction ( nondominant h and ) before undertaking a fatigue-inducing task of the thumb adductors . Subjects then underwent either 5 minutes of massage applied to the first dorsal interspace or 5 minutes of rest . Subjects were then retested . RESULTS The maximal force recorded after the massage protocol was not significantly different from the maximal force recorded after the rest protocol , with a mean difference of only 0.63 N ( 95 % confidence interval , -12.55 to 13.80 N ; P = .92 ) . The maximal gradient of force development after the massage protocol was not significantly different from the maximal gradient recorded after the rest protocol , with a mean decrease in gradient of 19.48 N/s ( 95 % confidence interval , -117.33 to 156.30 N ; P = .77 ) . CONCLUSIONS Effleurage massage was not an effective intervention for enhancing the restoration of postfatigue F(max ) and G(max ) in the small muscles of the h and . The wide variation in response to this massage protocol may support the notion that there is no universal effect of effleurage massage in enhancing recovery from fatigue It was hypothesized that athletic massage administered 2 hours after eccentric exercise would disrupt an initial crucial event in acute inflammation , the accumulation of neutrophils . This would result in a diminished inflammatory response and a concomitant reduction in delayed onset muscle soreness ( DOMS ) and serum creatine kinase ( CK ) . Untrained males were r and omly assigned to a massage ( N = 7 ) or control ( N = 7 ) group . All performed five sets of isokinetic eccentric exercise of the elbow flexors and extensors . Two hours after exercise , massage subjects received a 30-minute athletic massage ; control subjects rested . Delayed onset muscle soreness and CK were assessed before exercise and at 8 , 24 , 48 , 72 , 96 , and 120 hours after exercise . Circulating neutrophils were assessed before and immediately after exercise , and at 30-minute intervals for 8 hours ; cortisol was assessed before and immediately after exercise , and at 30-minute intervals for 8 hours ; cortisol was assessed at similar times . A trend analysis revealed a significant ( p < 0.05 ) treatment by time interaction effect for 1 ) DOMS , with the massage group reporting reduced levels ; 2 ) CK , with the massage group displaying reduced levels ; 3 ) neutrophils , with the massage group displaying a prolonged elevation ; and 4 ) cortisol , with the massage group showing a diminished diurnal reduction . The results of this study suggest that sports massage will reduce DOMS and CK when administered 2 hours after the termination of eccentric exercise . This may be due to a reduced emigration of neutrophils and /or higher levels of serum cortisol The recovery process in sport plays an essential role in determining subsequent athletic performance . This study investigated the effectiveness of different recovery interventions after maximal exercise . Eighteen trained male cyclists initially undertook an incremental test to determine maximal oxygen consumption . The four recovery interventions tested were : passive , active ( 50 % maximal oxygen uptake ) , massage , and combined ( involving active and massage components ) . All test sessions were separated by 2 to 3 days . During intervention trials subjects performed two simulated 5 km maximal effort cycling tests ( T1 and T2 ) separated by a 20 min recovery . Performance time for the tests ( t1 , t2 ) ; blood lactate ( BLa ) during T1 , T2 , and every 3 min during recovery ; and heart rate ( HR ) during the recovery intervention and T2 were recorded . Combined recovery was found to be better than passive ( P<0.01 ) and either active or massage ( P<0.05 ) in maintenance of performance time during T2 . Active recovery was the most effective intervention for removing BLa at minutes 9 and 12 , BLa removal during combined recovery was significantly better than passive at minute 3 , and significantly better than passive , active , and massage at minute 15 . In conclusion , combined recovery was the most efficient intervention for maintaining maximal performance time during T2 , and active recovery was the best intervention for removing BLa Jakeman , JR , Byrne , C , and Eston , RG . Efficacy of lower limb compression and combined treatment of manual massage and lower limb compression on symptoms of exercise-induced muscle damage in women . J Strength Cond Res 24(11 ) : 3157 - 3165 , 2010-Strategies to manage the symptoms of exercise-induced muscle damage ( EIMD ) are widespread , though are often based on anecdotal evidence . The aim of this study was to determine the efficacy of a combination of manual massage and compressive clothing and compressive clothing individually as recovery strategies after muscle damage . Thirty-two female volunteers completed 100 plyometric drop jumps and were r and omly assigned to a passive recovery ( n = 17 ) , combined treatment ( n = 7 ) , or compression treatment group ( n = 8) . Indices of muscle damage ( perceived soreness , creatine kinase activity , isokinetic muscle strength , squat jump , and countermovement jump performance ) were assessed immediately before and after 1 , 24 , 48 , 72 , and 96 hours of plyometric exercise . The compression treatment group wore compressive tights for 12 hours after damage and the combined treatment group received a 30-minute massage immediately after damaging exercise and wore compression stockings for the following 11.5 hours . Plyometric exercise had a significant effect on all indices of muscle damage ( p < 0.05 ) . The treatments significantly reduced decrements in isokinetic muscle strength , squat jump performance , and countermovement jump performance and reduced the level of perceived soreness in comparison with the passive recovery group ( p < 0.05 ) . The addition of sports massage to compression after muscle damage did not improve performance recovery , with recovery trends being similar in both treatment groups . The treatment combination of massage and compression significantly moderated perceived soreness at 48 and 72 hours after plyometric exercise ( p < 0.05 ) in comparison with the passive recovery or compression alone treatment . The results indicate that the use of lower limb compression and a combined treatment of manual massage with lower limb compression are effective recovery strategies following EIMD . Minimal performance differences between treatments were observed , although the combination treatment may be beneficial in controlling perceived soreness PURPOSE The purpose of this study was to assess research aim ed at measuring performance enhancements that affect success of individual elite athletes in competitive events . ANALYSIS Simulations show that the smallest worthwhile enhancement of performance for an athlete in an international event is 0.7 - 0.4 of the typical within-athlete r and om variation in performance between events . Using change in performance in events as the outcome measure in a crossover study , research ers could delimit such enhancements with a sample of 16 - 65 athletes , or with 65 - 260 in a fully controlled study . Sample size for a study using a valid laboratory or field test is proportional to the square of the within-athlete variation in performance in the test relative to the event ; estimates of these variations are therefore crucial and should be determined by repeated- measures analysis of data from reliability studies for the test and event . Enhancements in test and event may differ when factors that affect performance differ between test and event ; overall effects of these factors can be determined with a validity study that combines reliability data for test and event . A test should be used only if it is valid , more reliable than the event , allows estimation of performance enhancement in the event , and if the subjects replicate their usual training and dietary practice s for the study ; otherwise the event itself provides the only dependable estimate of performance enhancement . Publication of enhancement as a percent change with confidence limits along with an analysis for individual differences will make the study more applicable to athletes . Outcomes can be generalized only to athletes with abilities and practice s represented in the study . CONCLUSION estimates of enhancement of performance in laboratory or field tests in most previous studies may not apply to elite athletes in competitive events Manual massage is commonly assumed to enhance long term muscle recovery from intense exercise , partly due to its ability to speed healing via enhanced muscle blood flow . We tested these assumptions by daily ( for four days ) massaging the quadriceps muscles of one leg on subjects who had previously completed an intense bout of eccentric quadriceps work with both legs . Immediate post-exercise isometric and dynamic quadriceps peak torque measures had declined to approximately 60 - 70 % of pre-exercise values in both legs . Peak torques for both the massage and control leg tended to slowly return toward pre-exercise values through the subsequent four days ( 96 hrs ) . There was no significant difference between the isometric and dynamic peak torques between massage and control legs up to 96 hours post-exercise . Leg blood flow was estimated by determining femoral artery and vein mean blood velocities via pulsed Doppler ultrasound velocimetry . Massage of the quadriceps muscles did not significantly elevate arterial or venous mean blood velocity above resting levels , while light quadriceps muscle contractions did . The perceived level of delayed onset muscle soreness tended to be reduced in the massaged leg 48 - 96 hours post-exercise . It was concluded that massage was not an effective treatment modality for enhancing long term restoration of post-exercise muscle strength and its use for this purpose in athletic setting s should be question ed Objective : The aim of this study was to test the hypothesis that vibration treatment reduces delayed‐onset muscle soreness and swelling and enhances recovery of muscle function after eccentric exercise . Design : A r and omized crossover design was used . Fifteen young men performed ten sets of six maximal eccentric contractions of the elbow flexors with the right arm for one occasion and the left arm for the other occasion separated by 4 wks . One arm received a 30‐min vibration treatment at 30 mins after and 1 , 2 , 3 , and 4 days after the exercise ( treatment group ) , and the other arm did not receive any treatment ( control group ) . The order of the treatment and control conditions and the use of the dominant and nondominant arms were counterbalanced among subjects . Changes in indirect markers of muscle damage were compared between arms by a two‐way repeated‐ measures analysis of variance . Results : Compared with the control group , the treatment group showed significantly ( P < 0.05 ) less development and faster reduction in delayed‐onset muscle soreness at 2 to 5 days after exercise . The recovery of range of motion was significantly ( P < 0.05 ) faster for the treatment than for the control group . However , no significant effects on the recovery of muscle strength and serum creatine kinase activity were evident . Immediately after the vibration treatment , a significant ( P < 0.05 ) decrease in the magnitude of delayed‐onset muscle soreness and muscle strength and an increase in pressure pain threshold and range of motion were found . Conclusions : These results showed that the vibration treatment was effective for attenuation of delayed‐onset muscle soreness and recovery of range of motion after strenuous eccentric exercise but did not affect swelling , recovery of muscle strength , and serum creatine kinase activity Background The use of sports massage is very common in the athletic community . However , only a few studies have shown any therapeutic effect of massage . Hypothesis Sports massage can improve the recovery after eccentric exercise . Study Design Prospect i ve r and omized clinical trial . Methods Sixteen subjects performed 300 maximal eccentric contractions of the quadriceps muscle bilaterally . Massage was given to 1 leg , whereas the other leg served as a control . Subjects were treated once daily for 3 days . Maximal strength was tested on a Kin-Com dynamometer , and functional tests were based on 1-leg long jumps . Pain was evaluated using a visual analog scale . Results There was a marked loss of strength and function of the quadriceps directly after exercise and on the third day after exercise . The massage treatment did not affect the level or duration of pain or the loss of strength or function following exercise . Conclusion Sports massage could not improve the recovery after eccentric exercise |
13,765 | 22,019,084 | The limited amount of evidence from r and omized and non-r and omized open-label trials suggests that depressed NH residents have a modest response to antidepressant medications . | BACKGROUND Antidepressant medications are the most common psychopharmacologic therapy used to treat depressed nursing home ( NH ) residents .
Despite a significant increase in the rate of antidepressant prescribing over the past several decades , little is known about the effectiveness of these agents in the NH population .
OBJECTIVE To conduct a systematic review of the literature to examine and compare the effectiveness of antidepressant medications for treating major depressive symptoms in elderly NH residents . | The authors conducted a r and omized , double-blind , 10-week clinical trial of two doses of nortriptyline in eight nursing homes . Sixty-nine patients , average age 79.5 years , were r and omized to receive regular doses ( 60 mg-80 mg/day ) vs. low doses ( 10 mg-13 mg/day ) of nortriptyline . Among the more cognitively intact patients , there was a significant quadratic relationship defining a " therapeutic window " for nortriptyline plasma levels and clinical improvement . There were also significant differences in plasma level-response relationships between depressed patients who were cognitively impaired and those who were more cognitively intact . Depression remains a syndrome that responds to specific treatment , even in frail nursing home patients , and those depressions that occur in patients with significant dementia may represent a treatment-relevant condition with a different plasma level-response relationship than in depression alone A significant drug-placebo difference was found in a double-blind , placebo-controlled study of nortriptyline for treatment of major depression among frail elderly patients living in an institutional setting . This finding confirms the validity of the DSM-III-R diagnosis of major depression and establishes the need for specific psychiatric services for the chronically ill elderly living in nursing homes and congregate housing facilities . The incidence of adverse events requiring early termination of treatment was 34 % , demonstrating the vulnerability of these patients and their need for careful monitoring during treatment . High levels of self-care disability and low levels of serum albumin were both associated with decreased therapeutic responses , demonstrating the need for further research on psychopathology in these setting There has been limited research into defining what constitutes an adequate first-line antidepressant trial in elderly patients . The authors report the outcome of extended , high-dosage sertraline treatment in a sample of nursing home residents experiencing residual significant depressive symptoms after 10 weeks of treatment with sertraline at a final dosage of 100 mg/day . Subjects who had a Hamilton Depression Rating Scale score ≥ 12 after 10 weeks of treatment with sertraline were eligible for the 8-week open-label extension phase , which involved titrating the sertraline dosage to 200 mg/day . The cumulative response rate was 52 % for the extension phase , compared with 37 % for the acute phase . Examining acute phase nonresponders , 39 % responded during the extension phase . Rates of discontinuation due to adverse events were comparable in the 2 phases . Our findings suggest that an extended trial or high dosages of sertraline may benefit some depressed elderly patients with persistent depression after acute treatment . ( J Geriatr Psychiatry Neurol 2003 ; 16:109 - 111 SUMMARY Objective : To evaluate the efficacy and tolerability of mirtazapine orally disintegrating tablets in depressed , elderly nursing home residents , under naturalistic study conditions . Methods : In this open-label 12-week study , mirtazapine orally disintegrating tablets ( 15–45 mg day−1 ) were administered to patients > 70 years old with physician-diagnosed depression and a Mini-Mental State Examination ( MMSE ) score > 10 . Patients with medical comorbidities , cognitive impairment and /or concomitant medications were enrolled if they met study inclusion criteria and had illnesses and /or medication dosages that were considered stable . Assessment s were performed at baseline by physicians and at days 14 , 28 , 56 , and 84 ( or early termination ) by physicians or nurse coordinators using the Clinical Global Impression ( CGI ) scale , the 16-item Hamilton Rating Scale for depression ( Ham-D-16 ( the st and ard 17-item scale minus item 14 ) ) , and the Cornell Scale for Depression in Dementia ( CSDD ) . Tolerability was evaluated based on treatment-emergent adverse events . Results : A total of 119 patients in the intent-to-treat ( ITT ) group were treated with mirtazapine orally disintegrating tablets ( mean daily dose : 19.4 mg ) and evaluated for efficacy . At endpoint , 54 % of patients in the ITT group showed CGI-I response ( defined as a CGI-I score of 1 or 2 ( ' very much ' or ' much ' improved ) and 47 % were Ham-D-16 responders ( defined as decrease from baseline of at least 50 % in Ham-D-16 total score ) . CSDD mean scores and Ham-D-16 mean total scores demonstrated a progressive decrease from baseline to trial completion . The decrease in Ham-D scores from baseline to day 84 was statistically significant ( p < 0.0001 ) . Mean changes from baseline to day 84 were −6.6 ± 6.9 ( CSDD score ) and −7.9 ± 7.4 ( Ham-D-16 total score ) . Ham-D Factor I , Factor VI and item 1 scores also decreased . Fourteen of 124 patients in the all-subjects-treated ( AST ) group ( 11.3 % ) discontinued prematurely due to adverse events . The most frequently occurring adverse events were urinary tract infection ( 19 % ) , accidental injury ( 18 % ) , fall ( 18 % ) , somnolence ( 12 % ) , and upper respiratory infection ( 12 % ) . Mean body weight increased by 0.7 ± 2.25 kg ( 1.54 ± 5 lb ) from baseline to day 28 , and by 1.3 ± 3.36 kg ( 2.86 ± 7.4 lb ) from baseline to day 84 . Conclusions : The results suggest that mirtazapine orally disintegrating tablets provide antidepressant efficacy and are a relatively well-tolerated treatment for depression in this patient population of elderly nursing home residents with medical and cognitive comorbidities Studies have demonstrated that the selective serotonin reuptake inhibitor antidepressants have similar efficacy to other agents , such as tricyclic antidepressants . However , data are limited for direct comparisons with other antidepressants . The authors conducted a contemporaneous comparison of nursing home residents treated with open-label sertraline in doses up to 100 mg/day with nursing home residents treated in a double-blind r and omized study of low vs. regular doses of nortriptyline . There were 97 patients enrolled in the study ( 28 treated with sertraline ) , with an average treatment duration of 55 days . There were no differences in the tolerability of sertraline vs. nortriptyline . However , in this group of frail older adults , sertraline was not as effective as nortriptyline for the treatment of depression Depression is common across a broad spectrum of severity among nursing home residents . Previous research has demonstrated the effectiveness of antidepressants in nursing home residents with major depression , but it is not known whether antidepressants are helpful in residents with less severe forms of depression . We conducted a r and omized double-blind placebo-controlled 8-week trial comparing paroxetine and placebo in very old nursing home residents with non-major depression . The main outcome measure was the primary nurse 's Clinical Impression of Change ( CGI-C ) . Additional outcome measures were improvement on the interview-derived Hamilton Depression Rating Scale ( HDRS ) and Cornell Scale for Depression ( CS ) scores . Twenty-four subjects with a mean age of 87.9 were enrolled and twenty subjects completed the trial . Placebo response was high , and when all subjects were considered , there were no differences in improvement between the paroxetine and placebo groups . Two subjects that received paroxetine developed delirium , and subjects that received paroxetine were more likely to experience a decrease in Mini Mental State Exam scores ( P = .03 ) . There were no differences in serum anticholinergic activity between groups . In a subgroup analysis of 15 subjects with higher baseline HDRS and CS scores , there was a trend toward greater improvement in the paroxetine group in an outcome measure that combined the CGI-C and interview-based measures ( P = .06 ) . Paroxetine is not clearly superior to placebo in this small study of very old nursing home residents with non-major depression , and there is a risk of adverse cognitive effects . Because of the high placebo response and the trend towards improvement in the more severely ill patients , it is possible that a larger study would have demonstrated a significant therapeutic effect for paroxetine as compared with placebo . The study also illustrates the discordance between patient and caregiver ratings , and the difficulties in study ing very elderly patients with mood disorders The authors examined 50 patients , with a mean age of 89 years ( range : 80–98 ) , placed in a prospect i ve , open-label trial of either fluoxetine , sertraline , or paroxetine . At 12-week follow-up , there was a significant overall decline ( 36 % ) in Ham-D scores ; 42 % had at least a 50 % decline in their scores . There were no significant differences in responses to the three antidepressants , and all drugs were well tolerated . However , there were significant differences between diagnostic subgroups in the percentage of persons showing at least a 50 % decrease in their Ham-D scores : major depressive disorder ( MDD ; 93 % ) , Alzheimer 's disease with MDD ( 8 % ) , vascular dementia with MDD ( 6 % ) , and other CNS-related disorders with MDD ( 83 % ) . The findings confirm earlier accounts that antidepressants may be substantially less effective with MDD secondary to dementia in very old patients A sample of 31 female nursing home patients with late-stage Alzheimer 's disease participated in a double-blind clinical trial of the antidepressant medication sertraline . Measures of depression included various objective scales and two measures of facial expressions of emotion coded during a semistructured interview using a facial affect coding system . Repeated- measures ANOVAs at baseline and at the 8-week endpoint indicated that on all measures , both the treatment and placebo groups improved over time , with three of six measures showing a significant time effect . The " knit-brow " facial measure approached significance for a Treatment x Time effect . Thus , sertraline had no significant benefits over placebo . However , if , as we hypothesize , the knit-brow response is more sensitive to signs of depression in advanced dementia , our study justifies the further investigation of the use of sertraline in this population OBJECTIVES Depression in older patients contributes to personal suffering and family disruption and increases disability , medical morbidity , mortality , suicide risk , and healthcare utilization . The majority of clinical trials of antidepressant treatments are conducted in younger patients . For this reason , clinicians often have to extrapolate from studies in population s that do not present the same problems as older patients . For example , older patients often have serious coexisting medical conditions that may contribute to the depression and complicate the choice of treatment . Older patients as a rule need to be on many medications , some of which may contribute to depression and /or interact with antidepressants . Finally , older adults metabolize medications slowly and are more sensitive to side effects than younger patients . Because of these complexities , we conducted a consensus survey of expert opinion on the pharmacotherapy of depressive disorders in older patients to address clinical questions not definitively answered in the research literature . METHOD After review ing the literature and convening a work group of experts , we prepared a written survey with 64 questions that asked about 857 options . 618 of the options were scored using a modified version of the R AND 9-point scale for rating appropriateness of medical decisions . For the other options , the experts were asked to write in answers ( e.g. , average doses ) or to check a box to indicate their preferred answer . We sent the survey to 50 national experts on geriatric depression , all of whom completed it . Consensus on each option was defined as a nonr and om distribution of scores by chi-square " goodness-of-fit " test . We assigned a categorical rank ( first line/preferred choice , second line/alternate choice , third line/usually inappropriate ) to each option based on the 95 % confidence interval around the mean rating . Guideline tables indicating preferred treatment strategies were then developed for key clinical situations . RESULTS The expert panel reached consensus on 89 % of the options rated on the 9-point scale . The experts stress the importance of identifying coexisting medical conditions that may be contributing to the depression or complicate treatment . For unipolar nonpsychotic major depression , the preferred strategy is an antidepressant ( selective serotonin reuptake inhibitor [ SSRI ] or venlafaxine XR preferred ) plus psychotherapy . For unipolar psychotic major depression , the treatment of choice is an antidepressant ( SSRI or venlafaxine XR ) plus one of the newer atypical antipsychotics . Electroconvulsive therapy is also first line . For dysthymic disorder or persistent milder depression , the experts recommend combining an antidepressant ( SSRIs preferred ) and psychotherapy . If the patient has a comorbid medical condition ( e.g. , hypothyroidism ) that is contributing to the depression , the experts recommend treating both the depression and the medical condition from the outset . The SSRIs were the top-rated antidepressants for all types of depression . Among them , the experts gave the highest ratings for efficacy and tolerability to citalopram and sertraline . Paroxetine was another first-line option , and fluoxetine was rated high second line . The preferred psychotherapy techniques for treating depression in older patients are cognitive-behavioral therapy , supportive psychotherapy , problem-solving psychotherapy , and interpersonal psychotherapy . The experts also give strong support to including appropriate psychosocial interventions ( e.g. , psychoeducation , family counseling , visiting nurse services ) in the treatment program . The majority of experts would continue treatment with antidepressant medication for at least 1 year if a patient has had a single episode of severe unipolar major depression , for 1 - 3 years for a patient who has had 2 such episodes , and for longer than 3 years if there is a history of 3 or more episodes . CONCLUSIONS The experts reached a high level of consensus on the appropriateness of including both antidepressant medication , specifically SSRIs , and nonpharmacological modalities in treatment plans for severe depression . Within the limits of expert opinion and with the expectation that future research data will take precedence , these guidelines provide direction for addressing common clinical dilemmas in older individuals . They can be used to inform clinicians and educate patients regarding the relative merits of a variety of interventions . Nonetheless , the guidelines can not address the complexities involved in the care of each individual patient and can be most helpful in the h and s of experienced clinicians INTRODUCTION Treatment studies of depression in the very oldest patients are infrequent . For these reasons , this study of mirtazapine orally disintegrating tablets was carried out in nursing home residents > or=85 years old with physician-diagnosed depression . The naturalistic conditions of the study allowed us to include patients with cognitive impairment , concomitant medications and comorbid illness . METHODS This was a subgroup analysis of nursing home residents > or=85 years old who took part in a larger 12-week open-label trial . Patients were eligible if they had physician-diagnosed depression , and a Mini-Mental State Exam score > or=10 . The physician or nurse coordinator obtained data from healthcare professionals in daily contact with the patient to complete the Clinical Global Impression ( CGI ) scale , a modified 16-item Hamilton Depression Scale ( HAM-D ) , and the Cornell Scale for Depression in Dementia ( CSDD ) . Treatment-emergent adverse events were recorded . RESULTS Of the 50 patients enrolled at 23 sites , 72 % completed the 12-week trial . The mean age of the participants was 89.3 years . The mean HAM-D score declined from 16.9 at baseline to 7.3 at endpoint ( ITT , LOCF analysis ) For the CSDD , the mean score declined from 15.1 to 7.1 . The percentage of responders on the CGI-Improvement ( CGI-I ) scale increased at each assessment reaching 55 % at endpoint . Only 10 % of the patients discontinued treatment because of adverse events . There was a mean increase in weight of 1.32 lbs ( 0.6 kg ) at day 84 . CONCLUSION Although lacking a placebo control , this naturalistic study suggests that mirtazapine orally disintegrating tablets were effective and well tolerated in this sample of depressed nursing home residents > or=85 years of age BACKGROUND In nursing home residents and other frail elderly patients , old age and potential drug-drug and drug-disease interactions may affect the relative safety and efficacy of medications . The purpose of this study was to examine the efficacy and tolerability of venlafaxine and sertraline for the treatment of depression among nursing home residents . METHOD The study was a 10-week r and omized , double-blind , controlled trial of venlafaxine ( doses up to 150 mg/day ) versus sertraline ( doses up to 100 mg/day ) among 52 elderly nursing home residents with a DSM-IV depressive disorder and , at most , moderate dementia . The primary measure of outcome was the Hamilton Rating Scale for Depression ( HAM-D ) . Adverse events were monitored and recorded systematic ally during the trial . RESULTS Twelve subjects were discontinued due to serious adverse events ( SAE ) , 5 were discontinued due to other significant side effects , and 2 withdrew consent . Tolerability estimated by the time to termination was lower for venlafaxine than sertraline for serious adverse events ( log rank statistic = 5.28 , p = .022 ) , for serious adverse events or side effects ( log rank statistic = 8.08 , p = .005 ) , or for serious adverse events , side effects , or withdrawal of consent ( log rank statistic = 10.04 , p = .002 ) . Mean ( SD ) HAM-D scores at baseline were 20.2 ( 3.4 ) for sertraline and 20.3 ( 3.7 ) for venlafaxine ; intent-to-treat endpoint HAM-D scores were 12.2 ( 5.1 ) and 15.7 ( 6.2 ) ( F = 3.45 ; p = .069 ) . There were no differences in categorical responses for the intent-to-treat sample or completers . CONCLUSION In this frail elderly population , venlafaxine was less well tolerated and , possibly , less safe than sertraline without evidence for an increase in efficacy . This unexpected finding demonstrates the need for systematic research on the safety of drugs in the frail elderly |
13,766 | 24,807,583 | Although treatment of ASB with antimicrobial therapy may improve short-term microbiologic outcomes , the clinical significance is diminished because the effect is not sustained , there is no measurable improvement in morbidity or mortality , and some data indicate that therapy is deleterious . | Asymptomatic bacteriuria ( ASB ) is a common clinical finding characterized by the presence of bacteria in the urine of an individual without signs or symptoms suggestive of urinary tract infection .
Despite available guidelines on the diagnosis and management of ASB , it is often managed inappropriately .
We performed a systematic review of clinical trials evaluating antimicrobial therapy for ASB , identified translational barriers to evidence -based practice , and we offer strategies to optimize antimicrobial use for ASB . | Patients over the age of 65 years with clear catch specimens of urine containing organisms sensitive to norfloxacin were blindly r and omised to receive either norfloxacin in a dose of 400 mg twice daily for 7 days or a placebo for the same period . Urine cultures were repeated immediately prior to treatment , at the end of treatment and at 7 days , 1 month and 3 months after treatment . Physical and mental function were assessed by performing a Crighton Behavioural Rating Scale at the same time intervals . Observations were made on 29 each of subjects on norfloxacin and placebo . The proportions of patients abacteriuric at the end of treatment , 7 days and 3 months post- treatment were 16/24 ( 66 % ) , 12/24 ( 50 % ) and 5/24 ( 21 % ) in the norfloxacin group and 10/26 ( 38 % ) , 8/26 ( 31 % ) and 8/25 ( 32 % ) in the placebo group . Percentage calculations ( and denominators ) exclude those patients withdrawn or for whom there were no specimens available at the sampling interval in question . Means and 95 % intervals for the Crighton Behaviour Rating Scales initially and at 3 months in subjects on norfloxacin were 18.1 ( 15.1 - 20.7 ) and 19.1 ( 16.2 - 21.9 ) respectively . The same figures for the placebo group were 15.7 ( 12.6 - 18.8 ) and 16.6 ( 13.7 - 19.5 ) . It is concluded that a 7 day course of norfloxacin for the treatment of asymptomatic bacteriuria had no effect on the physical and mental function of elderly continuing care patients , and that one explanation for this is that there was a high rate of urinary re-infection Urinary incontinence is a multibillion-dollar health problem that afflicts almost 60 % of some 2 million residents of the 20 000 nursing homes in the United States . Bacteriuria is also prevalent in this population , and the two conditions commonly coexist [ 1 ] . Incontinent nursing home residents are frequently prescribed antimicrobial agents for urinary tract infections , but the quality and appropriateness of such prescriptions have been question ed [ 2 - 5 ] . Unnecessary antimicrobial treatment may result in the undesired development of resistant organisms and substantial unnecessary morbidity and health care expenditure . Well- design ed clinical trials have documented that treating asymptomatic bacteriuria in the nursing home population has no significant effects on morbidity and mortality and that it actually leads to the development of strains of bacteria that are resistant to commonly prescribed antimicrobial agents [ 6 , 7 ] . However , no studies have carefully examined the effects of eradicating bacteriuria on the severity of incontinence in this population . In a longitudinal study of a cohort of older women , Boscia and colleagues [ 8 ] found no difference in self-reported symptoms of incontinence in patients with and without bacteriuria . This was , however , a study of bacteriuria and not of incontinence , and the participants had , on average , mild incontinence [ 9 ] . In one study of behavioral therapy for incontinence in nursing home residents , incontinence appeared to worsen in several of the study participants when bacteriuria developed [ 10 ] . Epidemiologic studies from Europe have reached different conclusions about the association between bacteriuria and incontinence in the geriatric population [ 11 , 12 ] . Despite a lack of definitive data on the relation of bacteriuria to the pathogenesis and severity of incontinence in the nursing home population , recently implemented federal guidelines for the care of incontinence in nursing homes ( Resident Assessment Protocol ) [ 13 ] suggest that bacteriuria should be treated only when symptoms of urinary tract infection other than stable incontinence are present . If eradicating bacteriuria makes the bladder less irritable in this patient population , then the severity of incontinence and the use of expensive adult diapers might be reduced [ 14 ] . If , however , eradicating bacteriuria has no effect on the severity of incontinence , no rationale would exist for exposing incontinent nursing home residents with bacteriuria to the potential added morbidity and expense of antimicrobial therapy . We conducted a clinical trial to determine whether eradicating bacteriuria affects the severity of incontinence among nursing home residents . We defined bacteriuria as would a practicing clinician in a nursing home rather than by the strict definition used in most studies of the epidemiology of asymptomatic bacteriuria ( that is , two consecutive cultures with growth of more than 105 colony-forming units [ CFUs ] of the same organism ) . We hypothesized that sterilizing the urine would have no short-term effect on the severity of chronic incontinence in this population . Methods Setting Our study was the first phase of a multifaceted clinical trial addressing the assessment and treatment of incontinence in nursing homes . It was done in one nonprofit and five proprietary nursing homes located close to the offices of the University of California at Los Angeles Borun Center for Gerontological Research at the Jewish Home for the Aging . The nursing homes had a total of 1011 beds ( range , 99 to 256 beds ) and a total of 832 residents . Patients We identified potential patients by asking nursing home staff to identify residents who were incontinent of urine on a regular basis [ that is , several times per week to several times per day ] . Patients were excluded if 1 ) their care was being reimbursed by Medicare [ indicating either short-term rehabilitation or medical instability ] ; 2 ) their prognosis , as determined by the research staff nurse , was so poor that they would probably not live at least 3 to 4 months to complete the protocol ; 3 ) daytime incontinence was not documented by r and om-hour checks for wetness [ described below ] ; 4 ) the resident had a permanent indwelling bladder catheter ; 5 ) the resident failed a cognitive status screening test [ to pass , the resident had to either say their name or reliably point to one of two objects ] ; and 6 ) the resident manifested a severe behavioral disturbance , such as physical aggression or verbal abusiveness , during the wet-checking procedures . Informed consent was obtained from residents who could provide it ( as determined by a facility nurse or social worker ) . If the resident was not capable of consenting , their assent was obtained ( by describing a simple version of the protocol and then observing their cooperation as the protocol was initiated ) , and consent was then obtained from a responsible party . Procedures All patients for whom informed consent was obtained had a focused history , functional status assessment , cognitive assessment with the 30-point Mini-Mental State Examination , targeted physical examination , urinalysis , and urine culture . For the functional assessment , research staff used the Multidimensional Observational Scale for the Elderly Subject [ 15 ] to interview nursing home staff who knew the residents well . ( When our study was implemented , the Minimum Data Set was not yet available . ) Research staff used a st and ardized scale ( Performance on Timed Toileting Instrument [ 16 ] ) to objective ly assess functional status specifically related to toileting skills . The physical examination was done by research staff and a physician coinvestigator and included abdominal , genital , pelvic , rectal , and neurologic examinations . Research staff collected urine from female patients by cleaning the perineal area with Betadine and having them void into a fracture bed pan or measuring hat that had been cleaned with an antiseptic solution . We compared the culture results of urine sample s obtained by this procedure to urine sample s obtained by catheterization in 101 of our female patients [ 17 ] . The prevalence of bacteriuria in the catheterized specimens was 29 % . The sensitivity , specificity , and positive and negative predictive values of this procedure in detecting bacteriuria ( with a catheter specimen used as the criterion st and ard ) are 90 % , 92 % , 81 % , and 95 % , respectively . For men who could not void voluntarily , we used a previously vali date d technique that involved cleaning the glans penis with Betadine , applying a clean condom catheter , and processing the first voided specimen [ 18 ] . Urine specimens were subjected to screening tests done by research staff ( including a dipstick method for leukocyte esterase and nitrite and a rapid enzyme-based test for bacteriuria [ Uriscreen , Ventrex Laboratories , Portl and , Maine ] ) . A bio clinical laboratory used st and ard techniques to do a microscopic urinalysis and a urine culture and sensitivity test . We defined pyuria as the presence of more than 10 leukocytes per high-power field on microscopic examination of spun urine . Cultured specimens that grew more than 50 000 CFUs were considered to have significant growth . If significant growth of one or more urinary pathogens occurred on a second specimen , the patient was considered to be bacteriuric . Patients whose urine had significant growth of organisms that are not typically pathogens ( for example , lactobacillus and -streptococcus ) were not considered to be bacteriuric . Our quantitative definition of bacteriuria differs from the st and ard definition ( presence of more than 100 000 CFUs ) that has been used in most epidemiologic studies and intervention trials . However , there is controversy about the clinical significance of lower levels of growth [ 19 ] , and in some studies in the elderly , bacteriuria has been defined as growth of less than 100 000 CFUs [ 20 , 21 ] . We used the cutoff of 50 000 CFUs because our clinical laboratory reported results at this level , and we believe that most clinicians who practice in nursing homes would consider this to be significant growth when making decisions about treatment . Less than 10 % of our cultures that were considered to have significant bacteriuria had growth of more than 50 000 CFUs . In addition , each patient identified as bacteriuric who had growth of more than 50 000 CFUs on one culture did have a second culture with growth of more than 100 000 CFUs ; the only exceptions were two patients whose urine sample s before treatment were collected by catheterization ( see below ) . Most specimens obtained after antimicrobial treatment were collected by catheterization , which was done for a determination of postvoid residual volume in the second phase of the longer ongoing clinical trial . Six patients whose urine was initially not bacteriuric by the criteria outlined above were considered to be bacteriuric on the basis of the catheterized specimen and were enrolled in the antimicrobial trial . For these patients , follow-up urine sample s were collected by the methods described above rather than by repeat catheterization . Eradication of bacteriuria was documented by culture in all but seven cases ; in these cases , the screening tests were used to document that bacteriuria had been eradicated . We have shown that in our population , the presence of at least two negative results on these screening tests has a negative predictive value of more than 90 % [ 22 ] . Bacteriuric patients were r and omly assigned to receive either immediate treatment or delayed treatment ( which was administered 2 to 3 weeks after the immediate treatment group had been treated ) with a 7-day course of norfloxacin , 400 mg orally twice daily . In three cases , the organism or organisms were not susceptible to norfloxacin , and another antimicrobial agent ( trimethoprim-sulfamethoxazole ) was used on the basis of results of the sensitivity testing . Wet checks , the outcome measure used in our study and described in detail below , In a prospect i ve r and omized study ofloxacin ( 400 mg orally once daily ) versus co-trimoxazole ( 320/1,600 mg orally once daily ) were given for 3 weeks in 30 and 22 elderly semimobile patients respectively , suffering from asymptomatic bacteriuria . From the obtained results it was evident that : ( a ) ofloxacin was superior to co-trimoxazole regarding eradication of bacteriuria ( p less than 0.05 ) particularly in patients with a positive antibody-coated bacteria test ; ( b ) a high rate of superinfections and reinfections with strains resistant to co-trimoxazole was observed in both groups indicative of hidden underlying conditions predisposing to urinary tract infections and ( c ) ofloxacin did not accumulate in serum during prolonged therapy but the half-life ranged between 8.3 and 10.2 BACKGROUND Little is known about the role of asymptomatic bacteriuria ( AB ) treatment in young women affected by recurrent urinary tract infection ( UTI ) . We aim ed to evaluate the impact of AB treatment on the recurrence rate among young women affected by recurrent UTI . METHODS A total of 673 consecutive asymptomatic young women with demonstrated bacteriuria from January 2005 to December 2009 were prospect ively enrolled . Patients were split into 2 groups : not treated ( group A , n = 312 ) and treated ( group B , n = 361 ) . Microbiological and clinical evaluations were performed at 3 , 6 , and 12 months . Quality of life was also measured . Recurrence-free rate at the end of the entire study period was the main outcome measure . RESULTS At baseline , the 2 most commonly isolated pathogens were Escherichia coli ( group A , 38.4 % ; group B , 39.3 % ) and Enterococcus faecalis ( group A , 32.7 % ; group B , 33.2 % ) . At the first follow-up visit , there was no difference between the 2 groups ( relative risk [ RR ] , 1.05 ; 95 % confidence interval [ CI ] , 1.01 - 1.10 ) , whereas after 6 months , 23 ( 7.6 % ) in group A and 98 ( 29.7 % ) in group B showed recurrence with a statistically significant difference ( RR , 1.31 ; 95 % CI , 1.21 - 1.42 ; P < .0001 ) . At the last follow-up , 41 ( 13.1 % ) in group A and 169 ( 46.8 % ) in group B showed recurrence ( RR , 3.17 ; 95 % CI , 2.55 - 3.90 ; P < .0001 ) . One patient in group A and 2 patients in group B were found to have pyelonephritis . CONCLUSIONS This study shows that AB should not be treated in young women affected by UTI , suggesting it may play a protective role in preventing symptomatic recurrence BACKGROUND Persistent Escherichia coli asymptomatic bacteriuria ( ASB ) is common among persons with diabetes mellitus , but the duration of colonization and the rates of recolonization are unknown . We estimated the duration of colonization and the rate of recolonization among successively isolated E. coli from diabetic women with ASB and compared the virulence profiles with uropathogenic and commensal E. coli . METHODS A total of 105 women with diabetes were enrolled in a r and omized , controlled clinical trial for treatment of ASB in Manitoba , Canada , and were observed at least every 3 months for up to 3 years . We analyzed 517 isolates from 70 women with repeated E. coli ASB for genetic similarity using enterobacterial repetitive intergenic consensus polymerase chain reaction . Unique strains were screened for uropathogenic virulence characteristics using dot blot hybridization and compared with different collection s of E. coli isolates . RESULTS On average , differences were found among women assigned to treatment for ASB , those treated only for symptomatic infections , and untreated women in ( 1 ) follow-up time with bacteriuria ( 29 % , 31 % , and 66 % , respectively ; P<.001 ) , ( 2 ) duration of bacteriuria ( 2.2 , 2.5 , and 3.7 months , respectively ; P=.04 ) , and ( 3 ) carriage of unique isolates ( 2.4 , 2.8 , and 4 months , respectively ; P=.03 ) . Women assigned to antibiotic treatment usually had recurrent infection ( 76 % ) , 64 % of the time with a genetically new E. coli strain . Virulence characteristics of these isolates were comparable to those of fecal isolates from healthy women . CONCLUSIONS Treatment may reduce the overall proportion of time infected in the long term and carriage of a unique strain , but most treatment regimens were followed by subsequent recolonization . Infecting strains did not have virulence factors characteristic of uropathogenic E. coli Improving health care quality depends on having valid ways to measure quality . Unfortunately , there are few vali date d quality outcome measurements , because valid and feasible case-mix adjustors are lacking and patients are difficult to follow over time for clinical ly important outcomes , such as death . Processes of care are easier to identify and measure , but some of these measures will be proven invalid or inappropriate because their scientific rationale was flawed from the start , unanticipated consequences emerge after implementation , or later studies undermine them . We review how these issues played out in the measure of time to first antibiotic dose ( TFAD ) , also called door-to-needle time , for patients presenting to the hospital with community-acquired pneumonia ( CAP ) . We also propose lessons that can be learned from the experience . TFAD as a Quality Measure Community-acquired pneumonia is one of the most common admitting diagnoses in U.S. hospitals , accounting for more than 1 million hospitalizations yearly ( 1 ) , with short-term mortality rates ranging from 0.5 % to 27.1 % ( 2 ) . Given its risk , frequency , and perceived outcome variations , CAP was an obvious c and i date for quality measurement and improvement initiatives . Because outcome measurement in CAP was problematic for the usual reasons ( data collection burden , case-mix adjustment , and need for posthospital follow-up ) , investigators sought process measures associated with higher quality . During the 1990s , the notion of time-based quality measures gained favor because evidence emerged that rapid treatment of myocardial infa rct ion , and later trauma , stroke , and sepsis , improved outcomes ( 37 ) . Naturally , investigators began to examine whether rapid administration of antibiotics might improve CAP outcomes . In 1997 , a retrospective study of 14069 Medicare patients hospitalized for CAP found that , after adjustment for severity ( 2 ) and demographic factors , administration of antibiotics within 8 hours was associated with a lower 30-day mortality rate ( odds ratio [ OR ] , 0.85 [ 95 % CI , 0.75 to 0.96 ] ) ( 8) . Patients were included if they had chest radiography results within 2 days of admission consistent with pneumonia and an initial working diagnosis of pneumonia . In 2004 , a second retrospective study of 13771 Medicare patients ( age 65 years ) hospitalized for CAP ( 9 ) also found that , among the 75 % of patients without evidence of prehospital receipt of antibiotics , administration of antibiotics within 4 hours was associated with a lower 30-day mortality rate ( OR , 0.85 [ CI , 0.76 to 0.95 ] ) . Extrapolating these data to a hypothetical national Medicare sample , the authors estimated that achieving TFAD by 4 hours after presentation to the hospital would save more than 1200 lives yearly . The 2 studies reported that patients who received their first dose of antibiotics in the first hour of their emergency department stay had a higher mortality rate than those who received antibiotics later ; however , this finding was attributed to incomplete adjustment for severity of CAP and was therefore not felt to challenge the main conclusion about TFAD ( 8 , 9 ) . Two smaller studies of CAP found no association between early antibiotic administration and outcomes ( 10 , 11 ) . Nevertheless , the authors of the 2004 study ( 9 ) editorialized that the 4-hour TFAD quality measure was still valid ( 12 , 13 ) . Translation into a Performance St and ard Almost exclusively on the basis of results from the 1997 study , the Medicare National Pneumonia Project endorsed first antibiotics within 8 hours of hospital arrival as a CAP quality measure in 1998 . The Medicare National Pneumonia Project tightened its TFAD window to 4 hours in 2002 on the basis of the prepublication results of the 2004 study by Houck and colleagues ( 9 , 12 ) . In 2003 , the Infectious Diseases Society of America ( IDSA ) also endorsed a 4-hour timeframe ( 14 ) . With support from the Medicare National Pneumonia Project and IDSA and subsequent endorsement by the National Quality Forum , The Joint Commission and The Centers for Medicare & Medicaid Services ( CMS ) chose the 4-hour TFAD measure as 1 of their initial core measures of quality ( measure PN-5b ) . Since 2002 , this measure has been publicly reported for all U.S. hospitals . In 2006 , it became part of a measure set tied to additional payments under several pilot pay-for-performance programs ( 15 ) . The Response from Emergency Medicine The emergency medicine community began raising red flags about the TFAD measure soon after its formulation , and complaints from this community markedly increased after TFAD was publicly reported and became the subject of pay-for-performance programs ( 16 ) . Published studies challenging the measure soon followed . Although some question ed the association itself , most focused on the issue of diagnostic uncertainty . One study found that 22 % of 86 r and omly selected patients with pneumonia had uncertain presentations and often lacked infiltrates on chest radiography , which could have appropriately led to delayed antibiotic administration ( 17 ) . Another study documented cases that were labeled poor- quality care , in which delayed use of antibiotics was clinical ly appropriate ( 18 ) , whereas still another found that maneuvers to improve TFAD were not very cost-effective ( 19 ) . In fact , many eligible patients with a working diagnosis of CAP who did not receive antibiotics within 4 hours had no radiographic evidence of pneumonia in the emergency department and did not have a final emergency department diagnosis of CAP ( 20 , 21 ) . Moreover , other studies showed that TFAD measurement led to administration of antibiotics in many patients who proved not to have pneumonia or another infectious disease ( 22 , 23 ) . Finally , a recent systematic review concluded that evidence from observational studies fails to confirm decreased mortality with early administration of antibiotics in stable patients with [ CAP ] ( 24 ) . On the basis of these studies , analyses , and considerable anecdotal evidence , editorials in the emergency medicine literature argued vigorously for relaxing the TFAD st and ards ( 25 , 26 ) , pointing out that the measure was skewing emergency department triage priorities and promoting unnecessary antibiotic use ( 18 ) . The Response from Payers , Regulators , and Professional Societies Within months of the critical publications , The Joint Commission and CMS revisited measure PN-5b . In October 2006 , patients eligible for the measure had to have a final emergency department diagnosis of pneumonia ( rather than an initial working diagnosis ) and objective radiographic findings sometime during the hospitalization . Unfortunately , although the revised criteria solved some of the problems associated with PN-5b , they created new ones . For example , Fee and colleagues ( 27 ) worried that the new measures would generate pressure to administer antibiotics before patients were sent for computed tomography to rule out pulmonary embolism ( even in the face of nondiagnostic chest radiographs ) or to avoid writing pneumonia as the final emergency department diagnosis . In March 2007 , IDSA and the American Thoracic Society issued joint guidelines that abolished time-specific goals for CAP treatment , now recommending that patients receive their first dose of antibiotics as soon as possible after a definitive diagnosis of CAP , preferably in the emergency department ( 28 ) . One month later , The Joint Commission created a test measure ( PN-5c ) that relaxed the antibiotic administration window to 6 hours . That same month , the National Quality Forum withdrew its endorsement of measure PN-5b and endorsed PN-5c , which became the publicly reported measure in April 2008 . In addition , The Joint Commission created a new data element , diagnostic uncertainty , which may exclude patients from TFAD measurement ( 29 , 30 ) . Whether all of these revisions will solve the problems associated with measure PN-5b is unknown ; no study has yet shown a benefit from a 6-hour rule , and the diagnostic uncertainty construct has not , to our knowledge , been field-tested and vali date d. Unanticipated Consequences of TFAD Measurement and Reporting Prompt administration of antibiotics to patients with documented pneumonia makes sense , and seeking ironclad evidence to prove its value might seem to be analogous to requiring proof of the value of parachutes ( 31 ) . Moreover , a r and omized trial that withheld early antibiotic treatment in some patients with CAP would be unethical . It was therefore inevitable that decisions about the timing of antibiotic administration in CAP would be based on imperfect retrospective studies , out of necessity ( 8 , 9 ) . However , the TFAD measure was enacted largely on the evidence derived from 2 large studies , in which conditions ( retrospective review of patients with working diagnoses of pneumonia ) replicate only in part the predicament that busy emergency medicine physicians face daily : evaluating scores of patients with cough , fever , dyspnea , weakness , dizziness , confusion , or abdominal pain . As Pines ( 26 ) has written , Most ED [ emergency department ] patients do not present at triage with a sign on their forehead that reads , I have pneumonia ; give me antibiotics now ! Unlike myocardial infa rct ion , in which there is palpable clinical urgency to confirm the diagnosis and a series of tests ( cardiac biomarker measurement and electrocardiography ) available to reliably do so , no gold st and ard test for pneumonia exists . Although a triage rule of obtaining an electrocardiogram in any patient whose symptoms , signs , or risk factors make myocardial infa rct ion even a remote possibility makes perfect sense , a similar strategy for chest radiography would be re source intensive , often confusing ( given the relatively poor sensitivity and specificity of the test in CAP [ 32 ] ) , impractical , and even potentially harmful ( because of radiation exposure ) . In the days before measurement of TFAD , patients with uncertain diagnoses would continue to be evaluated until The goal of this study was to assess the overtreatment of asymptomatic bacteriuria ( ASB ) in hospitalized patients , calculate the total costs of inappropriate treatment , and determine if a multi-faceted educational intervention was effective in reducing the overtreatment of ASB in a re source -limited community hospital . The study encompassed three phases : a retrospective pre-intervention assessment of the baseline cost and treatment of ASB , the implementation of a multi-faceted educational intervention , and a prospect i ve post-intervention assessment of the efficacy of the intervention . A positive urine culture was defined by bacterial counts ≥105 cfu/mL. In the pre-intervention group , 64 ( 83 % ) of 109 patients were asymptomatic : 30 ( 47 % ) were treated . In the post-intervention group , 13 ( 17 % ) of 55 patients were asymptomatic : 2 ( 15 % ) were treated , ( p=0.04 ) . Fewer urine cultures were collected during the post-intervention period than the pre-intervention period ( 3,127 and 3,419 , respectively ) ( p<0.001 ) . The total cost of inappropriately treating ASB in the pre-intervention group was $ 1200 compared to $ 600 in the post-intervention group . The results demonstrated a significant decrease in the inappropriate treatment of ASB and the associated costs This prospect i ve r and omized study was undertaken to determine the efficacy of antimicrobial therapy compared with no therapy for bacteriuria in elderly ambulatory nonhospitalized women . Sixty-one women ( mean age , 85.8 years ) with bacteriuria were in the no therapy control group and 63 women ( mean age , 85.8 years ) with bacteriuria were in the therapy group ; none had symptoms of urinary tract infection . One short course of antimicrobial therapy achieved a cure rate of 68.3 % ( 43 of 63 women cured ) two weeks after treatment . During the six-month follow-up period , ten ( 16.4 % ) of 61 women in the no therapy group and five ( 7.9 % ) of 63 women in the therapy group developed symptomatic urinary tract infection . At the time of six-month follow-up , 19 ( 34.5 % ) of 55 women in the no therapy group and 35 ( 63.6 % ) of 55 women in the therapy group did not have bacteriuria . We conclude that for asymptomatic bacteriuria in elderly ambulatory nonhospitalized women , short-course antimicrobial therapy is effective at two-week follow-up and that antimicrobial therapy can eliminate bacteriuria in most of these women for at least a six-month period OBJECTIVE To determine whether treatment of symptomatic bacteriuria in older ambulatory women affects the subsequent development of symptoms of urinary tract infection . DESIGN A controlled clinical trial . PARTICIPANTS Older women not having urinary catheters . MEASUREMENTS Urine cultures every 6 months ( the same organism at 10(5 ) colony-forming units or more per mL on two midstream urine specimens defined asymptomatic bacteriuria ) and question naire surveys for the new development of symptoms of urinary tract infection ( dysuria , frequency , urgency , low back pain with fever ) 1 , 3 , and 6 months after the initial survey . RESULTS Of the 23 initially culture-positive participants receiving antibiotic treatment for symptomatic bacteriuria , nine were culture positive at 6 months , which contrasts with 18 of 27 who received no treatment or placebo , P = .05 . However , symptoms of urinary tract infection were more common in the antibiotic-treated group . CONCLUSION Antibiotic therapy effectively reduced the subsequent occurrence of positive urine cultures , but symptoms were not reduced . Based on this study of morbidity , previous studies failing to show any relation to mortality , and the cost and complications of antibiotic therapy in the older population , treatment of asymptomatic bacteriuria in older women is contraindicated Abstract Objective To assess whether a multifaceted intervention can reduce the number of prescriptions for antimicrobials for suspected urinary tract infections in residents of nursing homes . Design Cluster r and omised controlled trial . Setting 24 nursing homes in Ontario , Canada , and Idaho , United States . Participants 12 nursing homes allocated to a multifaceted intervention and 12 allocated to usual care . Outcomes were measured in 4217 residents . Interventions Diagnostic and treatment algorithm for urinary tract infections implemented at the nursing home level using a multifaceted approach — small group interactive sessions for nurses , videotapes , written material , outreach visits , and one on one interviews with physicians . Main outcome measures Number of antimicrobials prescribed for suspected urinary tract infections , total use of antimicrobials , admissions to hospital , and deaths . Results Fewer courses of antimicrobials for suspected urinary tract infections per 1000 resident days were prescribed in the intervention nursing homes than in the usual care homes ( 1.17 v 1.59 courses ; weighted mean difference −0.49 , 95 % confidence intervals −0.93 to −0.06 ) . Antimicrobials for suspected urinary tract infection represented 28.4 % of all courses of drugs prescribed in the intervention nursing homes compared with 38.6 % prescribed in the usual care homes ( weighted mean difference −9.6 % , −16.9 % to −2.4 % ) . The difference in total antimicrobial use per 1000 resident days between intervention and usual care groups was not significantly different ( 3.52 v 3.93 ; weighted mean difference −0.37 , −1.17 to 0.44 ) . No significant difference was found in admissions to hospital or mortality between the study arms . Conclusion A multifaceted intervention using algorithms can reduce the number of antimicrobial prescriptions for suspected urinary tract infections in residents of nursing homes BACKGROUND Clinical practice guidelines ( CPGs ) have been promoted as a strategy to measure and improve the quality of patient care . However , more effort has been expended on creating guidelines than implementing them . We surveyed family physicians about their knowledge of and attitudes toward 3 well-publicized CPGs . METHODS A survey question naire was sent to a national sample of 600 family physicians selected at r and om from a file from the American Academy of Family Physicians ( AAFP ) . RESULTS After 2 mailings , the response rate was 71 % . For each of the 3 guidelines , roughly 60 % of respondents were familiar or somewhat familiar with the CPG . More than half of family physicians studied said they have changed their medical practice s based on CPGs , and only 3 % said they do not believe in guidelines and would not use them . Use of CPGs was lowest among physicians in solo practice and among those working in rural areas . However , no significant differences in CPG use or familiarity were noted based on number of years in practice . Many respondents indicated an interest in keeping CPGs current via the internet . CONCLUSIONS Most American family physicians find CPGs to be helpful , and familiarity with them is fairly uniform across most subgroups studied Fifty elderly ( mean age , 83.4 + /- 8.8 years ) institutionalized women with asymptomatic bacteriuria were r and omly assigned either to receive therapy for treatment of all episodes of bacteriuria identified on monthly culture or to receive no therapy unless symptoms developed . Subjects were followed for one year . The therapy group had a mean monthly prevalence of bacteriuria 31 + /- 15 percent lower than those in the no-therapy group , but periods free of bacteriuria lasting six months or longer were documented for only five ( 24 percent ) subjects . For residents receiving no therapy , 71 percent showed persistent infection with the same organism(s ) . Antimicrobial therapy was associated with an increased incidence of reinfection ( 1.67 versus 0.87 per patient-year ) and adverse antimicrobial drug effects ( 0.51 versus 0.046 per patient-year ) as well as isolation of increasingly resistant organisms in recurrent infection when compared with no therapy . No differences in genitourinary morbidity or mortality were observed between the groups . Thus , despite a lowered prevalence of bacteriuria , no short-term benefits were identified and some harmful effects were observed with treatment of asymptomatic bacteriuria . These data support current recommendations of no therapy for asymptomatic bacteriuria in this population In a prospect i ve longitudinal study , ambulatory elderly men were followed from 1 to 4.5 years to gain insight into the prevalence rates , clinical characteristics , and patterns of clinical ly inapparent ( asymptomatic ) bacteriuria ( CIB ) . The prevalence of CIB was 12 % ( 29/238 ) and increases with age . Unlike the gram-negative organisms that cause overt urinary tract infection in this age group , gram-positive organisms dominated the CIB group . Both the CIB and abacteriuric patients have multiple chronic medical conditions and are indistinguishable on that basis . Twenty-nine elderly men with bacteriuria and 105 abacteriuric subjects were followed with serial urine cultures . During the study period the bacteriuric subjects exhibited spontaneous temporary or permanent resolution ( 76 % , 22/29 ) , intermittency ( 21 % , 6/29 ) , and probable bacterial persistence ( 38 % , 11/29 ) . No consistent pattern of bacteriuria was evident . Therefore , antimicrobial therapy is not warranted in the treatment of asymptomatic or clinical ly inapparent bacteriuria in ambulatory elderly men Asymptomatic bacteriuria , a common problem of the elderly , has been associated with increased mortality in the elderly [ 1 - 4 ] , although not all studies have confirmed this finding [ 5 - 9 ] . To reconcile these conflicting results , we did a longitudinal study of urinary tract infection in ambulatory elderly women to evaluate the putative relation between asymptomatic bacteriuria and mortality . We considered resolution of this issue to be important because of the implication s for clinical practice . If asymptomatic bacteriuria were shown to be an independent risk factor for mortality and if it could also be shown that eradication of the infection by antimicrobial therapy decreased the risk for death , then screening and antimicrobial treatment of elderly ambulatory women with asymptomatic bacteriuria might be warranted and the cost of identifying and treating such infections might be justified . Conversely , failure to confirm a relation would support the view that programs to screen for bacteriuria would not be justified if their goal was to enhance survival . This report summarizes the findings of our 9-year study to determine whether asymptomatic bacteriuria in elderly ambulatory women is a marker of increased mortality and , if so , whether it is because of an association with other determinants of mortality or because asymptomatic bacteriuria is itself an independent cause , the removal of which might improve longevity . The components of the study were a longitudinal study in elderly ambulatory women to compare mortality in those with and without asymptomatic bacteriuria and a double-blind , controlled clinical trial in which antimicrobial therapy was administered for asymptomatic bacteriuria to assess whether treatment decreases mortality . Methods Participant enrollment and the participating institutions have been described previously [ 10 , 11 ] . Elderly ambulatory residents of the Philadelphia Geriatric Center and of 21 continuing care retirement communities in the greater Philadelphia metropolitan area who gave informed consent were enrolled in this long-term study of urinary tract infection in the elderly . Enrollment continued throughout the course of the study . Philadelphia Geriatric Center houses about 1000 residents who primarily are Jewish ; incomes are higher than the maximum Social Security payment ; and congregate living is provided either in an apartment house or in a nursing home . In contrast , the continuing care retirement communities are smaller ( bed size range , 108 to 675 ) ; incomes are higher ; residents are primarily not Jewish ; and a higher proportion of residents are fully independent . All female residents were eligible to participate except those with indwelling catheters or those incapable of providing midstream clean-catch urine specimens for culture . Specimens were obtained on enrollment and every 6 months thereafter . The protocol was approved by the appropriate institutional review boards , and informed consent was obtained from the participants or their surrogates . Table 1 shows the study periods and chronology of important study events . Throughout the study , urine cultures were obtained at about 6-month intervals . An observational study to compare mortality of bacteriuric and nonbacteriuric volunteers regardless of treatment status was begun in January 1983 and ended in February 1992 . Initially , residents with asymptomatic bacteriuria were identified and followed , but treatment was not given . However , on 10 October 1983 , a controlled clinical trial was begun to evaluate whether antimicrobial therapy for asymptomatic bacteriuria decreased mortality ; every bacteriuric study participant identified after this date was enrolled in the trial . Mortality among residents who were treated with antimicrobial agents for asymptomatic bacteriuria each time it was present was compared with the mortality of those who received no therapy for their episodes of bacteriuria . At enrollment , participants were assigned to the treatment group or to the control group based on the last digit of an identification number unrelated to the conduct of the study . Urine cultures were read by personnel blinded to the study group assignment . When asymptomatic bacteriuria was identified , participants with even numbers were given antimicrobial therapy according to a defined protocol ( see below ) ; those with odd numbers served as controls . From 10 October 1983 to 10 December 1987 , controls were given no therapy . Thereafter , on the advice of external consultants , the protocol was changed so that participants not assigned to the active treatment group were given placebo pills in place of no treatment . The placebo pills were identical in appearance to each of the antimicrobial agents used . Thus , after 10 December 1987 , volunteers with asymptomatic bacteriuria were given therapy in either the form of antimicrobics or placebo after a new consent was obtained ; the volunteers and clinical personnel did not know study group assignments . Table 1 . Study Design and Enrollment The methods for collecting first-morning urine and for processing the specimens in our research microbiology laboratory have been previously described [ 10 , 11 ] . Participants were considered to have asymptomatic bacteriuria on a survey if two urine specimens were culture-positive ( 105 colony-forming units or more per mL of urine ) for the same organism within 2 weeks . From 10 October 1983 through 10 December 1987 , residents with asymptomatic bacteriuria who were assigned to receive antimicrobial treatment were given short-course therapy ( single dose or 3 days ) as follows : trimethoprim , 200 mg in one dose ; trimethoprim-sulfamethoxazole , 1 double-strength tablet ; cefaclor , 500 mg three times a day for 3 days ; amoxicillin , 250 mg three times a day for 3 days ; carbenicillin indanyl sodium , four times a day for 3 days ; or macrodantin , 100 mg twice a day for 3 days , depending on susceptibility of the infecting organism and history of drug allergy . Participants were considered cured if test-of-cure cultures contained less than 104 colony-forming units/mL of the infecting organism on cultures obtained 5 to 10 days after antimicrobial treatment or placebo or on cultures obtained on the next survey in those receiving no therapy . When positive for the same organism , patients were retreated for 14 days with test-of-cure culture afterward . If the organism differed , reinfection was diagnosed and a single dose or 3-day therapy was used ; treatment failures were treated as defined above . Test-of-cure cultures were obtained again after therapy and , if positive for the same organism , participants were treated for 14 days . No treatment was given after failure of a 14-day course or two reinfections after short courses . Controls received no therapy during this period . After 10 December 1987 , culture-positive patients were assigned to antimicrobial treatment or placebo . Single-dose therapy was given with trimethoprim , 200 mg , or norfloxacin , 400 mg , depending on the susceptibility of the organism ; the same drugs ( trimethoprim , 100 mg twice daily , and norfloxacin , 400 mg twice daily ) were used for 14 days of therapy in patients failing single-dose therapy . Single-dose therapy was used for reinfection . The placebo pills and regimen given to a placebo recipient matched the regimen administered to the participant in the active treatment group who was treated most recently ( for example , if the active treatment participant received short-course trimethoprim followed by 14 days of trimethoprim , the next placebo participant received short-course trimethoprim placebo followed by 14 days of trimethoprim placebo ) . Symptomatic infections were managed by the participant 's personal physician or by physicians associated with the facility in which the patient lived . Reports were received on an annual or semiannual basis from the participating institutions that detailed changes in their census . All deaths were noted , and registry coordinators review ed available documents to confirm each death . After 1 September 1987 , detailed functional and mental status assessment s were done when persons were newly enrolled into the study or were seen for an annual follow-up visit using techniques previously described [ 11 , 12 ] . Self-care activities of daily living were assessed by a modification of the Multilevel Assessment Instrument [ 13 ] , and mental status was assessed using a modified version of the Kahn and Goldfarb question naire [ 14 ] . A subjective measure of global health status ( scale , 1 to 4 ) was based on responses to the question : How do you rate your health : excellent ( score 1 ) , good , fair , and bad or poor ( score 4 ) ? Diagnoses recorded in the person 's medical record were extracted and provided a more objective measure of health status ; they were coded according to the ICD-9-CM three-digit codes [ 15 ] . The Geriatric Depression Scale [ 16 ] was used to assess depressive symptoms , and walking ability was assessed on a scale of 1 ( specialized help needed ) to 3 ( help not needed ) [ 11 ] . Statistical Analysis Observational Study These analyses compared residents with asymptomatic bacteriuria with residents who did not have asymptomatic bacteriuria on any of the urine culture surveys done during the period of their participation . For the purpose s of the survival analyses in the observational study , the results of urine cultures were considered a time-dependent covariate . Accordingly , participants were considered in the ever-positive group once asymptomatic bacteriuria was identified , and all subsequent time on study was contributed to the group with positive cultures regardless of urine culture results on subsequent surveys . Persons entering the study with a negative urine culture were considered in the never-positive group until asymptomatic bacteriuria was identified . Thus , a person who entered the study with negative cultures and who later became culture-positive would have contributed person-time to the follow-up of those in the BACKGROUND Asymptomatic bacteriuria is common among women with diabetes , and the treatment of such infections has been recommended to prevent complications related to symptomatic urinary tract infection . METHODS We enrolled women ( > 16 years of age ) with diabetes , bacteriuria ( > or = 105 colony-forming units of an organism per milliliter in cultures of two consecutive urine specimens ) , and no urinary symptoms ; 50 were r and omly assigned to receive placebo and 55 to receive antimicrobial therapy . For the first six weeks , which included the initial course of treatment , the study was placebo-controlled and double-blind . Subsequently , the women were screened for bacteriuria every three months for up to three years ; antimicrobial therapy was provided to women in the antimicrobial-therapy group who had asymptomatic bacteriuria . RESULTS Four weeks after the end of the initial course of therapy , 78 percent of placebo recipients had bacteriuria , as compared with 20 percent of women who received antimicrobial agents ( P<0.001 ) . During a mean follow-up of 27 months , 20 of 50 women in the placebo group ( 40 percent ) and 23 of 55 women in the antimicrobial-therapy group ( 42 percent ) had at least one episode of symptomatic urinary tract infection . The time to a first symptomatic episode was similar in the placebo group and the antimicrobial-therapy group ( P=0.67 by the log-rank test ) , as were the ( + /-SD ) rates of any symptomatic urinary tract infection ( 1.10+/-0.17 and 0.93+/-0.14 per 1000 days of follow-up , respectively ; relative risk , 1.19 ; 95 percent confidence interval , 0.28 to 1.81 ) , pyelonephritis ( 0.28+/-0.08 and 0.13+/-0.05 per 1000 days of follow-up ; relative risk , 2.13 ; 95 percent confidence interval , 0.81 to 5.62 ) , and hospitalization for urinary tract infection ( 0.10+/-0.36 and 0.06+/-0.22 per 1000 days of follow-up ; relative risk , 1.93 ; 95 percent confidence interval , 0.47 to 7.89 ) . The women in the antimicrobial-therapy group had almost five times as many days of antibiotic use for urinary tract infection as did the women in the placebo group ( 158.2+/-1.7 vs. 33.7+/-0.91 per 1000 days of follow-up ; relative risk , 0.21 ; 95 percent confidence interval , 0.20 to 0.22 ) . CONCLUSIONS Treatment of asymptomatic bacteriuria in women with diabetes does not appear to reduce complications . Diabetes itself should not be an indication for screening for or treatment of asymptomatic bacteriuria To test whether longer duration of treatment of asymptomatic bacteriuria in old age could improve the efficacy of cotrimoxazole therapy , three regimens were given to 75 ambulant bacteriuric residents of a retirement home , aged greater than or equal to 68 years . The groups and regimens were : A:23 subjects ( 160/800 mg b.i.d . orally x 3 days ) . B : 24 subjects ( 160/800 mg i.m . x 10 days ) ; C : 28 subjects ( 160/800 mg b.i.d . orally x 20 days ) . One week , one month and five months post-therapy urines were negative in 78.3 % vs 52.9 % vs 42.9 % of group A , in 54.2 % vs 56.5 % vs 50 % of group B and in 57.1 % vs 60.7 % vs 68 % of group C subjects respectively . The data indicate that : 1 ) the efficacy of any schedule is only moderate irrespective of the presence of antibody-coated bacteria in urine ; 2 ) a 3-day course appears more effective at one week post-therapy ; 3 ) at one and five months greater than or equal to 50 % of the subjects were infection-free , the 20 day treatment result ing in fewer failures ; 4 ) subjects with long-term eradication had no mobility problem , low serum creatinine and a normal urinary tract as seen by ultrasound BACKGROUND This study was undertaken to assess the impact of traditionally unmeasured patient-centered factors on primary care physicians ' decisions to adhere to an evidence -based clinical practice guideline for heart failure . METHODS Experimental and control scenarios were developed to test three patient-centered factors hypothesized to influence physician nonadherence to a heart failure guideline : patient concerns about finances , quality of life , and location of care . Each factor represented an implicit patient goal potentially in conflict with a goal of the guideline recommendations . A control scenario for one factor and an experimental scenario for a second were placed within a cross-sectional survey and question naires were mailed by r and om assignment to 978 Upstate New York family physicians . Experimental and control responses were compared by chi square . RESULTS The response rate was 47 % ( n = 456 ) . Each hypothetical patient-centered factor result ed in significant reductions in physicians ' predicted adherence . Reductions in reported pharmaceutical usage and testing of left ventricular ( LV ) function were associated with patient financial difficulties ( P < .01 ) . The poor quality -of-life scenario was associated with reduced testing for LV function but increased discussion of advance directives ( P < .01 ) . The clinical scenario limiting access to services for a rural patient was associated with decreases in physician choice of LV function tests and cardiology referrals ( P < .05 ) . CONCLUSIONS Patient-specific factors are associated with physician decisions to comply with guideline recommendations . These findings suggest that performance profiles measuring physician adherence to guidelines should be interpreted with caution , and that current case-mix method ologies may not adequately control for patient-centered factors that may influence health care quality To establish the value of screening for significant bacteriuria in an adult nonpregnant population clinical radiological and laboratory findings of a group of 107 women with asymptomatic bacteriuria are compared with a matched control group . Dysuria frequency and nocturia and loin pain and fever were more frequent in the group of bacteriuric patients than controls . Oral contraceptives were used nearly twice as often by the bacteriuric subjects than controls ; diastolic blood pressure serum urea and ESR differed significantly between the 2 groups . There were significantly more urinary tract abnormalities found in the bacteriuric subjects than in the controls . Screening was ineffective in preventing the development of symptoms CONTEXT While urine culture contamination may not be completely avoidable , some laboratories have lower contamination rates than others . A College of American Pathologists ( CAP ) 1998 Q-Probes study showed that many interventions commonly assumed to reduce contamination were not demonstrably effective . This article revisits the issue . OBJECTIVE To examine the frequency of urine culture contamination , review current laboratory practice s in the collection of urine culture specimens , and determine practice characteristics that may be associated with the contamination rate . DESIGN Laboratories participating in a CAP Q-Probes study were required to prospect ively collect data on 120 consecutive urine culture specimens and provide information on the patient 's demographics ( age and sex ) , the location where the specimen was collected , how the specimen was h and led , the number of isolates in quantities greater than or equal to 10,000 colony-forming units (CFU)/mL , and whether the laboratory considered the specimen to be contaminated . Specific inclusion and exclusion criteria were provided to the participants . Each laboratory completed a supplemental question naire that probed for specific laboratory urine culture collection practice s. RESULTS One hundred twenty-seven laboratories participated in the study . Results from a total of 14,739 urine specimens were received . For the purpose of this study , a urine specimen was determined to be contaminated if the culture yielded more than 2 isolates in quantities greater than or equal to 10,000 CFU/mL. Using these criteria the median institution had a contamination rate of 15.0 % . Laboratories in the 10th percentile ( low performance ) had an average contamination rate of 41.7 % , while laboratories in the 90th percentile had an average rate of 0.8 % . The collection site had no influence on the contamination rate , but post collection processing , especially refrigeration of the specimen , had a substantial effect . Providing instruction to patients produced a statistically significant lowering of contamination rates for specimens from male patients ( P = .006 ) but not for female patients , except when written instructions were provided in the emergency room , in which case specimen contamination rates for both male and female patients dropped ( P = .01 ) . CONCLUSIONS The median contamination rates remain at a level comparable to the results seen in a previous Q-Probes study , and some laboratories have very high contamination rates . Specimen refrigeration is associated with lower overall urine culture specimen contamination rate . Providing patient instruction is also associated with lower contamination rates under specific circumstances In 1963 , a r and om sample study was performed in Turku , including 405 subjects over 65 years of age . In this study , urinary tract infection was detected in 11 % of the men and in 33 % of the women . BACKGROUND In long-term care facilities , treatment of asymptomatic bacteriuria ( ASB ) is common . However , r and omized , controlled trials suggest that such treatment offers no benefit and may promote antimicrobial resistance . METHODS For 3 months before and 30 months after instituting an educational intervention , we monitored the appropriateness of urine culture collection and antibiotic treatment based on published guidelines and examined the effect on total antimicrobial use . The intervention included education of nursing staff to discourage the collection of urine cultures in the absence of symptoms suggestive of urinary tract infection and of primary care practitioners to not treat ASB . RESULTS In preintervention period , 23 of 38 ( 61 % ) antibiotic regimens prescribed for urinary tract indications were for ASB . In the 6 months after the intervention , inappropriate su bmi ssion of urine cultures decreased from 2.6 to 0.9 per 1000 patient-days ( P < .0001 ) , overall rate of treatment of ASB was reduced from 1.7 to 0.6 per 1000 patient-days ( P = .0017 ) , and total antimicrobial days of therapy were reduced from 167.7 to 117.4 per 1000 patient-days ( P < .001 ) . These reductions were maintained for 30 months after beginning the intervention . CONCLUSION Educational interventions requiring minimal re sources can result in sustained reductions in inappropriate treatment of ASB in long-term care and decreased total antimicrobial use . Education of the nursing staff regarding appropriate criteria for requesting urine cultures should be a component of such interventions Recent reports have demonstrated an association between bacteriuria and excess mortality . Therefore , 40 in patients 60 or more years old with asymptomatic bacteriuria participated in a double-blind trial to assess the effect of 1-day treatment with trimethoprim . The patients were allocated r and omly to receive 100 mg . trimethoprim ( 20 patients ) or placebo ( 20 patients ) to be taken in the morning and evening for 1 day . All patients treated with trimethoprim obtained sterile urine , whereas all patients treated with placebo remained bacteriuric ( p less than 0.002 ) . No side effects were recorded . However , many of the cured patients suffered rapid reinfection . Of the 20 initially cured patients 14 ( 70 per cent , 95 per cent confidence limits 46 to 88 per cent ) had recurrent bacteriuria after 6 weeks , indicating that although this treatment is effective immediately it imparts no long-term effect Abstract This study aim ed to determine whether long-term oral fluoroquinolone administration exerts a significant positive effect on mobility and mortality in elderly subjects with asymptomatic bacteriuria . 132 institutionalized patients were divided into 4 groups : groups A and B were treated with ofloxacin while groups C and D were positive and negative control groups . At 3 months following treatment discontinuation 57 % , 53 % and 26 % of patients in groups A , B and C respectively had negative urine cultures and all subjects were alive . After 3 years , positive cultures were 41.7 % , 54.5 % and 42.9 % respectively for uncatheterized subjects per group vs. 13.3 % for group D. In groups A , B , and C 20 % , 15 % and 29 % of survivors respectively had permanent bladder catheters vs. 11.5 % of survivors of group D. Survival in groups A , B and C , combined or per group did not differ significantly from group D , although it was shorter . “ Pulse ” antibiotic administration tended to perform better , in terms of clearing infection and maintaining continence . At 3 years , bacteriuria recurred and the need for bladder catheterization was doubled . Mortality increased independently of treatment . More elderly bacteriuric subjects should be studied to evaluate mobility and mortality issues Over a two-year period we obtained monthly urine sample s from all noncatheterized male residents on two geriatric wards to determine the occurrence and optimal management of bacteriuria in this population . Among 88 men the prevalence of bacteriuria was 33 per cent , and the incidence was 45 infections per 100 patients per year . Outcomes after single-dose therapy for asymptomatic bacteriuria with 43 courses of trimethoprim/sulfamethoxazole and 23 of tobramycin included 15 cures , 40 relapses , and 11 treatment failures . Thirty-six residents who had a relapse or in whom single-dose therapy failed were r and omly assigned to receive therapy to eradicate bacteriuria or to receive no therapy . All 20 residents who received no therapy remained bacteriuric . The 16 residents who received therapy had fewer months of bacteriuria after r and omization , but at the end of the study only one remained free of bacteriuria . Mortality and infectious morbidity after r and omization were similar in the two groups . These data suggest that asymptomatic bacteriuria is common in elderly institutionalized men and that therapy is neither necessary nor effective |
13,767 | 24,941,398 | Pressure symptoms or cosmetic complaints were not investigated in LT4 studies .
Nodule volume reductions were achieved by PEI , LP and RF , and to a lesser extent , by LT4 .
However , the clinical relevance of this outcome measure is doubtful .
PEI , LP and RF led to improvements in pressure symptoms and cosmetic complaints .
Adverse events such as light-to-moderate periprocedural pain were seen after PEI , LP and RF . | BACKGROUND Thyroid nodules ( TN ) are common in the adult population .
Some physicians use suppressive levothyroxine ( LT4 ) therapy to achieve a reduction in the number and volume of TN .
In addition , minimally invasive treatments , such as percutaneous ethanol injection ( PEI ) sclerotherapy , laser photocoagulation ( LP ) , and microwave ( MW ) , radiofrequency ( RF ) and high-intensity focused ultrasound ( HIFU ) ablation , have been proposed , especially for pressure symptoms and cosmetic complaints , as an alternative to surgery .
However , the risk to benefit ratio of all treatments for benign TN is currently unknown .
OBJECTIVES To assess the effects of LT4 or minimally invasive therapies ( PEI , LP , and RF/HIFU/MW ablation ) on benign TN . | Patients with solitary thyroid nodules that are benign on aspiration biopsy are often treated nonsurgically . To find out if thyroxine therapy is effective , 74 patients were r and omized to receive levothyroxine treatment or nothing . There were 8 males and 66 females . Their mean age was 39 years . The mean nodule size was 3.6 cm and the mean nodule duration was 11 months . All patients had normal serum thyroxine and thyroid stimulating hormone ( TSH ) levels , and positive thyrotropin releasing hormone ( TRH ) tests . The dose of thyroxine was adjusted until the TRH test was negative . Patients were followed at 6-month intervals in the first 2 years and yearly thereafter , with measurement of the nodule diameter . The mean follow-up period was 1.5 years . In the 37 patients receiving thyroxine therapy , 8 had disappearance of nodules , 6 had greater than 50 % reduction in nodule size . In 19 , the nodules were unchanged and in 4 , the nodules were enlarged . In the 37 patients receiving no drug , 8 had disappearance of nodules , 5 had greater than a 50 % reduction in nodule size , 17 had nodules unchanged , and 7 had enlarged nodules ( p > 0.9 ) . The mean reduction in nodule diameter at various follow-up periods was greater in the thyroxine group , but the difference did not reach statistical significance . Carcinoma was found in 1 patient in each group and both of them experienced nodule enlargement . We conclude that an adequate suppressive dose of levothyroxine does not alter the natural course of benign solitary thyroid nodules . An enlargement of the nodule or a change in its consistency should be further investigated to exclude malignancy . RésuméLes patients présentant un nodule thyroïdien solitaire bénin à la biopsie par aiguille ne sont souvent pas traités chirurgicalement . Pour évaluer 1'efficacité de la thyroxine dans ces cas , 74 patients ont été r and omisés , recevant de la lévothyroxine ou rien . Il y avait 8 hommes et 66 femmes ; 1'âge moyen était de 39 ans . La taille moyenne du nodule était de 3.6 cm , et 1'évolution moyenne était de 11 mois . Tous les patients avaient un taux sérique de thyroxine et de TSH normal ; le test de la TRH était normal . La thyroxine a été dosée jusqu'à obtenir une réponse négative à la TRH . Les patients étaient suivis à intervalles de 6 mois pendant 2 ans puis une fois par an . Le diamètre du nodule etait mesuré à chaque examen . Le suivi moyen était de 1.5 ans . Pour 37 patients qui recevaient de la thyroxine , le nodule a disparu chez 8 et s'est réduit de plus de 50 % chez 6 . Le nodule était inchangé chez 19 et a continué d'évoluer chez 4 . Parmi les 37 patients n'ayant pas reçu de thyroxine , le nodule a disparu chez 8 , s'est réduit en taille de plus de 50 % chez 5 , est resté inchangé chez 17 et a augmenté de volume chez 7 ( p > 0.9 ) . La réduction moyenne du diamètre du nodule était supérieure chez les patients dans le groupe thyroxine mais cette différence n'était pas statistiquement significative . Dans chaque groupe , il y avait un cancer , et dans les deux cas , le nodule avait grossi . Nous concluons que la lévothyroxine aux doses suppressives ne modifie pas 1'évolution des nodules solitaires de la thyroïde . Une augmentation du volume ou une modification dans sa consistance dem and e des examens complémentaires pour exclure une évolution maligne . ResumenLos pacientes con nódulos tiroideos solitarios que demuestran ser benignos en la biopsia por aspiración frecuentemente reciben tratamiento no operatorio . Con el objeto de determinar si el tratamiento con tiroxina es efectivo , se estudiaron 74 pacientes mediante aleatorización : un grupo recibió levotiroxina y el otro ninguna terapia endocrina . El grupo tuvo 8 hombres y 66 mujeres ; la edad promedio fue 39 años . El tamaño promedio de los nódulos fue 3.6 cm y el promedio de evolución del nódulo fue 11 meses . La totalidad de los pacientes exhibió niveles séricos de tiroxina y de TSH normales , y pruebas normales de TRH . La dosis de tiroxina fue ajustada hasta que la prueba de TRH result ó negativa . Los pacientes fueron seguidos a intervalos de 6 meses en el curso de los primeros 2 años , y anualmente de ahí en adelante , registr and o en cada visita el diámetro del nódulo . El promedio del seguimiento fue 1.5 años . En el grupo de 37 pacientes tratados con tiroxina , 8 exhibieron desaparición de los nódulos y 6 reducción de más del 50 % en el tamaño del nódulo ; en 19 los nódulos no demostraron cambio y en 4 aumentaron de tamaño . En los 37 pacientes que no recibieron terapia , 8 demostraron desaparición del nódulo y 5 reduccción de más del 50 % en su tamaño ; en 17 el nódulo no modificó el tamaño y en 7 el nódulo se agr and ó ( p > 0.9 ) . La reducción promedio en el diámetro del nódulo observada en los diferentes períodos de seguimiento fue mayor en el grupo tratado con tiroxina , pero la diferencia no alcanzó significancia estadística . Se halló carcinoma en un paciente en cada grupo , y ambos mostraron crecimiento del nódulo . Hemos concluído que una dosis supresiva de levotiroxina no altera la evolución natural de los nódulos tiroideos benignos . El crecimiento del nódulo o un cambio en su consistencia debe ser investigado para excluir posible malignidad High-frequency ultrasound examination of the thyroid was performed in 253 subjects ( 130 women and 123 men ; age range , 19 - 50 years ) that were r and omly selected from the population in an area of Finl and where goiter is not endemic . Thyroid echo abnormalities were detected in 69 subjects ( 27.3 % ) . Prevalence of abnormalities increased with age , and women showed more lesions than did men in each of the 3 decades . The abnormality was solitary in 39 subjects ( 57 % ) , multiple in 15 ( 22 % ) , and diffuse in 15 ( 22 % ) . Of the 68 individual nodules , 48 ( 70 % ) were smaller than 1 cm in diameter . Anechoic rounded nodules 1 - 5 mm in diameter were found in 28 subjects . Fine-needle aspiration biopsy was performed in 30 subjects . Cytologic examination revealed no unequivocal malignancies . In eight subjects ( 3.2 % ) with a diffuse echo abnormality , cytologic evaluation indicated lymphocytic thyroiditis . It is concluded that the prevalence of small thyroid echo abnormalities in a r and omly selected adult population is rather high , a fact that supports use of a conservative approach to these types of findings Abstract Objective . Many patients with nonerosive reflux disease ( NERD ) have insufficient relief on proton pump inhibitors ( PPIs ) . Some patients have a hypersensitive esophagus and may respond to transient receptor potential vanilloid 1 ( TRPV1 ) antagonists . Aim . To investigate the effect of the TRPV1 antagonist AZD1386 on experimental esophageal pain in NERD patients . Material and methods . Enrolled patients had NERD and a partial PPI response ( moderate-to-severe heartburn or regurgitation ≥3 days/week before enrolment despite ≥6 weeks ' PPI therapy ) . Fourteen patients ( 21–69 years , 9 women ) were block-r and omized into this placebo-controlled , double-blinded , crossover study examining efficacy of a single dose ( 95 mg ) of AZD1386 . On treatment days , each participant 's esophagus was stimulated with heat , distension , and electrical current at teaching hospitals in Denmark and Sweden . Heat and pressure pain served as somatic control stimuli . Per protocol results were analyzed . Results . Of 14 r and omized patients , 12 were treated with AZD1386 . In the esophagus AZD1386 did not significantly change the moderate pain threshold for heat [ –3 % , 95 % confidence interval ( CI ) , –22;20 % ] , distension ( –11 % , 95 % CI , –28;10 % ) , or electrical current ( 6 % , 95 % CI , –10;25 % ) . Mean cutaneous heat tolerance increased by 4.9 ° C ( 95 % CI , 3.7;6.2 ° C ) . AZD1386 increased the maximum body temperature by a mean of 0.59 ° C ( 95 % CI , 0.40–0.79 ° C ) , normalizing within 4 h. Conclusions . AZD1386 had no analgesic effect on experimental esophageal pain in patients with NERD and a partial PPI response , whereas it increased cutaneous heat tolerance . TRPV1 does not play a major role in heat- , mechanically and electrically evoked esophageal pain in these patients . Clinical Trials.gov identifier : D9127C00002 OBJECTIVE To study the efficacy of levothyroxine suppressive therapy in the management of benign thyroid nodules . METHODS We performed a double-blind clinical trial comparing levothyroxine treatment ( 1.5 to 2.0 mg/kg of body weight daily ) ( N = 32 ) with placebo ( N = 30 ) for a 1-year period in patients with a benign , cold thyroid nodule confirmed by biopsy and 99mTc-pertechnetate scanning , who were r and omly assigned to the treatment or control group . High-resolution sonography was used to measure the size of the nodules before and after the treatment . Suppression of thyrotropin was evaluated by the administration of thyrotropin-releasing hormone to 10 patients r and omly in each group . RESULTS The mean volume of the thyroid nodules decreased significantly after 6 months in both the levothyroxine group ( from 12.8 + /- 11.9 mL to 9.4 + /- 9.8 mL ; P = 0.003 ) and the placebo group ( from 13.2 + /- 10.2 mL to 11.5 + /- 8.0 mL ; P = 0.003 ) . After 12 months , however , the volume of the nodules had increased . Thus , no significant decrease was found in the mean nodule volume in either study group at 1 year in comparison with the mean volume at baseline ( final mean volume : 12.4 + /- 16.7 mL in the levothyroxine group and 11.7 + /- 13.6 mL in the placebo group ) . CONCLUSION Suppressive therapy with levothyroxine for a period of 12 months proved to be ineffective in significantly reducing the size of the thyroid nodules in our patients despite effective suppression of the thyrotropin level OBJECTIVE We examined the effects of l‐thyroxine therapy versus placebo over a 12‐month period on volume of solitary thyroid nodules PURPOSE To prospect ively evaluate the efficacy of additional radiofrequency ( RF ) ablation by comparing the results of one and two sessions . MATERIAL S AND METHODS All patients gave written informed consent to participate in this institutional review board-approved prospect i ve study . From September 2007 to February 2008 , 30 patients with benign predominantly solid thyroid nodules causing pressure symptoms and /or cosmetic problems were r and omly assigned to undergo single-session ( group 1 , n = 15 ) or two-session ( group 2 , n = 15 ) RF ablation . RF ablation was performed by using an 18-gauge internally cooled electrode with ultrasonographic guidance . Nodule volume and cosmetic and symptom scores were evaluated before ablation and at 1 , 3 , and 6 months after initial ablation , and quantitative comparisons of these were performed by using the Mann-Whitney and Wilcoxon signed rank tests ; the Spearman rank test was used for correlation between nodule volume reduction and applied energy . RESULTS At 6-month follow-up , there was significant nodule volume reduction , from 13.3 mL ± 12.9 ( st and ard deviation ) to 3.8 mL ± 4.4 in group 1 ( P = .001 ) , and from 13.0 mL ± 6.8 to 3.0 mL ± 2.2 in group 2 ( P = .001 ) . Each group showed significant improvement in cosmetic ( P < .0001 ) and symptom ( P = .001 ) scores . However , there was no significant difference in volume reduction , cosmetic score , and symptom score between two groups ( P = .078 , P > .99 , and P = .259 , respectively ) . In group 1 , three of four patients who had a pretreatment nodule volume larger than 20 mL underwent additional RF ablation because of unresolved clinical problems after the first session . CONCLUSION Single-session RF ablation showed significant volume reduction and satisfactory clinical response in most patients . Therefore , additional RF ablation should be limited to patients with a large nodule ( > 20 mL ) or unresolved clinical problems The prevalence of thyroid nodules in the general population has been estimated to be approximately 5 % by neck palpation and as much as 30 % to 50 % by ultrasonography [ 1 , 2 ] . Because most nodules are cold at scintigraphy , the management of cold thyroid nodules is a common presenting problem both to endocrinologists and general internists . Evaluation by fine-needle aspiration biopsy indicates surgical removal only for approximately 5 % of cases because of malignancy and in 10 % to 20 % of cases ( those with follicular lesions ) because malignancy can not be excluded [ 1 - 5 ] . Clinical evaluation may suggest the need for surgery in an additional 5 % of patients [ 6 , 7 ] . Thus , most cold thyroid nodules ( 70 % to 80 % ) are managed medically . Until recently , most clinicians would have treated these patients with levothyroxine at thyroid-stimulating hormone (TSH)suppressing doses because TSH is the major thyroid stimulator for both function and growth [ 8 , 9 ] . Thus , TSH suppression would be expected to cause either nodule reduction or growth inhibition [ 10 , 11 ] . In the last 5 years , however , study findings have challenged this policy : Two r and omized , controlled studies in which ultrasonography was used to evaluate nodule volume changes failed to prove the efficacy of levothyroxine [ 12 , 13 ] ; and recent reports of bone mineral density decreases in patients treated with levothyroxine have raised concern about the riskbenefit ratio of levothyroxine administration [ 14 - 16 ] . General clinical experience , however , and previous open , noncontrolled studies [ 10 , 11 ] indicate that at least some cold nodules decrease in size when treated with levothyroxine . This controversy suggests the need for further r and omized clinical trials of levothyroxine treatment . Because potassium iodide , either alone or in combination with levothyroxine , is used outside the United States for treating diffuse and nodular goiter caused by iodine deficiency [ 17 - 19 ] and for treating sporadic goiter [ 20 ] , we tested iodide treatment in patients with solitary cold thyroid nodules . Methods Patients and Study Design We enrolled euthyroid patients with benign solitary solid cold nodules of the thyroid who were referred to our thyroid clinic . We first selected patients who had a solitary thyroid nodule and no major concomitant disease at clinical examination . Radioiodine scanning and ultrasound examination of the thyroid ( Diasonics DRF 250 ultrasound scanner equipped with a linear 10-MHz probe ; Sonotron SA , Les Ulis Cedex , France ) and fine-needle aspiration biopsy of the nodule were then done . Because of the probe used , the accuracy of measures by ultrasonography could be obtained only for nodules with a diameter of 3.5 cm or less ; we therefore excluded patients with larger nodules . We also measured the following in all patients : levels of serum thyroxine , total triiodothyronine , free triiodothyronine , and free thyroxine sub ( commercial radioimmunoassay methods ) ; TSH and thyroglobulin levels ( immunoradiometric methods ) ; antithyroglobulin and antimicrosomal antibodies ( hemoagglutination method ) ; and urinary iodine levels ( colorimetric method ) . We included only newly diagnosed nodules ( recognized less than 1 year before the study began ) . Using ultrasonography , we measured nodule size in three planes and recorded it on film . Nodule volume was calculated according to the following formula for a spherical ellipsoid : volume = ( /6 ) x AP x width x length , where AP is the anteroposterior diameter [ 21 ] . For each patient , ultrasound measurements were done by the same operator , who had no access to the patient 's clinical and laboratory data or group assignment . Intraobserver variation of nodule measurement was assessed before the study began by a pilot investigation of 25 patients with a thyroid nodule . In these patients , nodules were measured twice at baseline and after 20 to 30 days , result ing in a weighted statistic of 99.9 % [ 22 ] . We selected only solid nodules , including nodules with absent or minimal ( < 10 % ) cystic component . In addition , we carefully examined both thyroid lobes for the presence of additional nodules . Patients with a second thyroid nodule not evident at physical examination were included if the maximum diameter of the second nodule did not exceed 50 % of the maximum diameter of the main nodule . We also measured contralateral thyroid lobe diameters and recorded the data [ 23 ] . A radioiodine scan ( 25 microcuries ) was done in all patients to exclude all hot nodules , which are usually autonomous and unresponsive to medical treatment [ 24 ] . A fine-needle aspiration biopsy examination was then done as previously described [ 3 ] . Patients with a cytologic diagnosis of malignancy , follicular lesion , cyst-hemorrhagic lesion , or thyroiditis were excluded ; we selected only colloid-parenchymatous nodules that showed colloid and benign follicular cells in variable proportion . In addition , we excluded patients with abnormal thyroid hormone or TSH serum levels , circulating thyroid antibodies , or concomitant cardiovascular or liver diseases , osteoporosis , or pregnancy . All patients lived in an area with a sufficient iodine supply and a goiter prevalence in schoolchildren of less than 1 % . Urinary iodine excretion in this area ranges from 80 to 300 g/d . However , because iodine intake may affect nodule growth and response to therapy , the urinary iodine concentration of our patients was measured in a urine sample taken in the morning . Urinary iodine excretion less than 8.0 g/dL or exceeding 27.0 g/dL was a criterion for exclusion . Patients selected by these procedures gave informed consent and entered the study . We then r and omly assigned patients to receive one of three treatments [ using r and omized blocks with a coin slightly biased in favor of treatment groups and with allocation blinded only to the ultrasonography operator ] : 1 ) no treatment ; 2 ) oral levothyroxine at an initial dose of 1.0 g/kg body weight per day to be taken in one single dose in the morning ; and 3 ) oral iodine supplementation at 1.5 mg every 2 weeks , provided as potassium iodide tablets . For patients in the second group , the dose was increased to 1.8 g/kg per day after 15 days and then individually adjusted after the first 4 months to allow a serum TSH level less than normal values ( < 0.3 mU/L ) . At that point , the average levothyroxine dosage was 1.94 0.16 g/kg per day . Each treatment was continued for 12 months . Patients were evaluated at 4-month intervals by clinical and ultrasound examination . Levels of free triiodothyronine , free thyroxine , TSH , thyroglobulin , urinary iodine excretion , and antithyroid antibodies were also measured every 4 months . Compliance with therapy was individually controlled in patients receiving levothyroxine by carefully asking the patient and by measuring TSH serum levels at 4-month intervals . Urinary iodine was also measured in all patients at 4-month intervals to check both treatment compliance ( in patients receiving potassium iodide ) and the absence of iodine contamination in patients receiving no treatment and in those receiving levothyroxine . End Points We considered two end points : 1 ) the type of nodule volume variation from 0 to 12 months and 2 ) a nodule reduction of 50 % of the initial volume after the 12-month observation period . Sample Size According to a previous report [ 12 ] , a spontaneous decrease of 50 % or more of the initial volume could be assumed to occur in 20 % of patients . We therefore considered therapy successful when it caused a similar ( 50 % ) volume reduction at least 2.5 times more frequently than occurred with no treatment . Given a type I error of 0.05 ( two-sided ) and a power of 0.9 and considering that approximately 10 % of patients might be lost to follow-up , we estimated the necessary total sample size to be 160 patients . Statistical Analysis We planned an interim analysis of the results after 12 months of observation for the first half of the patients who entered the study . Because nodule volumes were distributed in a skewed manner , appropriate transformation such as logarithms were applied to these data for statistical inference , and proper means ( that is , geometric means ) were used to describe results . We evaluated the statistical significance of nodule size variation in the three groups by repeated- measures analysis [ 25 ] and considered data obtained at months 0 , 4 , 8 , and 12 from patients who completed 1 year of follow-up . We then fitted a linear r and om-effects model with a structured variance-covariance matrix to each loge-volume profile at 0 , 4 , 8 , and 12 months of observation and considered such covariates as group assignment ( no treatment , levothyroxine , or potassium iodide ) , patient age ( in years ) , cytologic findings ( colloid or parenchymatous nodular hyperplasia ) , and echographic patterns ( hypoechogenic , isoechogenic , hyperechogenic , or mixed nodules ) . We subsequently fitted a second model to the same data , also taking into account the nodule volume class ( 5 mL , 5.1 to 10 mL , or > 10 mL ) . We used the BMDP statistical package ( Statistical Software , Inc. , Los Angeles , California ) . We used a log-linear model [ 26 ] to test differences in the proportion of volume reduction by the GLIM statistical package ( Royal Statistical Society , London , United Kingdom ) . A paired t-test was used for comparisons between values before and after 12 months of therapy . Every test of hypothesis was done at a 0.05 level of significance ( two-sided ) . Results The study was stopped because at the interim analysis , we obtained clinical ly important results for the first 80 patients who entered the study ; we did not include 18 patients who were still being studied at the time of interim analysis . After r and omization , the characteristics of these 80 patients and their nodules were homogeneous in the three groups , and we saw no statistical differences ( Table 1 ) . Twelve nodules evenly distributed among the three groups had a cystic component of less than 10 % . Of the 80 patients , 70 ( 87.5 % ) 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 AIM OF THE STUDY To compare clinical and ultrasound ( US ) changes induced in cold thyroid nodules by US-guided percutaneous laser ablation ( PLA ) versus follow-up or levothyroxine ( LT4 ) suppressive therapy . METHODS 62 patients r and omly assigned to a single PLA ( Group 1 ) , LT4 ( Group 2 ) , or follow-up ( Group 3 ) . Entry criteria : euthyroid patients with a solid thyroid nodule > 5 mL and benign cytological findings . TREATMENT Group 1 : PLA was performed with a 1.064 mum neodymium yttrium-aluminum-garnet laser with output power of 3 W for 10 minutes ; Group 2 : the LT4 dose was adjusted to induce thyrotropin suppression ; Group 3 : no treatment . RESULTS In Group 1 a significant nodule reduction was found 6 and 12 months after PLA ( delta volume : -42.7 + /- 13.6 % ; p = 0.001 ) . A reduction > 50 % was found in 33.3 % of cases . In Group 2 a nonsignificant nodule shrinkage was observed . A nonsignificant volume increase was observed in Group 3 . Improvement of local symptoms was registered in 81.2 % of patients in Group 1 vs. 13.3 % in Group 2 and 0.0 % in Group 3 ( p = 0.001 ) . No complications were noted . CONCLUSIONS A single PLA induced significant volume reduction and improvement of local symptoms . PLA was more effective than LT4 . Follow-up was associated with nodule growth and progression of local symptoms . PLA should be considered a potential mini-invasive alternative to surgery in symptomatic patients with benign cold thyroid nodules We prospect ively evaluated the effect of thyrotropin (TSH)-suppressive therapy with levothyroxine ( LT4 ) on the size of a benign , solitary , solid nodule and multinodular goiter in a relatively low iodine intake area . In this study , 101 euthyroid subjects with a benign , solitary , predominantly solid nodule ( n = 54 ) confirmed by biopsy or multinodular goiter ( n = 47 ) received 200 microg of levothyroxine daily as a single morning tablet for 12 months . Thirty-five receiving no therapy were considered as controls ( solitary nodules , n = 20 , multinodular , n = 15 ) . Patients were admitted to the study after evaluation of thyroid biochemical parameters ( thyroxine [ T4 ] , free thyroxine [ FT4 ] , triiodothyronine [ T3 ] , thyrotropin [ TSH ] , and thyroglobulin [ Tg ] ) , thyroid scanning , ultrasound examination , and fine-needle aspiration biopsy . Every 3 months , thyroid function tests and every 6 months ultrasound examinations were repeated . Twelve months later 20 of 54 ( 37.1 % ) patients with single , solid nodules had 50 % or more regression of the nodular volume ( responders ) . Eleven of 54 ( 20.3 % ) patients had more than 20 % , but less than 49.9 % reduction of nodular volume ( partial responders ) . Nonresponders were 23 of 54 ( 42.5 % ) . One-third of subjects with multinodular goiter had 50 % or more regression of the gl and ular volume , whereas 46.8 % were considered as nonresponsive . The mean serum Tg levels decreased significantly only in responders with solitary nodular disease or multinodular goiter . In the control group only 1 patient ( 5 % of total ) with a solitary nodule had a 50 % reduction in the nodular volume . Five others had a partial response ( < 49 % , > 20 % reduction ) . None of the patients with multinodular goiter had a significant reduction ( > 50 % ) of the combined nodular volumes . We concluded that LT4 may be effective , among other factors , in arresting the growth or in reducing the volume of relatively small , benign , solitary , solid thyroid nodules or the combined nodular volume of multinodular goiter Osteoporosis and thyroid dysfunction are both common in older women ; 8 % to 13 % of women older than 50 years of age have biochemical evidence of thyroid dysfunction ( 1 , 2 ) , and 30 % are osteoporotic according to bone density criteria ( 3 ) . Although osteoporotic fractures have long been associated with florid hyperthyroidism ( 4 ) and , more recently , with a history of hyperthyroidism in older women ( 5 ) , the relationship between biochemical evidence of excess thyroid hormone and fracture risk is not known ( 6 , 7 ) . Indirect evidence suggests that excess thyroid hormone due to endogenous disease or exogenous overuse of thyroid hormone may be associated with detrimental effects on bone , even in asymptomatic persons . For example , several biochemical markers of bone turnover are elevated in women with excess thyroid hormone ( 8 , 9 ) . Findings from studies of the relationship between excess thyroid hormone and bone mass are conflicting ( 10 - 17 ) . However , factors other than bone mass , such as neuromuscular function and bone quality , contribute to risk for fracture ( 5 ) and may be adversely affected by excess thyroid hormone . Results of previous small , retrospective studies of thyroid function and fractures have also been conflicting ( 18 - 21 ) . To our knowledge , no large prospect i ve studies have examined the relationship between excess thyroid hormone and subsequent fracture . In light of the conflicting information on bone mass and the paucity of studies with fracture as an end point , several experts have noted the need for longitudinal studies of thyroid function and fracture risk ( 22 - 26 ) . To test the hypothesis that low levels of serum thyroid-stimulating hormone ( TSH ) increase the risk for hip , vertebral , and any nonspine fracture , we performed a prospect i ve study of postmenopausal women enrolled in the Study of Osteoporotic Fractures . Methods Patients The Study of Osteoporotic Fractures is a prospect i ve cohort study of risk factors for fracture among 9704 women ( 5 ) . White women older than 65 years of age were recruited in 1986 to 1988 from population -based listings at four clinical centers ( Portl and , Oregon ; Minneapolis , Minnesota ; Pittsburgh , Pennsylvania ; and Baltimore , Maryl and ) . The institutional review boards of all four centers gave approval for this study involving human research subjects . Measurements Baseline Measurements Participants were interviewed and examined during the baseline visit . Detailed information about physician-diagnosed medical conditions and past medication use was collected , and trained interviewers confirmed current medication use by examination of pill bottles . Participants were asked specifically about self-rated health , previous physician diagnoses of hyperthyroidism or Graves disease , and previous use of thyroid hormone . In addition to st and ardized assessment s of height and weight , bone mass of the calcaneus was determined by using single-photon absorptiometry ( OsteoAnalyzer , Siemens-Osteon , Wahiawa , Hawaii ) and lateral radiographs of the thoracic and lumbar spine were obtained ( 27 , 28 ) . Serum was collected from each participant and stored at 190 C. Approximately 2 years after the baseline visit , bone mineral density of the proximal femur was measured in 82 % of the cohort by using dual-energy x-ray absorbtiometry ( Hologic QDR 1000 , Waltham , Massachusetts ) ( 29 ) . Levels of TSH were measured in archived sera obtained at baseline by using a highly sensitive , third-generation chemiluminescent assay ( Endocrine Science , Calabasas , California ) . The normal range for this assay is 0.5 to 5.5 mU/L ; the functional sensitivity ( defined as the concentration at which the interassay coefficient of variation is 20 % ) is approximately 0.05 mIU/L ( 30 ) . At TSH concentrations of 0.5 mIU/L , the intra-assay coefficient of variation is 4.7 % and the interassay coefficient of variation is 6.3 % . Thirty r and omly selected specimens were blindly su bmi tted for duplicate analysis ; the correlation between these two TSH results was high ( r = 0.95 ) . Previous studies have shown that TSH levels are highly stable in frozen sera over prolonged periods ( 31 , 32 ) . Other studies have demonstrated that among ambulatory adults , TSH levels of 0.1 mIU/L or less are highly correlated with a diminished response to thyroid-releasing hormone stimulation ( 33 ) and are associated with an increased incidence of atrial fibrillation ( 34 ) . Ascertainment of Incident Fractures After the baseline visit , women were contacted by mail every 4 months about the occurrence of fractures . Hip fractures were confirmed by review of the appropriate radiographs by a radiologist at the coordinating center ; other nonspine fractures were confirmed by review of written radiology reports . Fractures result ing from excessive trauma ( such as motor vehicle accidents ) were excluded . Follow-up for fracture and vital status was more than 99 % complete . Lateral spine radiographs were repeated in 7299 women ( 79 % of surviving women ) after a mean ( SD ) follow-up of 3.7 0.4 years , and 7238 pairs of radiographs were judged to be adequate for assessment of incident vertebral fractures . Women without follow-up radiographs were older and reported poorer health at baseline compared with those who had follow-up radiographs ( 35 ) . Vertebral fractures were identified by using computer-assisted morphometric evaluation ( 36 ) , and incident vertebral fractures were defined as a 20 % or greater and 4 mm or greater reduction in anterior , mid-vertebral , or posterior vertebral height between the baseline and follow-up radiographs ( 37 ) . The persons who assessed the radiographs had no knowledge of the participant 's medical history or TSH level . Selection of Case and Control Sample s for Fracture Analyses Using an efficient case-cohort approach that maintains statistical power but avoids expensive biochemical measurements in the entire cohort ( 38 - 40 ) , we r and omly selected baseline serum sample s from 148 women with hip fracture and 149 women with incident vertebral fracture after the baseline visit . We r and omly selected 398 women from the original cohort , independent of fracture status , to be controls . This r and om sample , which we refer to as the sub sample in this report , included 14 of the 148 women selected as incident hip fracture cases and 15 of the 149 women selected as incident vertebral fracture cases ; these women were removed from the sub sample and were analyzed as cases of hip and vertebral fracture , respectively . To create a fracture-free control group , we excluded women from the sub sample with other nonspine fractures during follow-up ( n = 80 for the hip fracture analyses and n = 58 for the vertebral fracture analyses ) . Ninety women in the sub sample had missing or technically inadequate radiographs and could not be analyzed for vertebral fracture outcomes . The analyses of any nonspine fracture were performed in the r and omly selected sub sample by using st and ard prospect i ve cohort methods . After 14 women with unconfirmed fracture , 5 women with fracture from extreme trauma , and 6 women with spine fractures were excluded , the analysis of nonspine fracture included 100 women with documented nonspine fracture occurring after study entry and 273 without fracture . R and om selection was done by using a computerized r and om-number generator . Statistical Analysis Continuous variables were plotted , and distributions , means , and st and ard deviations were examined . Levels of TSH were categorized as low ( 0.1 mIU/L ) , borderline low ( > 0.1 but < 0.5 mIU/L ) , normal ( 0.5 to 5.5 mIU/L ) , or high ( > 5.5 mIU/L ) . Associations with hip fracture were examined by using proportional hazards analyses ( Epicure , Hirosoft International , Seattle , Washington ) that took into account the case-cohort sampling design . The proportionality assumption was not violated . Results are reported as relative hazards with 95 % CIs . Logistic regression was used to analyze incident vertebral fracture ; these results are reported as odds ratios with 95 % CIs . Cox proportional-hazards models were used to determine associations with nonspine fracture among the r and omly selected sub sample . Multivariate models were constructed to adjust for potential confounders . Potential confounders were selected on the basis of biologic plausibility ( for example , use of thyroid hormone ) or a strong univariate association ( P 0.1 ) with TSH level ( for example , age ) or fracture ( for example , estrogen use ) . We found no association ( P>0.1 ) between TSH level and maternal history of fracture , height , neuromuscular function , or corticosteroid use , which are known to be associated with fracture in this cohort ( 5 ) . The final multivariate models for each fracture type included TSH level , age , previous hyperthyroidism , self-rated health , and current use of thyroid hormone and estrogen . To determine whether the increased risk for fracture in women with low TSH levels was mediated by reduced bone mass or some other mechanism , we examined the effect of further adjusting the final multivariate models for calcaneal bone mass measured at the baseline visit . The effect of adjustment for bone mineral density at the femoral neck , measured approximately 2 years after the baseline visit , was similar to that observed for calcaneal bone mineral density . Role of the Funding Source The funding source had no role in the collection , analysis , interpretation , or publication of these data . Results During a maximum follow-up of 5.9 years , 332 women had a first hip fracture , 389 had an incident vertebral fracture detected on paired spinal radiographs , and 2520 had nonspine fractures . Women who had incident hip , vertebral , or any nonspine fractures were older and had lower bone mass than controls ( Table 1 ) . Women with hip fractures were more likely to report previous hyperthyroidism . Mean TSH levels were similar among women with and without fracture , but the proportion of women with a low TSH level ( 0.1 mIU/L ) was significantly greater among those with hip or vertebral fracture . Overall , 11 % of Background : Suppressive therapy with levothyroxine for reducing the size of thyroid nodules has not been really accepted . The purpose of this study was to assess the effect of levothyroxine on the size of benign thyroid nodules . Methods : Forty patients with confirmed benign nodule were r and omly divided into two groups . Group I received 50g/day levothyroxine for six months but group II did not take it . Sonography was used to measure the dimensions of nodules before and after six months . TSH serum levels were measured before and after treatment . This clinical trial study was registered as I RCT 201103185692 N3 . The data were collected and analyzed . Results : The mean age of levothyroxine group was 41.57±9.41 and control group was 44.45±10.9 years ( p=0.386 ) . The TSH levels and longitudinal and transverse dimensions in both groups were similar ( p>0.05 ) . The TSH levels before and after treatment were 2±1.65 and 0.52±0.67 mUI/L ( p=0.001 ) . The Longitudinal and transverse dimensions before and after treatment in case group were 1.9±1.11 , 1.90±1.15 and 1.44±0.90 , 1.49±1.02 cm respectively ( p=0.74 , p=0.7 , respectively ) but in control group , were 2.19±1.32 , 1.97±1.4 and 1.57±0.95 , 1.26±0.7 , respectively ( p=0.35 and 0.1 , respectively ) . Conclusion : The results show that suppressive therapy with levothyroxine lead no alteration in the size of benign nodules BACKGROUND AND PURPOSE We evaluated the differences between percutaneous ethanol injection with and without aspiration of ethanol-mixed fluid for treatment of benign cystic thyroid nodules . METHODS We examined 60 patients with benign cystic thyroid nodules confirmed by fine-needle aspiration biopsy and divided them into 2 groups according to nonaspiration ( group A , n = 30 ) or aspiration ( group B , n = 30 ) of ethanol-mixed fluid after intracystic ethanol injection . We evaluated in both groups the complete disappearance of the cystic portion of the thyroid nodule on follow-up ultrasonography ( first follow-up ultrasonography ; mean , 4.6 months in group A ; mean , 4.4 months in group B ) ( chi-square test ) , side effects or complications during and after the procedure ( chi-square test ) , and the total procedure time ( Student t test ) . RESULTS Most patients showed complete disappearance of the cystic portion of the thyroid nodule ( group A , n = 29 ; group B , n = 28 ) , and they revealed no recurrence on follow-up ultrasonography . There was no statistical difference in the success rates between group A and group B ( P > .05 ) . Pain , the most common side effect , and other mild side effects or complications occurred in small numbers of patients in each group , but there was no significant difference in side effects or complications between the 2 groups ( P > .05 ) , except for intracystic hemorrhage ( P < .05 ) and the complaint of all group B patients due to a double puncture ( P < .001 ) . The total procedure time was nearly double in group B than in group A because of the additional procedures , such as complete evacuation of the ethanol-mixed fluid and the 10-minute compression . CONCLUSION Percutaneous ethanol injection without aspiration of ethanol-mixed fluid seems to be the preferable method of treatment of benign cystic thyroid nodules from the perspective of both the physician and the patient objective To evaluate the effect of treatment with TSH suppressive dose of levothyroxine In patients with benig nthyroid nodules The levothyroxine suppressive efficacy in benign thyroid nodules treatment is well described in uninodular non-toxic goiter , whereas only few controlled trials enrolled patients with multinodular disease . The aim of the present study is to evaluate the short term effects of levothyroxine treatment in never treated , pre-menopausal women affected by thyroid multinodular disease . Seventy-one pre-menopausal women with thyroid multinodular disease , still presenting normal TSH levels , from Latina area were r and omly assigned to a levothyroxine treated or control group . Biochemical and ultrasonography evaluations of thyroid were monitored at the enrollment and after 6 , 12 and 24 months of treatment . In the levothyroxine treated group , after 1 year of treatment , thyroid and dominant nodule volume and number of nodules > 0.5 mL significantly decreased from a median of 12.0 to 9.8 mL ( p < 0.001 ) , from 1.0 to 0.5 mL ( p < 0.001 ) and from 0.5 to 0 , respectively . Conversely , in the control group significant augmented values of these parameters were observed ( p = 0.007 , p < 0.001 and p < 0.001 , respectively ) . Furthermore , these observations were also confirmed by results obtained after a 24 months follow-up period . Our data support previous observations on the clinical usefulness of L-T(4 ) treatment in preventing thyroid and nodule volume and nodule numbers growth . These findings confirm the tendency of benign nodular disease toward progression and the efficacy of TSH suppression in preventing its evolution by means of removing the major growth factor for thyroid nodules still responsive to physiological stimuli Thyroid nodules are present in up to 50 percent of adults in the fifth decade of life . Patients are often treated with thyroxine in order to reduce the size of the nodule , but the efficacy of thyrotropin-suppressive therapy with thyroxine remains uncertain . In this study , 53 patients with a colloid solitary thyroid nodule confirmed by biopsy were r and omly assigned in a double-blind manner to receive placebo ( n = 25 ) or levothyroxine ( n = 28 ) for six months . Before treatment , pertechnetate-99 m thyroid scanning showed that 22 percent of the nodules were functional , 25 percent hypofunctional , and 53 percent nonfunctional . High-resolution ( 10-MHz ) sonography was used to measure the size of the nodules before and after treatment . Suppression of thyrotropin release was confirmed in the levothyroxine-treated group by the administration of thyrotropin-releasing hormone ; thyrotropin release was normal in the placebo group . Six months of therapy did not significantly decrease the diameter or volume of the nodules in the levothyroxine group as compared with the placebo group . We conclude that the efficacy of levothyroxine therapy in reducing the size of colloid thyroid nodules is not apparent within six months , despite effective suppression of thyrotropin The efficacy of thyroxine ( T(4 ) ) for solitary non-toxic thyroid nodule remains uncertain . In this study , 60 patients with solitary non-toxic thyroid nodule were divided r and omly into two groups . Group I ( n = 30 ) received thyroxine 100 microg/day for 6 months and group II ( n = 30 ) received placebo . The volume of the thyroid nodules in 11 patients decreased more than 50 % after thyroxine therapy ( 36.7 % , responders ) . In these 11 patients , the mean serum thyroglobulin level decreased significantly ( 340 + /- 115 to 162 + /- 86 microg/l , p < 0.01 ) . Compared with the non-responders ( n = 19 , 63.3 % ) , the serum thyroglobulin level before treatment was significantly higher ( 340 + /- 115 vs. 220 + /- 102 microg/l , p < 0.05 ) . Thyroxine-suppressive therapy is proved as a useful tool in reducing nodule size in some patients with solitary thyroid nodules . The patients with a higher serum thyroglobulin level generally respond better to thyroxine-suppressive therapy AIM To evaluate the long-term efficacy of interstitial laser photocoagulation ( ILP ) in solitary benign thyroid nodules . DESIGN AND METHODS A total of 78 euthyroid out patients ( 45 participating in r and omized trials ) with a benign solitary solid and scintigraphically cold thyroid nodule causing local discomfort were assigned to ILP . ILP ( using one laser fiber ) was performed under continuous ultrasound ( US ) guidance and with an output power of 1.5 - 3.5 W. Thyroid nodule volume was assessed by US and thyroid function determined by routine assays , before and during follow-up . Pressure symptoms and cosmetic complaints were evaluated on a visual analogue scale ( 0 - 10 cm ) . Of the total patients , six had thyroid surgery 6 months after ILP and three were lost to follow-up . The median follow-up for the remaining 69 patients was 67 months ( range 12 - 114 ) . RESULTS The overall median nodule volume decreased from 8.2 ml ( range 2.0 - 25.9 ) to 4.1 ml ( range 0.6 - 33.0 ; P<0.001 ) at the final evaluation , corresponding to a median reduction of 51 % ( range : -194 to 95 % ) . This correlated with a significant decrease in pressure as well as cosmetic complaints . After 12 - -96 months ( median 38 months ) of ILP , 21 patients ( 29 % ) had thyroid surgery because of an unsatisfactory result . All had benign histology . Thyroid function was unaltered throughout and side effects were restricted to mild local pain . CONCLUSION US-guided ILP results in a satisfactory long-term clinical response in the majority of patients with a benign solitary solid cold thyroid nodule . Further large-scale studies should aim at optimizing selection criteria for ILP , preferably in r and omized studies BACKGROUND Percutaneous radiofrequency thermal ablation ( RTA ) is a promising new therapeutic approach to manage thyroid nodules ( TNs ) . The aim of this study was to investigate the long-term effectiveness of RTA in inducing shrinkage of TNs as well as in controlling compressive symptoms and thyroid hyperfunction in a large series of elderly subjects with solid or mainly solid benign TNs . METHODS Ninety-four elderly patients with cytologically benign compressive TNs were prospect ively enrolled in the study ; 66 of them had nontoxic goiter and 28 had toxic or pretoxic goiter . RTA was performed by using a RITA StarBurst Talon hook-umbrella needle inserted in every single TN under ultrasonographic real-time guidance . TN volume , TN-related compressive symptoms and thyroid function were evaluated at baseline and 12 to 24 months after RTA . RESULTS All TNs significantly decreased in size after RTA . The mean decrease in TN volume 12 months after RTA was from 24.5 + /- 2.1 to 7.5 + /- 1.2 mL ( p < 0.001 ) , with a mean percent decrease of 78.6 + /- 2.0 % . Two years after RTA , a 79.4 + /- 2.5 % decrease of TNs size was observed . Compressive symptoms improved in all patients and completely disappeared in 83 of 94 ( 88 % ) patients . Hyperthyroidism resolved in most patients allowing methimazole therapy to be completely withdrawn in 79 % of patients with pretoxic and toxic TNs ( 100 % with pretoxic TNs and 53 % with toxic TNs ) . The treatment was well tolerated by all patients . No patient needed hospitalization after RTA and no major complications were observed . CONCLUSIONS RTA is an effective and simple procedure for obtaining lasting shrinkage of TNs , controlling compressive symptoms , and treating thyroid hyperfunction . When performed in experienced medical centers , RTA may be a valid alternative to conventional treatments for nontoxic and pretoxic TNs . It is particularly attractive for elderly people for whom surgery and radioiodine therapy are often contraindicated or ineffective We studied the effect of percutaneous ethanol injection ( PEI ) in the treatment of cold , cytologically benign , large ( > 10 mL ) thyroid nodules ( CBNs ) in 41 patients . The end-point of our study was to evaluate the efficacy of PEI on : 1 ) local symptomatology , assessed by an arbitrary symptom score ; and 2 ) nodule volume and tracheal displacement ( at ultrasonography ) . Follow-up ranged from 12 - 36 ( 21 + /- 9 ) months . Symptom score was significantly reduced ( P < 0.01 ) after 6 months and at the end of the follow-up ( 2.1 + /- 0.3 vs. 0.2 + /- 0.5 and vs. 0.2 + /- 0.4 ) . A significant ( P < 0.01 ) nodule volume reduction was observed , without differences between solid or mixed CBNs ; the reduction was 50 % or more in 92.7 % of patients . Neither clinical parameters nor pretreatment nodule ultrasonographic features were related to nodule reduction . Disappearance or significant reduction ( > 0.5 cm ) of tracheal displacement was obtained in 61 % and in 39 % of patients , respectively . One patient experienced prethyroid region edema , pain , and mild fewer , which reversed within 1 week ; and one patient had dysphonia , caused by vocal cord palsy , which reversed spontaneously within 1 month . At the end of the follow-up , nodules with just necrotic material at cytology showed a greater ( P < 0.05 ) volume reduction than nodules with residual benign thyroid cells . Our data suggest that PEI is a safe and effective treatment of large CBNs , although sometimes serious side effects do occur Context Although benign thyroid nodules are common , we know relatively little about their natural history . Contribution This observational study from a single tertiary care facility used repeated ultrasonography to show that benign thyroid nodules typically increase in volume over a 3- to 5-year period . Solid nodules grew more than cystic nodules , and only 1 of 74 reaspirated nodules was malignant . Implication s Nodule growth alone does not predict malignancy . The Editors Thyroid nodules are present in nearly 50 % of adults , increasing in prevalence with age ( 1 ) . The evaluation of thyroid nodules that measure 1 cm or greater in diameter typically includes a screening measure of serum thyroid-stimulating hormone ( TSH ) levels and fine-needle aspiration ( FNA ) . Most FNA results are benign ( 90 % to 95 % ) , and follow-up examinations are advised . Recommendations include periodic clinical examinations or ultrasonography , with or without suppressive l-thyroxine therapy ( 1 , 2 ) . Nodules that increase in size during follow-up are often regarded as suspicious for malignancy , and repeated FNA or surgery is advised ( 3 - 6 ) . Data supporting these recommendations are limited , however , as few reports have evaluated thyroid nodule growth using the most sensitive technique , high-resolution ultrasonography . Furthermore , criteria defining nodule growth are inconsistent ; some guidelines use an increase in maximal diameter of greater than 50 % , while others suggest an increase in maximal diameter greater than 5 mm or an increase in calculated volume greater than 15 % ( 5 - 10 ) . We used ultrasonography of thyroid nodules to determine the natural history of cytologically benign thyroid nodules over a 1-month to 5-year follow-up period . Methods We retrospectively review ed the records of all patients referred to the dual-discipline Thyroid Nodule Clinic at Brigham and Women 's Hospital , Boston , Massachusetts , for evaluation of nodular thyroid disease between 1995 and 2000 . All patients referred to the clinic underwent ultrasonography of the thyroid by a radiologist and ultrasonography-guided FNA of nodules measuring 1 cm or greater in maximal diameter by an endocrinologist . All ultrasonography evaluations were adequate for review and interpretation . All patients with benign cytology on initial FNA were advised to schedule follow-up ultrasonography 9 to 12 months later . Repeated FNA was performed on the follow-up visit at the discretion of the endocrinologist , usually because of nodule growth . The study sample included all patients with nodules with benign cytologic results on the initial visit who returned for follow-up ultrasonography within the 5-year period . Thyroid ultrasonography was performed by one of three radiologists using a 5- to 15-MHz transducer . The length , width , and depth of each nodule were reported , and each nodule was classified as solid , less than 25 % cystic , 25 % to 50 % cystic , 50 % to 75 % cystic , or greater than 75 % cystic . Nodule volume was calculated by using the formula for a rotational ellipsoid ( length width depth /6 ) ( 7 , 11 , 12 ) . Ultrasonography-guided FNA was performed with a 25-gauge needle ( three to four aspirations per nodule ) , and specimens were processed by using the Thin-Prep technique ( Cytyc Corp. , Boxborough , Massachusetts ) . All slides were read by a cytopathologist at Brigham and Women 's Hospital . Specimens were considered benign when six or more groups of benign follicular cells ( each group containing 15 cells ) were identified without atypical features . Repeated ultrasonographies were performed , and findings were directly compared with the previous images . Change in nodule size over the interval between examinations was assessed by using three criteria : 1 ) change in maximal diameter greater than 50 % [ 7 , 8 , 12 , 13 ] ; 2 ) change in maximal diameter of 3 mm or more ; 3 ) change in calculated volume of 15 % or more ( 11 , 14 ) . The latter two criteria are defined by established inaccuracy rates for each method ( 11 , 15 ) . The Investigational Review Board of Brigham and Women 's Hospital granted permission to perform this review . Descriptive statistics are presented according to nodule or patient as appropriate . The main outcome for the single-variable and multivariable predictive models was nodule growth , defined as an increase in volume of 15 % or greater . Single-variable and multivariable mixed-effects logistic regression was used to predict growth , while accounting for the correlation structure in the data where some patients had more than one nodule ( 16 ) . Potential predictors were the time between examinations , cystic content ( solid , < 25 % cystic , 25 % to 50 % cystic , 50 % to 75 % cystic , or > 75 % cystic ) , TSH level ( mIU/L ) , l-thyroxine use , age , and sex . Unadjusted and adjusted odds ratios and 95 % CIs were calculated . Time to growth was determined by using life-table methods . Data were analyzed by using SAS software , version 8.2 ( SAS Institute , Inc. , Cary , North Carolina ) . The funding sources had no role in the design , conduct , or reporting of the study or the decision to publish the manuscript . Results A total of 1009 patients were examined in the Thyroid Nodule Clinic between 1995 and 2000 , and 1358 nodules were biopsied . On initial FNA , 854 nodules ( in 700 patients ) measured 1 cm or greater in maximal diameter with benign cytologic results . Two hundred sixty-eight patients ( 38 % ) with 330 benign thyroid nodules ( 39 % ) returned for follow-up ultrasonography , with a mean interval of 20 months ( range , 1 to 65 months ) between examinations ( Appendix Figure ) . The baseline demographic and ultrasonography characteristics of these 268 patients and their nodules were similar to those of the 432 patients who did not return for follow-up ( Table 1 ) . Table 1 . Demographic and Ultrasonography Characteristics of Patients with a Benign Thyroid Nodule 1 cm in Maximal Diameter Who Returned for Follow-up Ultrasonography as Recommended Compared with Those Who Did Not Change in nodule size over each patient 's follow-up period was assessed by three methods to facilitate comparison with previous studies . With use of a greater than 50 % change in maximal diameter , 14 nodules ( 4 % ) were determined to have increased in size upon repeated ultrasonography . With evaluating change in maximal diameter of 3 mm or greater or change in calculated volume ( cm3 ) of 15 % or greater , 86 nodules ( 26 % ) and 129 nodules ( 39 % ) , respectively , were determined to have increased in size on follow-up ultrasonography . The time interval between examinations was significantly correlated with nodule growth ( r = 0.22 ; P < 0.001 ) . Table 2 shows mixed-models logistic regression analysis for prediction of thyroid nodule growth ( volume change 15 % ) . Time between examinations and lower cystic content remained statistically significant predictors of growth in the final multivariable model . Each year , the background odds of growth increased by 50 % . The estimated median time to achieve volume growth of 15 % or greater was 35 months ( 95 % CI , 29 to 41 months ) . The estimated proportion with growth was 53 % ( CI , 46 % to 61 % ) at 3 years and 89 % ( CI , 81 % to 97 % ) at 5 years using life-table methods . The patient 's age , sex , baseline serum TSH concentration , or l-thyroxine use did not predict nodule growth . Table 2 . Single-Variable Predictors and Final Multivariable Model To Predict Thyroid Nodule Growth ( Volume Increase 15 % ) Sixty-one patients underwent repeated FNA at the time of the second ultrasonography . The nodules in this group were larger on initial examination ( 2.7 cm vs. 2.3 cm ; P = 0.001 ) and had increased in volume by an average of 69 % during follow-up compared with 14 % in those nodules not rebiopsied ( P < 0.001 ) . Patient characteristics were similar except for a longer interval between examinations ( 28 months vs. 18 months ) and younger age ( 43 years vs. 48 years ) noted among the rebiopsied group . One of the 74 repeated FNA sample s suggested a follicular neoplasm , and the remainder were benign . The nodule was removed ; it was a poorly differentiated papillary carcinoma . It had enlarged from 10.1 cm3 to 18.1 cm3 in volume ( an 80 % increase ) over 38 months . Discussion We used ultrasonography to assess the natural history of 330 benign thyroid nodules measuring 1 cm or more in maximal diameter followed for a mean period of 20 months . Although the 268 patients ( with 330 nodules ) represent only 39 % of the benign nodules seen in the Brigham and Women 's Hospital Thyroid Nodule Clinic between 1995 and 2000 , they appear to be representative of the whole group with respect to demographic and nodule characteristics . Using the most rigorous criteria ( 15 % increase in volume ) , we documented growth in 39 % of benign thyroid nodules during follow-up , which indicates that many such nodules grow . Consistent with our findings , Br and er and colleagues ( 10 ) found that 35 % of benign nodules increased in size over 4.9 to 5.6 years . However , the criteria for growth were not defined , and minimal data on repeated FNA were provided ( 10 ) . Similarly , Papini and colleagues ( 15 ) documented an increase in mean nodule volume among patients in the control group of a 5-year r and omized study that assessed the efficacy of l-thyroxine suppression therapy for nodular goiter . Our results also support previous conclusions that more cystic nodules are less likely to grow compared with nodules with a greater solid component ( 5 ) . Current opinion suggests that increasing nodule size has modest but significant power for predicting thyroid cancer ( 2 ) . Kuma and colleagues found malignancy in 26 % of previously unbiopsied nodules that increased in size over a 10- to 30-year period ( 5 ) . A follow-up study 2 years later reported a malignancy rate of 4.5 % among nodules that were previously found to be benign on FNA and subsequently grew ( although no definition of growth was provided ) ( 6 ) . In our study , only 1 of 74 rebiopsied nodules was malignant on repeated FNA biopsy . Although only 22 % of nodules seen in follow-up were rebiopsied , this group had OBJECTIVE To provide an overview of ultrasound (US)-guided percutaneous ethanol injection ( PEI ) therapy for thyroid cystic nodules and discuss the practical and technical details . METHODS We present preliminary data of a controlled r and omized study involving 281 patients ( 221 women and 60 men ; 18 to 85 years old ) with benign thyroid cystic nodules . Study inclusion criteria were local discomfort or cosmetic damage , cystic volume more than 2 mL , 50 % or more fluid component , benignity as confirmed by cytologic specimen obtained by US-guided fine-needle aspiration biopsy ( FNAB ) , and euthyroidism . Exclusion criteria were inadequate , suspicious , or positive FNAB cytology , high serum calcitonin , and contralateral laryngeal cord palsy . By r and om assignment , 138 patients underwent simple cyst evacuation , and 143 underwent cyst evacuation plus PEI by a skilled operator using a US-guided technique . The amount of ethanol injected was 50 to 70 % of the cystic fluid extracted . RESULTS Before treatment , the mean ( + /-SD ) nodule volume was 19.0 + /- 19.0 mL versus 20.0 + /- 13.4 mL in the PEI versus the simple evacuation group ( no significant difference ) . After 1 year , volumes were 5.5 + /- 11.7 mL versus 16.4 + /- 13.7 mL ( P<0.001 ) , with a median 85.6 % versus 7.3 % reduction , respectively ( P<0.001 ) , of the initial volume . The median nodule volume reduction after PEI was 88.8 % and 65.8 % in empty body and mixed thyroid cysts , respectively . Compressive and cosmetic symptoms disappeared in 74.8 % and 80.0 % of patients treated with PEI versus 24.4 % and 37.4 % of patients treated with simple evacuation , respectively ( P<0.001 ) . Side effects were minor . CONCLUSION These data provide definitive evidence that PEI is a safe and effective treatment for thyroid cystic nodules . Unicameral thyroid cysts are the most suitable c and i date nodules for PEI CONTEXT Recurrence rate , after aspiration , in cystic thyroid nodules is very high . Interstitial laser photocoagulation ( ILP ) is a minimally invasive procedure that reduces the need for surgery in patients with a benign solid thyroid nodule . OBJECTIVE The aim of the study was to evaluate the efficacy of ILP on remission rates in recurrent , predominantly cystic thyroid nodules . DESIGN AND METHODS Forty-four consecutive out patients with a symptomatic , recurrent , and cytologically benign cystic ( cyst volume ≥ 2 mL ) thyroid nodule were r and omized to a single aspiration with ( n = 22 ) or without ( n = 22 ) subsequent ILP and followed up after 1 , 3 , and 6 months . RESULTS Successful outcome ( cyst volume ≤ 1 mL ) was obtained in 15 of 22 ( 68 % ) patients in the ILP group , compared to 4 of 22 ( 18 % ) in the aspiration group ( P = .002 ) . In the ILP group , the solid part of the nodule was reduced from a median of 1.8 to 1.0 mL ( P = .02 ) . In the aspiration-alone group , neither the cyst volume nor the solid nodule volume was significantly reduced . The reduction in median visual analog score ( 0 - 10 cm ) for pressure symptoms was significantly higher in the ILP group ( from 3.0 to 0.0 cm ) than in the aspiration-alone group ( from 4.0 to 3.5 cm ) ( P = .006 , between groups ) . No major side effects occurred , and thyroid function was unaffected throughout . CONCLUSIONS US-guided aspiration and subsequent ILP of benign recurrent predominantly cystic thyroid nodules is safe . It significantly reduces recurrence rate , the volume of the solid nodule component , and pressure symptoms . ILP constitutes an important alternative to surgery in such patients Thyroid nodules are prevalent ; when evaluated by ultrasonography ( US ) , 15 - 25 % of solitary thyroid nodules are cystic or predominantly cystic , and most are benign . Simple aspiration is the treatment of choice , but the recurrence rate is 10 - 80 % depending on the number of aspirations and the cyst volume . The aim of this study was to evaluate the effect on recurrence rate of benign recurrent thyroid cysts in a double-blind r and omized study comparing ethanol instillation with instillation of isotonic saline and subsequent complete emptying . Sixty-six consecutive patients with recurrent and benign ( based on US-guided biopsy ) thyroid cysts ( > or=2 ml ) were r and omly assigned to either subtotal cyst aspiration , flushing with 99 % ethanol , and subsequent complete fluid aspiration ( n = 33 ) , or to subtotal cyst aspiration , flushing with isotonic saline , and subsequent complete fluid aspiration ( n = 33 ) . In case of recurrence ( defined as cyst volume > 1 ml ) at the monthly evaluations , the treatment was repeated but limited to a maximum of three treatments . Procedures were US-guided , and patients were followed for 6 months . Age , sex , number of previous aspirations , pretreatment cyst volume , and serum TSH did not differ in the two groups . Cure ( defined as a cyst volume < or=1 ml at the end of follow-up ) was obtained in 27 of 33 [ 82 % ; confidence interval ( CI ) , 65 - 93 ] patients treated with ethanol and in 16 of 33 ( 48 % ; CI , 31 - 66 ) patients treated with saline ( P = 0.006 ) . In the ethanol group , 21 of 33 ( 64 % ) patients were cured after one session only , compared with six of 33 ( 18 % ) in the saline group ( P = 0.002 ) . The number of previous aspirations ( P = 0.005 ) and baseline cyst volume ( P = 0.005 ) had influence on outcome , i.e. the chance of success decreased with the number of previous aspirations and with increasing cyst volume . Seven patients ( 21 % ) treated with ethanol had moderate to severe pain ( median duration , 5 min ; CI , 2 - 10 ) , and one had transient dysphonia . Indirect laryngoscopy was performed before and after the last session and was normal in all patients . We concluded that treatment of recurrent thyroid cysts with ethanol is superior to simple aspiration and flushing with saline and devoid of serious side effects . Our study demonstrates that flushing with ethanol is a clinical ly significant nonsurgical alternative for thyroid cysts that recur despite repeat aspirations AIM To evaluate the efficacy of ultrasound (US)-guided interstitial laser photocoagulation ( ILP ) on thyroid function , nodule size and patient satisfaction in benign solitary solid cold thyroid nodules by comparing one ILP session with no treatment in a prospect i ve r and omised study . MATERIAL S AND METHODS Thirty euthyroid out patients with a benign solitary solid and a scintigraphically cold thyroid nodule causing local discomfort were assigned to one session of ILP ( n = 15 ) or observation ( n = 15 ) and followed for 6 months . Thyroid nodule volume and total thyroid volume were assessed by US and thyroid function was determined by routine assays before and during follow-up . Pressure and cosmetic complaints before and at 6 months were evaluated on a visual analogue scale . ILP was performed under US guidance and with an output power of 2.5 - 3.5 W. RESULTS In the ILP group , the nodule volume decreased from 8.2 ml ( 6.1 ; 11.9 ) ( median ; quartiles ) to 4.8 ml ( 3.0 ; 6.6 ) after 6 months ( P = 0.001 ) . The overall median reduction was 44 % ( 37 ; 52 ) , which correlated with a significant decrease in pressure symptoms as well as cosmetic complaints . In the control group , a non-significant increase in median nodule volume of 7 % ( 0 ; 34 ) after 6 months was seen . No major side-effects were seen in the ILP group . There was no correlation between thermal energy deposition and nodule volume reduction . Thyroid function was unaltered throughout . CONCLUSION US-guided ILP , given as a single treatment , result ed in a satisfactory clinical response in the majority of patients with a benign solitary solid cold thyroid nodule , and may become a clinical ly relevant alternative to surgery in selected patients This r and omized controlled study was design ed to test the efficacy and safety of percutaneous ultrasound (US)-guided laser photocoagulation ( PLP ) for treatment of subjects with compressive symptoms due to benign thyroid nodules and /or at high surgical risk . Twenty six subjects were r and omized to the intervention ( no. 13 , age 68±3 yr , mean±SEM ) or observation ( no. 13 , age 71±2 yr ) groups . In the control group , the volume of nodules did not significantly change over the 30 week period of observation . In the intervention group , median nodule volume at baseline was 8.2 ml ( range 2.8–26.9 ) and was not significantly different from that of the control group . Nodules decreased significantly ( p<0.0001 ) by 22 % after 2 weeks ( 6.5ml ; range 2.4–16.7 ) and by 44 % after 30 weeks ( 4.6 ml ; range 0.69–14.2 ) . Energy given was correlated ( p<0.05 ) with the reduction of thyroid nodule volume . All patients tolerated the treatment well and reported relief from compressive and cosmetic complaints ( p<0.05 ) . At the time of enrolment 7/13 ( 54 % ) and 6/13 ( 46 % ) of patients in the intervention and control groups , respectively , had sub clinical hyperthyroidism . PLP normalized thyroid function at 6 and 30 weeks after treatment . In conclusion , PLP is a promising safe and effective procedure for treatment of benign thyroid nodules in patients at high surgical risk BACKGROUND Thyroid surgery is common , but complications may occur . High-intensity focused ultrasound ( HIFU ) is a minimally invasive alternative to surgery . We hypothesized that an optimized HIFU device could be safe and effective for ablating benign thyroid nodules without affecting neighboring structures . METHODS In this open , single-center feasibility study , 25 patients were treated with HIFU with real-time ultrasound imaging 2 weeks before a scheduled thyroidectomy for multinodular goiter . Thyroid ultrasonography imaging , thyroid function , were evaluated before and after treatment . Adverse events were carefully recorded . Each patient received HIFU for one thyroid nodule , solid or mixed , with mean diameter ≥8 mm , and no suspicion of malignancy . The HIFU device was progressively adjusted with stepwise testing . The energy level for ablation ranged from 35 to 94 J/pulse for different groups of patients . One pathologist examined all removed thyroids . RESULTS Three patients discontinued treatment due to pain or skin microblister . Among the remaining 22 patients , 16 showed significant changes by ultrasound . Macroscopic and histological examinations showed that all lesions were confined to the targeted nodule without affecting neighboring structures . At pathological analysis , the extent of nodule destruction ranged from 2 % to 80 % . Five out of 22 patients had over 20 % pathological lesions unmistakably attributed to HIFU . Seventeen cases had putative lesions including nonspecific necrosis , hemorrhage , nodule detachment , cavitations , and cysts . Among these 17 cases , 12 had both ultrasound changes and cavitation at histology that may be expected for an HIFU effect . In the last three patients ablated at the highest energy level , significant ultrasound changes and complete coagulative necrosis were observed in 80 % , 78 % , and 58 % of the targeted area , respectively . There were no major complications of ablation . CONCLUSION This study showed the potential efficacy of HIFU for human thyroid nodule ablation . Lesions were clearly visible by histology and ultrasound after high energy treatments , and safety and tolerability were good . We identified a power threshold for optimal necrosis of the target thyroid tissue . Further studies are ongoing to assess nodule changes at longer follow-up times PURPOSE To obtain the treatment parameters of internally cooled microwave antenna and to evaluate the feasibility of ultrasound-guided percutaneous microwave ablation ( MWA ) for benign thyroid nodules . MATERIAL S AND METHODS MWAs were performed by microwave antenna ( 16 G ) in ex vivo porcine liver . The lesion diameters achieved in different groups ( 20 , 25 , and 30 W for 3 , 5 , 7 , 10 , and 12 min ) were compared . The clinical study was approved by the ethics committee . Written informed consent was obtained from all patients . MWA was performed in 11 patients ( male to female ratio=1:10 ; mean age , 50±7 years ) with 11 benign thyroid nodules . Ultrasound scan , laboratory data , and clinical symptoms were evaluated before and 1 day and 1 , 3 , 6 , 9 , and 12 months after the procedure . RESULTS In ex vivo study , the ablation lesion at 30 W 12 min tended to have appropriate scope and spherical shape . In clinical study , the follow-up periods ranged from 1 to 9 months . At the last follow-up , the largest diameter decreased from 2.9±1.0 ( range , 1.6 - 4.1 ) to 1.9±0.7 ( range , 0.4 - 3.0 ) cm ( P<0.01 ) , and the volume decreased from 5.30±4.88 ( range , 0.89 - 14.81 ) to 2.40±2.06 ( range , 0.02 - 6.35 ) ml ( P<0.01 ) . The volume reduction ratio was 45.99±29.90 ( range , 10.56 - 98.15 ) % . The cosmetic grading score was reduced from 3.20±0.79 to 2.30±0.95 ( P<0.05 ) . One patient experienced temporary nerve palsy and was recovered within 2 months after treatment . CONCLUSION The internally cooled microwave antenna can yield ideal ablation lesions , and ultrasound-guided percutaneous MWA is a feasible technique for benign thyroid nodules PURPOSE To compare volume reduction of single-session ethanol ablation ( EA ) and radiofrequency ( RF ) ablation for cystic thyroid nodule treatment . MATERIAL S AND METHODS All patients gave written informed consent to participate in this prospect i ve institutional review board-approved study . From May 6 , 2010 , to August 8 , 2011 , in this single-institutional , noninferiority trial , 50 patients , each with a single cystic thyroid nodule , were r and omly assigned to EA ( 25 patients ; mean age for women , 45.7 years , and for men , 37.5 years ) or RF ablation ( 25 patients ; mean age for women , 45.1 years , and for men , 43.7 years ) treatment . Internal fluid was aspirated prior to EA or RF ablation . Primary end point was the volume reduction ratio ( percentage ) at 6-month follow-up ; the noninferiority margin was chosen as -8 % ( EA minus RF ablation ) . Secondary end points included therapeutic success rate , improvement of symptoms and cosmetic problems , and number of major complications . Analysis was performed primarily in intention-to-treat manner . A one-sided 95 % confidence interval ( CI ) for the mean difference in volume reduction ratio 6 months after treatment was calculated to test for noninferiority . Subsequent superiority comparison of EA with RF ablation on a condition of establishment of the noninferiority of EA to RF ablation was preplanned and used two-sided 95 % CI of the outcome difference . RESULTS The mean volume reduction was 96.9 % in EA and 93.3 % in RF ablation ( n = 21 for each ) ( difference , 3.6 % ; lower bound of the one-sided 95 % CI of the difference , 1.2 % ) , thus demonstrating the noninferiority of EA to RF ablation . Two-sided 95 % CI of the outcome difference was 0.7 % to 6.5 % , demonstrating significant superiority of EA to RF ablation . All patients demonstrated therapeutic success ( P > .99 ) . Mean symptom and cosmetic scores showed no significant difference in either group ( P = .806 and P = .682 , respectively ) . There were no major complications ( P > .99 ) . CONCLUSION EA may be the first-line treatment modality for cystic thyroid nodules , which has comparable therapeutic efficacy to , but is less expensive than , RF ablation PURPOSE Percutaneous radiofrequency thermal ablation ( RTA ) was reported as an effective tool for the management of thyroid nodules ( TNs ) . The aim of this study was to investigate the effects of RTA and to establish whether they were treatment-related by comparison with a matched , untreated control group . PATIENTS AND METHODS The study population included 40 patients with compressive TNs : 22 had nontoxic TNs , and 18 had toxic TNs and were treated with methimazole . In all patients , a fine-needle aspiration cytology was performed to exclude a thyroid malignancy . STUDY DESIGN Twenty patients were treated with RTA ( group A ) , and 20 others did not receive any treatment ( group B ) . At baseline , age , gender , and TN features did not differ significantly between groups . All patients were clinical ly , biochemically , and morphologically evaluated at baseline and after 1 , 3 , 6 , and 12 months . RESULTS TN volume significantly decreased in group A ( 1.8 ± 0.3 ml at 12 months vs. 13.3 ± 1.8 ml at baseline ; P < 0.0001 ) and remained stable in group B [ 11.7 ± 1.5 ml at 12 months vs. 11.2 ± 1.5 ml at baseline ; P = not significant ( NS ) ] . At 3- , 6- , and 12-month evaluations , TN volume was significantly lower in group A than in group B ( P < 0.005 ) . At the end of the follow-up , pressure symptoms were improved in all patients in group A but persisted unchanged in group B. In group A , hyperthyroidism completely recovered in 40 % and improved in 40 % of patients with toxic TNs , whereas it persisted in all patients with toxic TNs in group B. RTA was safe and well tolerated in all patients . CONCLUSIONS RTA induced a marked TN volume shrinkage result ing in parallel improvement of pressure symptoms . In most patients with toxic TNs , hyperthyroidism significantly improved as well . RTA may represent a valid therapeutic approach in patients with TNs not receiving conventional treatments We studied for 5 yr a homogeneous group of 83 patients r and omly assigned to a levothyroxine ( L-T4 ) suppressive therapy or to a control group to evaluate changes in nodule or thyroid size , appearance of new nodules , and correlations with clinical parameters . In the control group , mean nodule volume increased significantly after 5 yr ( 2.12 + /- 1.46 vs. 1.46 + /- 0.77 mL ) , whereas in the treatment group it decreased , although not significantly ( 1.45 + /- 1.17 mL vs. 1.53 + /- 0.61 mL ) . Baseline nodule volume was not different in the two groups , but a significant difference was observed at 5 yr . After 5 yr , sonograms detected 12 new nodules in the control group ( 28.5 % ) and 3 ( 7.5 % ) in the treatment group . Nodule shrinkage was more frequent in patients with complete TSH suppression , but no correlation was found with other parameters . A significant increase in thyroid size was observed in the control group . In conclusion , long term TSH suppression induced volume reduction in only a subgroup of thyroid nodules , but effectively prevented the appearance of new lesions and increases in nodule and thyroid volume . As the changes in the natural history of nodular goiter are related to prolonged TSH suppression , which can induce unfavorable side-effects , L-T4 suppressive therapy should be reserved for small nodules in younger patients Purpose : To determine the efficacy and safety of ultrasound-guided percutaneous ethanol ablation for the management of benign thyroid cysts . Study design : In this prospect i ve study , 40 patients with fine-needle aspiration cytology-proven benign thyroid cysts underwent alcohol ablation . Sonographically , 24 nodules were predominantly cystic ( simple cysts ) , and 16 showed both solid and cystic elements ( complex cysts ) . The cyst fluid was aspirated , and an amount of sterile 95 % ethanol equivalent to ∼ 50 % of the aspirated fluid was injected . Initially , a 20-gauge needle on a 20 ml syringe was used . Later , a three-way cannula was used in which one port was used for aspiration of the cyst fluid and the other for injection of the alcohol . Results : The pretreatment volume of the cysts was 5.8–18.5 ml ( mean ( SD ) 12.26 ( 3.6 ) ) . Cyst volume after treatment was 0–8 ml ( mean ( SD ) 3.73 ( 2.8 ) ) . Ten cysts had disappeared completely after treatment . Cosmetic symptoms disappeared in 90 % of the patients . Twenty-four patients complained of a local burning sensation at the injection site . The use of the three-way cannula helped to decrease the procedure time by decreasing the chances of needle displacement . Conclusion : Ultrasound-guided ethanol ablation is a safe , highly effective , relatively rapid treatment modality that is both patient and surgeon friendly and should be considered as the treatment of choice for benign cystic thyroid nodules OBJECTIVE The management of cystic lesions in the thyroid remains controversial . We examined the efficacy and safety of ultrasound guided percutaneous ethanol injection for the treatment of benign cystic thyroid nodules in euthyroid patients The aim of the present study was to evaluate the efficacy of percutaneous ethanol injection therapy ( PEIT ) with special reference to dose response and symptom score and to describe side effects in a parallel-group r and omized clinical trial with 6 months of follow-up , comparing 2 different treatment strategies . Sixty euthyroid out patients with a benign solid and scintigraphically solitary cold thyroid nodule causing local discomfort were assigned to 1 session with a single intranodular injection of sterile 98 % ethanol ( PEIT-1 , n = 30 ) or 3 weekly sessions with 1 injection of sterile 98 % ethanol ( PEIT-3 , n = 30 ) . In the PEIT-1 group , the pretreatment nodule volume was 9.9+/-5.7 mL ( mean + /- SD ) . It decreased to 7.0+/-4.7 mL after 1 month , and 5.6+/-5.9 mL after 6 months ( p = 3.2x10(-6 ) ) , and the ethanol dose given was 24.7%+/-7.5 % of the pretreatment nodule volume . The overall reduction in nodule volume was 46 % . In the PEIT-3 group the pretreatment nodule volume was 9.4+/-4.2 mL. It decreased to 5.9+/-3.5 mL 1 month after the last session , and 4.6+/-2.6 mL after 6 months ( p = 4.0x10(-10 ) ) , and the cumulative ethanol dose given was 47.9%+/-21.3 % of the pretreatment nodule volume . The overall reduction in nodule volume was 51 % , and the difference between the 2 treatment regimens was 5.3%+/-5.5 % ( mean + /- SE of difference , p = 0.3 ) . A satisfactory treatment dose , defined as a total intranodular spread of ethanol visualized on the monitor screen , was achieved in only 50%-60 % of the sessions . This was due to pain that necessitated premature discontinuation of the injection and was apparently severe enough in 3 patients in the PEIT-3 group that they refused additional treatment . Twenty-two of 30 ( 73 % ) patients in the PEIT-1 group and 19 of 30 ( 63 % ) in the PEIT-3 group had a marked effect on symptoms at 6-month follow-up ( p = 0.6 ) . Side effects comprised transient thyrotoxicosis in 2 patients , permanent ipsilateral facial dysesthesia and increased flow of tears in 1 patient , paranodular fibrosis impeding subsequent surgery in 1 case and various degrees of pain and tenderness related to PEIT in nearly all . Major side effects were dose dependent . We conclude that PEIT is effective in inducing necrosis and reducing the volume of benign solid cold thyroid nodules . The additive effect of 2 additional doses compared with 1 dose is insignificant . The optimum management strategy has yet to be clarified . Limitations relate to the procedure being quite painful despite local anesthesia and the fact that side effects are in no way negligible , and therefore , a word of caution in routine use is advisable BACKGROUND AND PURPOSE Percutaneous ethanol injection ( PEI ) has been established as an effective and safe treatment for thyroid cystic nodules ( TCN ) . Certain tetracyclines have also been used successfully as sclerosing agents , and it has been proposed that a low pH might account for their efficacy in this indication . This study compared the effectiveness of ethanol and dilute hydrochloric acid ( pH 1.0 ) in the sclerotherapy of TCN . METHODS A total of 27 patients with TCN with a mean cystic volume of 16.6 mL ( 5 - 45 mL ) were r and omly assigned to receive 1 of the following 3 treatments : 1 ) needle aspiration only , 9 patients ; 2 ) PEI , 10 patients ; or 3 ) percutaneous hydrochloric acid injection ( PHI ) , 8 patients . The procedures were performed weekly until cure was evident . Resolution was defined as the disappearance of cyst or reduction of cystic volume to below 0.5 mL. Treatment was considered a failure if the condition did not resolve after 5 sessions of intervention . The 10 original patients treated by PEI and 14 additional patients subsequently enrolled and treated by PEI were followed for 24 months in order to evaluate the long-term effects of PEI treatment . Follow-up physical examination and ultrasound scan was performed every 3 months during the first year and every 6 months during the second year . A cystic volume of greater than 1 mL was regarded as a recurrence . RESULTS PHI did not have a better cure rate than aspiration alone ( 37.5 % vs 44.4 % , p = 0.778 ) . PEI had a significantly higher cure rate than PHI ( 90 % vs 37.5 % , p = 0.023 ) and aspiration alone ( 90 % vs 44.4 % , p = 0.038 ) . No patient who received aspiration only complained of cervical pain . Four patients who received PEI and 3 patients who received PHI complained of self-limited cervical pain soon after sclerosant injection . Completed follow-up in the 24 patients ranged from 3 to 24 months ( mean , 15.5 + /- 7.7 months ) , and only 3 patients ( 12.5 % ) were found to have recurrence within the first 9 months . The likelihood of recurrence was not correlated with pretreatment cystic volume . CONCLUSIONS Use of a low-pH sclerosant ( PHI ) was of no benefit . PEI provides a rapid , tolerable , and sustained effect and can be used as first-line treatment in patients with TCN The efficacy of suppressing TSH secretion with levothyroxine ( L-T(4 ) ) in reducing solitary thyroid nodule growth is still controversial . In this prospect i ve multicenter , r and omized , double-blind , placebo-controlled trial , 123 patients with a single palpable benign nodule were included and r and omly allocated to an 18-month treatment with L-T(4 ) or placebo . Individual dose was adjusted to allow a serum TSH level below 0.3 mIU/liter . Clinical and ultrasonographic nodule characteristics were assessed before treatment and 3 , 6 , 12 , and 18 months thereafter . The largest mean nodule size assessed on palpation and largest volume , assessed by ultrasonography , decreased in the L-T(4 ) group and increased slightly in the placebo group [ size , -3.5 + /- 7 mm vs. + 0.5 + /- 6 mm ( P = 0.006 ) ; volume , -0.36 + /- 1.71 ml vs. + 0.62 + /- 3.67 ml ( P = 0.01 ) , respectively ] . The proportion of clinical ly relevant volume reduction ( > or = 50 % ) rose significantly in the L-T(4 ) group [ 26.6 % vs. 16.9 % ( P = 0.04 ) ] . The proportion of patients with a reduced number of infra clinical additional nodules was significantly higher in the L-T(4 ) group [ 9.4 % vs. 0 ( P = 0.04 ) ] . It is concluded from this study that suppressive L-T(4 ) therapy is effective in reducing solitary thyroid nodule volume and improving infra clinical extranodular changes In a prospect i ve study , 53 consecutive patients with solitary thyroid cysts were r and omized to ultrasonically guided cyst aspiration and subsequent flushing with isotonic saline ( n = 30 ) or tetracycline hydrochloride ( n = 23 ) . The patients were followed up clinical ly and ultrasonically 1 , 3 , 6 , and 12 months after treatment . If the cyst recurred , a repeated treatment was offered . Cure was defined as the absence of any residual nodule and an ultrasonic cyst volume of less than 1 mL 12 months after the last treatment . During follow-up , two patients without recurrence after saline treatment and six patients without recurrence after tetracycline treatment developed solid cold nodules . Fourteen ( 47 % ) of 30 patients in the saline group and ten ( 43 % ) of 23 patients in the tetracycline group were cured ( not statistically significant ) . Tetracycline does not seem to offer any advantage over isotonic saline in the treatment of thyroid cysts , and some of these patients still need thyroid surgery objective The efficacy and the effective dose of levothyroxine suppressive therapy in the treatment of benign thyroid nodules are controversial . In this study , we aim ed to determine the response of solitary thyroid nodules to low‐ or high‐level TSH suppression in a placebo‐controlled , r and omized crossover trial Multinodular goitre ( MNG ) is a common clinical finding , particularly in females and is usually asymptomatic . When symptoms occur because of local pressure-related effects the only treatment is surgical involving partial or total thyroidectomy . A number of epidemiological observations and experimental data have suggested that oestrogen aromatase activity may be involved in the pathogenesis of MNG . This study examines the effect of anastrozole , a non-steroidal aromatase inhibitor that inhibits the peripheral conversion of testosterone to oestradiol , in reducing the size of MNG . Thirty-two post-menopausal female patients , median age 63 years ( range 42 - 84 ) were r and omised in a double-blind fashion to receive either anastrozole 1 mg daily or placebo for 3 months . Ultrasonographic measurement of each thyroid lobe and isthmus together with complete biochemical and hormone profiles were performed at the start and end of treatment . There was no significant reduction in the goitre size for patients in the anastrozole group ( p = 0.246 ) or the placebo group ( p = 0.418 ) . There were no significant changes in hormone profiles ( including throglobulin concentration ) within each group between the start and end of the study . We conclude that the use of anastrozole in the treatment of MNG does not appear to have any effect in reducing the size of MNG The results of studies using suppressive doses of L-T4 on benign solitary solid cold thyroid nodules have been conflicting . Recently , intranodular injection of absolute ethanol has been proposed as an effective treatment , but has been evaluated only in uncontrolled studies . Our objective was to evaluate the effect of two alternative medical treatment modalities , percutaneous ethanol injection therapy and L-T4 , on the benign solitary solid cold thyroid nodule . In a prospect i ve r and omized clinical trial , 50 euthyroid patients with a single solid colloid thyroid nodule causing local discomfort were assigned to a single intranodular injection of sterile 98 % ethanol ( n = 25 ) or suppressive doses of L-T4 ( n = 25 ) . We aim ed at an ethanol dose of 20 - 50 % of the pretreatment nodular volume . The initial daily dose of L-T4 was 1.5 microg/kg BW and was adjusted monthly during the first 6 months to reduce serum TSH to subnormal levels ( < 0.40 mU/L ) . Thyroid nodule volume and total thyroid volume were assessed by ultrasound , and thyroid function was determined by routine assays before and during follow-up . Symptom scores before and at 12 months were evaluated by a question naire rating pressure symptoms and cosmetic symptoms . The median ethanol dose given was 21 % [ 95 % confidence interval ( CI ) , 18;25 ] of the pretreatment nodule volume . In this group , the median reduction in nodule volume was 47 % ( CI , 33;57 ; P < 0.0001 ) compared to 9 % ( CI , -7;22 ; P = 0.09 ) in the L-T4 group . The difference between the two treatment regimens was statistically significant ( P < 0.0001 ) . The median reduction in perinodular thyroid volume was 20 % ( CI , 11;31 ; P = 0.03 ) in the L-T4 group , whereas no change was seen in the ethanol group ( -2.5 % ; CI , -18;11 ; P = 0.9 ) . Fourteen of 25 ( 56 % ) patients treated with ethanol injection and 8 of 25 ( 32 % ) treated with L-T4 had complete relief of symptoms at 12 months of follow-up ( P = 0.09 ) . No major side-effects were seen in either group . Percutaneous ethanol injection therapy administered as a single small dose results in a satisfactory clinical response in approximately 50 % of patients by halving the nodule volume . The thyroid nodule-reducing effect of L-T4 suppressive therapy is insignificant , but a subjective satisfactory clinical response is seen in a subgroup of patients , probably explained by the concomitant reduction of perinodular thyroid volume OBJECTIVE To compare the efficacy of interstitial laser photocoagulation ( ILP ) with radioiodine in hot thyroid nodules . DESIGN Thirty consecutive out patients with sub clinical or mild hyperthyroidism and a scintigraphically solitary hot nodule with extragl and ular suppression were r and omized to either one ILP session or one radioiodine ( (131)I ) dose . METHODS ILP was performed under continuous ultrasound-guidance and with an output power of 2.5 - 3.5 W. (131)I was given as a single dose based on thyroid volume and a 24-h thyroid (131)I uptake . Thyroid function and nodule volume were evaluated at inclusion and at 1 , 3 and 6 months after treatment . RESULTS Normalization of serum TSH was achieved in 7 out of 14 patients in the ILP group and in all 15 patients in the (131)I group ( P=0.0025 ) . In the ILP group , mean thyroid nodule volume reduction was 44+/-5 % ( s.e.m . ; P<0.001 ) , and in the (131)I group 47+/-8 % ( P<0.001 ) , within 6 months , without between-group difference ( P=0.73 ) . The mean reduction of total thyroid volume was 7+/-5 % in the ILP group ( P=0.20 ) and 26+/-8 % ( P=0.006 ) in the (131)I group ( P=0.06 between-group ) . Two patients in the (131)I group developed hypothyroidism but no major side effects were seen . CONCLUSIONS This first r and omized study , comparing ILP with st and ard therapy , demonstrates that ILP and (131)I therapy approximately halves thyroid nodule volume within 6 months ; but in contrast to (131)I , extranodular thyroid volume is unaffected by ILP and no patient developed hypothyroidism . Using the present design , ILP seems inferior to (131)I therapy in normalization of serum TSH . The potential value of ILP as a non-surgical alternative to (131)I needs further investigation OBJECTIVE To compare the rate of bone mineral loss in thyroxine-treated women with low thyrotropin ( thyroid stimulating hormone , TSH ) levels with that in women without known thyroid disease . DESIGN Cases selected from a prospect i ve calcium trial . SETTING Subjects were recruited from the Boston area . MEASUREMENTS AND MAIN RESULTS Of 361 women enrolled in a 2-year calcium supplement trial , 18 received thyroxine for hypothyroidism . Of these , 10 were considered overtreated , because they had low TSH levels . Rates of loss of bone mineral density from the radius , spine , and hip during 1.9 + /- 0.6 years were measured by single- and dual-photon absorptiometry . When compared with women with no known thyroid disease ( 236 controls for the spine , 246 for the radius , and 237 for the femoral neck ) , women with low TSH levels had greater annualized , adjusted mean rates of bone loss from the spine ( -2.89 % + /- 0.65 % compared with -1.13 % + /- 0.13 % , P = 0.009 ) and similar but not significant trends at the radius ( -1.18 % + /- 0.75 % compared with -0.13 % + /- 0.17 % ) and femoral neck ( -1.39 % + /- 0.80 % compared with -0.28 % + /- 0.19 % ) . These means were adjusted for variables that affected the rate of loss in the control group ( baseline bone mineral density and body mass index , calcium intake , and years since menopause ) . There were no statistical differences between the low TSH and control groups for any laboratory variables measured , including serum calcium , phosphorus , parathyroid hormone or alkaline phosphatase , plasma 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D , or 24-hour urine calcium-to-creatinine ratio . CONCLUSIONS Thyroxine-treated women with low TSH levels lose bone mineral from the spine more rapidly than do women without known thyroid disease . These patients are therefore at increased risk for osteoporosis . The absence of detectable biochemical changes in women with low TSH levels may result from their relatively modest degree of overtreatment OBJECTIVE Interstitial laser photocoagulation ( ILP ) is a safe and effective procedure when inducing thyroid nodule necrosis . In this prospect i ve r and omized study , we evaluated a possible dose-response relationship as well as patient satisfaction . DESIGN Thirty euthyroid out patients with a cytologically benign solitary solid and scintigraphically cold thyroid nodule causing local discomfort were assigned to one session of ILP ( ILP-1 ) ( n = 15 ) or three monthly ILP sessions ( ILP-3 ) ( n = 15 ) and followed for 6 months . ILP was performed under continuous ultrasound (US)--guidance and with an output power of 2.5 - 3.5 W. Thyroid nodule volume was assessed by US . Pressure and cosmetic complaints were evaluated on a visual analogue scale . MAIN OUTCOME In the ILP- 1 group , thyroid nodule volume decreased from 10.1 + /- 4.3 mL ( mean + /- st and ard deviation [ SD ] ) to 5.7 + /- 3.2 mL ( p = 0.0004 ) , and in the ILP-3 group from 10.8 + /- 5.5 mL to 4.6 + /- 3.0 mL ( p = 0.0005 ) during follow-up . The overall mean difference between the two groups was 13 % , corresponding to an improved mean thyroid nodule volume reduction of 30 % ( p = 0.03 ) . In both groups subjective symptoms were significantly reduced , and without difference between the two groups ( p = 0.7 ) . No major side effects were seen in either group . CONCLUSION As a nonsurgical therapeutic option , ILP-1 approximately halves thyroid nodule volume with concomitant symptom relief . There is little incremental effect of additional ILP treatment , which should be limited to patients with large nodules or limited nodule reduction after the first treatment OBJECTIVE To evaluate the efficacy of ultrasound (US)-guided laser thermal ablation ( LTA ) in reducing the volume of hypofunctioning benign thyroid lesions . METHODS The criteria for entry into the study were as follows : ( 1 ) presence of a hypofunctioning thyroid nodule with a volume exceeding 8 mL , ( 2 ) benign cytologic findings , ( 3 ) local compression symptoms or patient concern , and ( 4 ) refusal of or in eligibility for surgical treatment . Twenty patients ( 15 women and 5 men ; mean age , 63.3 + /- 14.1 years ) fulfilling the entry criteria were enrolled in the study . Under US monitoring , a 75-mm , 21-gauge spinal needle was inserted into the thyroid gl and , and a flat-tipped 300-microm quartz fiberoptic guide was placed through the needle into the tissues . LTA was performed with use of a 1.064-microm continuous-wave neodymium yttrium-aluminum-garnet laser that had an output power of 3 W for 10 minutes . US scans were used to assess the decrease in nodule volume at 1 month and 6 months after LTA . RESULTS After LTA , mean nodule volume decreased from a baseline value of 24.1 + /- 15.0 mL to 13.3 + /- 7.7 mL at 1 month and to 9.6 + /- 6.6 mL at 6 months . Mean nodule volume reduction in comparison with baseline was 43.8 + /- 8.1 % at 1 month and 63.8 + /- 8.9 % at 6 months . LTA induced burning cervical pain , which rapidly decreased after the laser energy was turned off . Three patients ( 15 % ) required treatment with betamethasone for 48 hours . No patient had local bruising , cutaneous burning , or dysphonia . CONCLUSION LTA may be an effective procedure for the treatment of benign cold thyroid nodules that cause pressure symptoms in patients who are not c and i date s for surgical treatment or who refuse to undergo a surgical procedure Context : Nodular goiter is common worldwide , but there is still debate over the medical treatment . Objective : The objective of the study was the measurement of the effect of a treatment with ( nonsuppressive ) T4 , iodine , or a combination of both compared with placebo on volume of thyroid nodules and thyroid . Design : This was a multicenter , r and omized , double-blind trial in patients with nodular goiter in Germany [ LISA ( Levothyroxin und Iodid in der Strumatherapie Als Mono-oder Kombinationstherapie ) trial ] . Setting : The study was conducted in outpatient clinics in university hospitals and regional hospitals and private practice s. Participants : One thous and twenty-four consecutively screened and central ly r and omized euthyroid patients aged 18–65 yr with one or more thyroid nodules ( minimal diameter 10 mm ) participated in the study . Intervention : Intervention included placebo , iodine ( I ) , T4 , or T4+I for 1 yr . T4 doses were adapted for a TSH target range of 0.2–0.8 mU/liter . Outcome Measures : The primary end point was percent volume reduction of all nodules measured by ultrasound , and the main secondary end point was a change in goiter volume . Results : Nodule volume reductions were −17.3 % [ 95 % confidence interval ( CI ) −24.8/−9.0 % , P < 0.001 ] in the T4+I group , −7.3 % ( 95 % CI −15.0/+1.2 % , P = 0.201 ) in the T4 group , and −4.0 % ( 95 % CI −11.4/+4.2 % , P = 0.328 ) in the I group as compared with placebo . In direct comparison , the T4+I therapy was significantly superior to T4 ( P = 0.018 ) or I ( P = 0.003 ) . Thyroid volume reductions were −7.9 % ( 95 % CI −11.8/−3.9 % , P < 0.001 ) , −5.2 % ( 95 % CI −8.7/−1.6 % , P = 0.024 ) and −2.5 % ( 95 % CI −6.2/+1.4 % , P = 0.207 ) , respectively . The T4+I therapy was significantly superior to I ( P = 0.034 ) but not to T4 ( P = 0.190 ) . Conclusion : In a region with a sufficient iodine supply , a 1-yr therapy with a combination of I and T4 with incomplete suppression of thyrotropin reduced thyroid nodule volume further than either component alone or placebo |
13,768 | 28,128,439 | targeted agents improved the efficacy of conventional chemotherapy both when considered together ( HR for OS : 0.84 , 95 % CI 0.77 to 0.91 ; 6 RCTs ; high- quality evidence ) and when bevacizumab was used alone ( HR for PFS : 0.67 , 95 % CI 0.60 to 0.75 ; 4 RCTs ; high- quality evidence ) .With regard to secondary endpoints , tumour response rates generally paralleled the survival results ; moreover , higher anticancer efficacy was generally associated with worse treatment-related toxicity , with the important exception of bevacizumab-containing regimens , where the addition of the targeted agent to chemotherapy did not result in a significant increase in the rate of SAE .
Finally , we found that oral ( instead of intravenous ) fluoropyrimidines significantly reduced the incidence of adverse effects ( without compromising efficacy ) in people treated with oxaliplatin-based regimens .
Systemic therapy offers a survival benefit to people with metastatic CRC who did not respond to first-line treatment , especially when targeted agents are combined with conventional chemotherapeutic drugs . | BACKGROUND The therapeutic management of people with metastatic colorectal cancer ( CRC ) who did not respond to first-line treatment represents a formidable challenge .
OBJECTIVES To determine the efficacy and toxicity of second-line systemic therapy in people with metastatic CRC .
SELECTION CRITERIA R and omized controlled trials ( RCTs ) assessing the efficacy ( survival , tumour response ) and toxicity ( incidence of severe adverse effects ( SAEs ) ) of second-line systemic therapy ( single or combined treatment with any anticancer drug , at any dose and number of cycles ) in people with metastatic CRC that progressed , recurred or did not respond to first-line systemic therapy . | PURPOSE In metastatic colorectal cancer , phase III studies have demonstrated the superiority of fluorouracil ( FU ) with leucovorin ( LV ) in combination with irinotecan or oxaliplatin over FU + LV alone . This phase III study investigated two sequences : folinic acid , FU , and irinotecan ( FOLFIRI ) followed by folinic acid , FU , and oxaliplatin ( FOLFOX6 ; arm A ) , and FOLFOX6 followed by FOLFIRI ( arm B ) . PATIENTS AND METHODS Previously untreated patients with assessable disease were r and omly assigned to receive a 2-hour infusion of l-LV 200 mg/m(2 ) or dl-LV 400 mg/m(2 ) followed by a FU bolus 400 mg/m(2 ) and 46-hour infusion 2,400 to 3,000 mg/m(2 ) every 46 hours every 2 weeks , either with irinotecan 180 mg/m(2 ) or with oxaliplatin 100 mg/m(2 ) as a 2-hour infusion on day 1 . At progression , irinotecan was replaced by oxaliplatin ( arm A ) , or oxaliplatin by irinotecan ( arm B ) . RESULT Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI ( P = .99 ) . Median second progression-free survival ( PFS ) was 14.2 months in arm A versus 10.9 in arm B ( P = .64 ) . In first-line therapy , FOLFIRI achieved 56 % response rate ( RR ) and 8.5 months median PFS , versus FOLFOX6 which achieved 54 % RR and 8.0 months median PFS ( P = .26 ) . Second-line FOLFIRI achieved 4 % RR and 2.5 months median PFS , versus FOLFOX6 which achieved 15 % RR and 4.2 months PFS . In first-line therapy , National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis , nausea/vomiting , and grade 2 alopecia were more frequent with FOLFIRI , and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6 . CONCLUSION Both sequences achieved a prolonged survival and similar efficacy . The toxicity profiles were different PURPOSE The aim of this r and omised trial was to evaluate the activity and toxicity of a biweekly regimen including 6S-leucovorin-modulated 5-fluorouracil ( LFA-5-FU ) , combined with either irinotecan ( CPT-11 + LFA 5-FU ) or raltitrexed ( Tomudex ) ( TOM + LFA-5-FU ) , in advanced colorectal cancer patients , and to make a preliminary comparison of both these experimental regimens with a biweekly administration of LFA-5-FU modulated by methotrexate ( MTX + LFA-5-FU ) . PATIENTS AND METHODS One hundred fifty-nine patients with advanced colorectal carcinoma previously untreated for the metastatic disease ( 34 of them previously exposed to adjuvant 5-FU ) were r and omly allocated to receive : CPT-11 , 200 mg/m2 i.v . on day 1 , followed on day 2 by LFA , 250 mg/m2 i.v . infusion and 5-FU , 850 mg/m2 s i.v . bolus ( arm A ) ; TOM , 3 mg/m2 i.v . on day 1 , followed on day 2 by LFA , 250 mg/m2 i.v . infusion and 5-FU , 1050 mg/m2 i.v . bolus ( arm B ) ; or MTX , 750 mg/m2 i.v . on day 1 , followed on day 2 by LFA , 250 mg/m2 i.v . infusion and 5-FU , 800 mg/m2 i.v . bolus ( arm C ) . Courses were repeated every two weeks in all arms of the trial . Response rate ( RR ) was evaluated after every four courses . The sample size was defined to have an 80 % power to detect a 35 % RR for each experimental treatment , and to show a difference of at least 4 % in RR with the st and ard treatment if the true difference is 15 % or more . RESULTS The RRs were : 34 % ( 95 % confidence interval ( 95 % , CI ) : 21%-48 % ) in arm A , including 3 complete responses ( CRs ) and 15 partial responses ( PRs ) , 24 % ( 95 % CI : 14%-38 % ) in arm B , including 2 CRs and 11 PRs , and 24 % ( 95 % CI : 14%-38 % ) , with 2 CRs and 11 PRs , in arm C. After a median follow-up time of 62 ( range 18 - 108 ) weeks , the median time to progression was 38 , 25 , and 27 weeks for arm A , B , and C , respectively . With 94 patients still alive , the one-year probability of survival was 61 % , 54 % , and 59 % , respectively . WHO grade 3 or 4 neutropenia and diarrhoea affected 46 % and 16 % , respectively , of patients treated with CPT-11 + LFA 5-FU . Median relative dose intensity over eight cycles ( DI8 ) was 78 % for CPT-11 and 82 % for 5-FU . Severe toxicities of TOM + LFA-5-FU were neutropenia ( 16 % ) and diarrhoea ( 16 % ) , but median relative DI8 was 93 % for TOM , and 82 % for 5-FU . CONCLUSIONS CPT-11 + LFA-5-FU compares favorably in term of activity and toxicity with other combination regimens including CPT-11 and continuous infusional 5-FU . The hypothesis of a RR 15 % higher than the MTX + LFA-5-FU treatment can not be ruled out after this interim analysis . The TOM + LFA 5-FU regimen showed a RR and a toxicity profile very close to the MTX + LFA 5-FU combination , and dose not deserve further evaluation in advanced colorectal cancer patients Elderly patients are recommended to have a reduced starting dose ( 300 mg m−2 once every 3 weeks ) of irinotecan monotherapy . The aims of this analysis are to compare toxicity and survival according to age , performance status ( PS ) , gender and prior radical pelvic radiotherapy ( RT ) . The primary end points were overall survival and an irinotecan-specific toxicity composite end point ( TCE ) defined as the occurrence of grade 3 or 4 diarrhoea , neutropenia , febrile neutropenia , fever , infection or nausea and vomiting . Between 1997 and 2003 , 339 eligible patients with advanced colorectal cancer ( CRC ) progressing on or within 24 weeks of completing fluoropyrimidine-based chemotherapy were prospect ively registered in a multicentre r and omised trial . All patients commenced irinotecan at 350 mg m−2 once every 3 weeks . There were no differences in proportions of patients developing TCE by age ( < 70 vs ⩾70 : 37.8 vs 45.8 % ; P=0.218 ) , PS ( 0–1 vs 2 : 39.3 vs 41.5 % ; P=0.793 ) or prior RT ( RT vs no RT : 45.1 vs 38.5 % ; P=0.377 ) . Males experienced more toxicity than females ( 44.3 vs 32.6 % ; P=0.031 ) , but this was not significant after controlling for other co-variates ( P=0.06 ) . Patients aged ⩾70 had similar objective responses ( 11.1 vs 9 % ; P=0.585 ) and survival ( median 9.4 vs 9 months ; log rank P=0.74 ) compared to younger patients . Elderly patients derive the same benefit without experiencing more toxicity with second-line irinotecan treatment for advanced CRC . Our data do not support the recommendation to reduce the starting dose for the elderly patients BACKGROUND In the non-curative setting , the sequence in which anticancer agents are used , singly or in combination , may be important if patients are to receive the maximum period of disease control with the minimum of adverse effects . We compared sequential and combination chemotherapy strategies in patients with unpretreated advanced or metastatic colorectal cancer , who were regarded as not potentially curable irrespective of response . METHODS We studied patients with advanced colorectal cancer , starting treatment with non-curative intent . 2135 unpretreated patients were r and omly assigned to three treatment strategies in the ratio 1:1:1 . Strategy A ( control group ) was single-agent fluorouracil ( given with levofolinate over 48 h every 2 weeks ) until failure , then single-agent irinotecan . Strategy B was fluorouracil until failure , then combination chemotherapy . Strategy C was combination chemotherapy from the outset . Within strategies B and C , patients were r and omly assigned to receive , as the combination regimen , fluorouracil plus irinotecan ( groups B-ir and C-ir ) or fluorouracil plus oxaliplatin ( groups B-ox and C-ox ) . The primary endpoint was overall survival , analysed by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N 79877428 . RESULTS Median survival of patients allocated to control strategy A was 13.9 months . Median survival of each of the other groups was longer ( B-ir 15.0 , B-ox 15.2 , C-ir 16.7 , and C-ox 15.4 months ) . However , log-rank comparison of each group against control showed that only C-ir -- the first-line combination strategy including irinotecan -- satisfied the statistical test for superiority ( p=0.01 ) . Overall comparison of strategy B with strategy C was within the predetermined non-inferiority boundary of HR=1.18 or less ( HR=1.06 , 90 % CI 0.97 - 1.17 ) . INTERPRETATION Our data challenge the assumption that , in this non-curative setting , maximum tolerable treatment must necessarily be used first-line . The staged approach of initial single-agent treatment up grade d to combination when required is not worse than first-line combination , and is an alternative option for discussion with patients PURPOSE Irinotecan given until disease progression is an accepted st and ard treatment for advanced colorectal cancer ( CRC ) resistant to fluoropyrimidines . It is not known whether a predefined period of irinotecan treatment would result in similar duration of disease control . We performed a multicenter phase III trial to compare the two policies of defined- duration versus continuous irinotecan treatment . PATIENTS AND METHODS Three hundred thirty-three eligible patients with advanced CRC progressing on or within 24 weeks of completing fluoropyrimidine-based chemotherapy were prospect ively registered . After receiving eight cycles of irinotecan given at 350 mg/m2 once every 3 weeks , 55 patients with responding or stable disease were r and omly assigned to stop irinotecan ( n = 30 ) or continue until disease progression ( n = 25 ) . Registered patients were not r and omly assigned predominantly due to disease progression ( n = 236 ) and intolerable toxicity ( n = 38 ) . RESULTS From the time of r and om assignment , there were no differences in failure-free survival ( P = .999 ) or overall survival ( P = .11 ) between the two arms . No difference was seen in mean global health status quality -of-life score between the two arms at 12 weeks after r and om assignment . No grade 3 diarrhea and febrile neutropenia was seen in the continue-irinotecan arm after r and om assignment . CONCLUSION For most patients , the decision to continue on irinotecan beyond 24 weeks is influenced by disease progression or treatment-related toxicity . However , for 17 % of patients in whom this decision is clinical ly relevant , there seems to be little benefit from continuing irinotecan , though the drug was well tolerated without any deterioration in quality of life PURPOSE In North America , no effective therapy has been available for patients with progressive metastatic colorectal cancer after front-line treatment with irinotecan , bolus fluorouracil ( FU ) , and leucovorin ( IFL ) . PATIENTS AND METHODS Patients with metastatic colorectal cancer who progressed after IFL therapy were r and omly assigned to bolus and infusional FU and leucovorin ( LV5FU2 ) , single-agent oxaliplatin , or the combination ( FOLFOX4 ) . This planned interim analysis evaluated objective response rate ( RR ) , time to tumor progression ( TTP ) , and alleviation of tumor-related symptoms ( TRS ) in an initial cohort of patients . RESULTS Between November 2000 and September 2001 , 463 patients from 120 sites in North America were r and omly assigned to treatment . FOLFOX4 proved superior to LV5FU2 in all measures of clinical efficacy . Objective RRs determined by an independent radiology panel were 9.9 % for FOLFOX4 versus 0 % for LV5FU2 ( Fisher 's exact test , P < .0001 ) . Median TTP was 4.6 months for FOLFOX4 versus 2.7 months for LV5FU2 ( two-sided , stratified log-rank test , P < .0001 ) . Relief of TRS occurred in 33 % of patients treated with FOLFOX4 versus 12 % of patients treated with LVFU2 ( chi2 test , P < .001 ) . Single-agent oxaliplatin was not superior to LV5FU2 in any measure of efficacy . Patients treated with FOLFOX4 experienced a higher incidence of clinical ly significant toxicities than patients treated with LV5FU2 , but these toxicities were predictable and did not result in a higher rate of treatment discontinuation or 60-day mortality rate . CONCLUSION For patients with metastatic colorectal cancer , second-line treatment with FOLFOX4 is superior to treatment with LVFU2 in terms of RR , TTP , and relief of TRS PURPOSE In metastatic colorectal cancer , a combination of leucovorin ( LV ) and fluorouracil ( FU ) with oxaliplatin ( FOLFOX ) 4 is a st and ard first-line regimen . The cumulative neurotoxicity of oxaliplatin often requires therapy to be stopped in patients who are still responding . This study evaluates a new strategy of intermittent oxaliplatin treatment that is based on FOLFOX7 , a simplified leucovorin and fluorouracil regimen with high-dose oxaliplatin . PATIENTS AND METHODS Previously untreated patients were r and omly assigned to either FOLFOX4 administered every 2 weeks until progression ( arm A ) or FOLFOX7 for six cycles , maintenance without oxaliplatin for 12 cycles , and re introduction of FOLFOX7 ( arm B ) . RESULTS Six hundred twenty patients were enrolled , including an exploratory cohort of 95 elderly or poor prognosis patients . Median progression-free survival and survival times were 9.0 and 19.3 months , respectively , in patients allocated to arm A compared with 8.7 and 21.2 months , respectively , in patients allocated to arm B ( P = not significant ) . Response rates were 58.5 % with arm A and 59.2 % with arm B. National Cancer Institute Common Toxicity Criteria grade 3 or 4 toxicity was observed in 54.4 % of the patients in arm A v 48.7 % of patients in arm B. From cycle 7 , fewer patients experienced grade 3 or 4 toxicity in arm B. Grade 3 sensory neuropathy was observed in 17.9 % of the patients in arm A v 13.3 % of patients in arm B ( P = .12 ) . In arm B , oxaliplatin was reintroduced in only 40.1 % of the patients but achieved responses or stabilizations in 69.4 % of these patients . CONCLUSION Oxaliplatin can be safely stopped after six cycles in a FOLFOX regimen . Further study is needed to fully evaluate oxaliplatin re introduction BACKGROUND Cetuximab , an IgG1 chimeric monoclonal antibody against epidermal growth factor receptor ( EGFR ) , has activity against colorectal cancers that express EGFR . METHODS From December 2003 to August 2005 , 572 patients who had colorectal cancer expressing immunohistochemically detectable EGFR and who had been previously treated with a fluoropyrimidine , irinotecan , and oxaliplatin or had contraindications to treatment with these drugs underwent r and omization to an initial dose of 400 mg of cetuximab per square meter of body-surface area followed by a weekly infusion of 250 mg per square meter plus best supportive care ( 287 patients ) or best supportive care alone ( 285 patients ) . The primary end point was overall survival . RESULTS In comparison with best supportive care alone , cetuximab treatment was associated with a significant improvement in overall survival ( hazard ratio for death , 0.77 ; 95 % confidence interval [ CI ] , 0.64 to 0.92 ; P=0.005 ) and in progression-free survival ( hazard ratio for disease progression or death , 0.68 ; 95 % CI , 0.57 to 0.80 ; P<0.001 ) . These benefits were robust after adjustment in a multivariable Cox proportional-hazards model . The median overall survival was 6.1 months in the cetuximab group and 4.6 months in the group assigned to supportive care alone . Partial responses occurred in 23 patients ( 8.0 % ) in the cetuximab group but in none in the group assigned to supportive care alone ( P<0.001 ) ; the disease was stable in an additional 31.4 % of patients assigned to cetuximab and in 10.9 % of patients assigned to supportive care alone ( P<0.001 ) . Quality of life was better preserved in the cetuximab group , with less deterioration in physical function and global health status scores ( both P<0.05 ) . Cetuximab treatment was associated with a characteristic rash ; a rash of grade 2 or higher was strongly associated with improved survival ( hazard ratio for death , 0.33 ; 95 % CI , 0.22 to 0.50 ; P<0.001 ) . The incidence of any adverse event of grade 3 or higher was 78.5 % in the cetuximab group and 59.1 % in the group assigned to supportive care alone ( P<0.001 ) . CONCLUSIONS Cetuximab improves overall survival and progression-free survival and preserves quality -of-life measures in patients with colorectal cancer in whom other treatments have failed . ( Clinical Trials.gov number , NCT00079066 [ Clinical Trials.gov ] . ) Overexpression of insulin‐like growth factor receptor type 1 ( IGF‐1R ) may promote tumor development and progression in some cancer patients . Our objective was to assess tumor uptake of fluorodeoxyglucose by positron‐emission tomography in patients with chemotherapy‐refractory colorectal cancer treated with an anti‐insulin‐like growth factor receptor type 1 ( anti‐IGF‐1R ) monoclonal antibody , robatumumab . This was a r and omized , open‐label study with two periods ( P1 and P2 ) . Patients were r and omized 3:1 into treatment arms R/R and C/R that received , respectively , one cycle of 0.3 mg/kg robatumumab or one or more cycles of second‐line chemotherapy in P1 , followed in either case by 10 mg/kg robatumumab biweekly in P2 . The primary measure of fluorodeoxyglucose uptake was maximum st and ardized uptake value ( SUVmax ) . The primary endpoint was the proportion of patients in the R/R arm having a mean percent decrease from baseline in SUVmax ( DiSUV ) greater than 20 % 12–14 days postdose in P2 . Secondary endpoints included Response Evaluation Criteria in Solid Tumors (RECIST)‐defined tumor response and pharmacodynamic measures of target engagement . Among 41 patients who were evaluable for the primary endpoint , seven ( 17 % , 95 % CI 7%–32 % ) had DiSUV greater than 20 % . Fifty robatumumab‐treated patients were evaluable for RECIST‐defined tumor response and six ( 12 % ) had stable disease lasting greater than or equal to 7 weeks in P2 . Pharmacodynamic endpoints indicated target engagement after dosing with 10 mg/kg robatumumab , but not 0.3 mg/kg . The most frequently reported adverse events were fatigue/asthenia , nausea , anorexia , and gastrointestinal disturbances . In this study , few patients with chemotherapy‐refractory colorectal cancer appeared to benefit from treatment with the IGF‐1R antagonist robatumumab PURPOSE The objective of this multicenter study was to compare the efficacy and toxicity profiles of a combination of 5-fluorouracil ( 5-FU ) given by bolus injection together with intravenous leucovorin ( LV ) versus high-dose 5-FU in continuous infusion ( CI ) in the treatment of advanced colorectal cancer . PATIENTS AND METHODS A total of 306 patients were r and omized to receive either 5-FU 425 mg/m2 given by bolus injection on days 1 - 5 plus intravenous ( i.v . ) LV 20 mg/m2 every four to five weeks or 5-FU 3.5 g/m2/week in a 48-hour CI . Therapy was continued until disease progression . Second-line chemotherapy was allowed in both arms . RESULTS The response rates in 306 patients with measurable lesions were 19.2 % ( modulated arm ) and 30.3 % ( CI arm , P < 0.05 ) . The median progression-free survival times were 23.5 weeks ( modulated arm ) and 25 weeks ( CI arm , P = NS ) . Median survival times were 42.5 weeks ( modulated arm ) and 48 weeks ( CI arm , P = NS ) . There were no significant differences in grade 3 - 4 toxicity profiles but if we consider all grade s we observed more mucositis in the modulated arm and more h and -foot syndrome in the CI arm . CONCLUSIONS In terms of response rate , the continuous infusion regimen was more effective than the modulated regimen . There was no significant difference in survival and time to progression , and none in grade 3 - 4 toxicity PURPOSE To determine whether R115777 improves survival in patients with refractory advanced colorectal cancer ( CRC ) in a multicenter , double-blind , prospect i ve r and omized study . PATIENTS AND METHODS Three hundred sixty-eight patients were r and omly assigned to R115777 ( 300 mg twice daily ) orally for 21 days every 28 days or placebo in a 2:1 ratio . All patients received best supportive care . The primary end point was overall survival ; secondary end points were progression free survival , tumor response , toxicity , and quality of life . RESULTS The two treatment groups were well balanced for baseline demographics , including previous chemotherapy for advanced CRC . The median overall survival for R115777 was 174 days ( 95 % CI , 157 to 198 days ) , and 185 days ( 95 % CI , 158 to 238 days ) for those patients receiving placebo ( P = .376 ) . One patient achieved a partial response in the R115777 arm . Stable disease ( > 3 months ) was observed in 24.3 % patients in the R115777 group compared to 12.8 % in the placebo arm . This did not translate into a statistically significant increase in progression-free survival . Overall , treatment was well tolerated . There was an increased incidence of reversible myelosuppression ( neutropenia , thrombocytopenia ) , rash , and grade 1 to 2 diarrhea in the R115777 arm . There was no statistically significant difference in quality of life between arms . CONCLUSION Single agent R115777 , given at this dose and schedule , has an acceptable toxicity profile , but does not improve overall survival compared to best supportive care alone in refractory advanced CRC BACKGROUND The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined . Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer . METHODS In this open-label , r and omised , phase 3 trial , we r and omly assigned patients ( 1:1 ratio ) with advanced , measurable , non-resectable colorectal cancer and WHO performance status 0 - 2 to receive either first-line treatment with bolus ( 400 mg/m(2 ) ) and infusional ( 2400 mg/m(2 ) ) fluorouracil plus leucovorin ( 400 mg/m(2 ) ) ( simplified LV5FU2 regimen ) , second-line LV5FU2 plus oxaliplatin ( 100 mg/m(2 ) ) ( FOLFOX6 ) , and third-line LV5FU2 plus irinotecan ( 180 mg/m(2 ) ) ( FOLFIRI ) or first-line FOLFOX6 and second-line FOLFIRI . Chemotherapy was administered every 2 weeks . R and omisation was done central ly using minimisation ( minimisation factors were WHO performance status , previous adjuvant chemotherapy , number of disease sites , and centre ) . The primary endpoint was progression-free survival after two lines of treatment . Analyses were by intention-to-treat . This trial is registered at Clinical Trials.gov , NCT00126256 . FINDINGS 205 patients were r and omly assigned to the sequential group and 205 to the combination group . 161 ( 79 % ) patients in the sequential group and 161 ( 79 % ) in the combination group died during the study . Median progression-free survival after two lines was 10·5 months ( 95 % CI 9·6 - 11·5 ) in the sequential group and 10·3 months ( 9·0 - 11·9 ) in the combination group ( hazard ratio 0·95 , 95 % CI 0·77 - 1·16 ; p=0·61 ) . All six deaths caused by toxic effects of treatment occurred in the combination group . During first-line chemotherapy , significantly fewer severe ( grade 3 - 4 ) haematological adverse events ( 12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group ; p<0·0001 ) and non-haematological adverse events ( 26 events vs 186 events ; p<0·0001 ) occurred in the sequential group than in the combination group . INTERPRETATION Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced , non-resectable colorectal cancer . FUNDING Sanofi-Aventis France AIM OF THE STUDY To investigate the incidence and clinical implication s of venous thromboembolism ( VTE ) in advanced colorectal cancer ( ACC ) patients treated and followed-up through a prospect i ve r and omised trial , comparing FOLFIRI chemotherapy given as an intermittent or as a continuous schedule . PATIENTS , MATERIAL S AND METHODS A total of 266 patients were r and omised by 15 experimental centres : 168 ( 63.2 % ) were males , median age : 64.6 years , age range : 37 - 76 years . Almost all ( 95.5 % ) patients had metastatic disease , while the remainder were classified with locally advanced irresectable disease . For 138 ( 51.9 % ) of the patients , the chemotherapy treatment was intermittent FOLFIRI and the remaining patients received continuous treatment . All toxicities , including VTE , were prospect ively collected . RESULTS During the study protocol , the central data management gathered two cases of VTE . Our analysis retrieved 27 ( 10.2 % ) patients who developed a VTE , almost all ( 89 % ) during the course of chemotherapy treatment : 20 out of 27 during FOLFIRI , the remaining 7 during following lines or follow-up . VTE was the most frequent grade 3/4 toxicity . The incidence of VTE was significantly increased in the patients receiving continuous rather than intermittent treatment ( HR 2.67 , 95 % CI 1.17 - 6.10 ; p<0.02 ) . CONCLUSION VTE is a common complication among advanced colorectal cancer patients and yet this type of toxicity is widely underestimated . In this r and omised trial , VTE was the most frequent grade 3/4 toxicity . Use of an intermittent schedule is associated with a reduced risk of developing VTE Purpose To evaluate the efficacy and safety of irinotecan as second-line treatment in patients with advanced colorectal cancer ( ACC ) failing or relapsing after 5-fluorouracil ( 5-FU ) plus leucovorin ( LV ) st and ard chemotherapy . Patients and methods Irinotecan was r and omly administered in two different schedules ( once every 3 weeks , and every 10 days ) in patients failing prior 5-FU plus LV . Patients were r and omized to two treatment groups : group A received irinotecan 350 mg/m2 every 21 days and group B received irinotecan 175 mg/m2 days 1 and 10 every 21 days . Results Group A comprised 60 patients : 34 male/26 female , median age 64 years ( range 48–70 years ) , and median Karnofsky performance status ( PS ) 90 . Their metastatic sites included liver ( n=47 ) , lymph nodes ( n=27 ) , lung ( n=14 ) , abdomen ( n=14 ) , pelvis ( n=8 ) , " other " ( n=2 ) , and local recurrence ( n=12 ) . Group B comprised 60 patients : 36 male/24 female , median age 62 years ( 46–70 years ) , and median PS 90 . Their metastatic sites included liver ( n=49 ) , lymph nodes ( n=29 ) , lung ( n=17 ) , abdomen ( n=16 ) , pelvis ( n=11 ) , " other " ( n=2 ) , and local recurrence ( n=13 ) . Group A showed the following responses : complete response ( CR ) 2 , partial response ( PR ) 12 , stable disease ( SD ) 21 , progressive disease ( PD ) 26 , overall response rate ( ORR ) 23 % , tumor growth control 58 % . Group B showed the following responses : CR 1 , PR 14 , SD 22 , PD 23 ; ORR 25 % ; tumor growth control 62 % . Toxicities included acute cholinergic syndrome ( group A 53 % , group B 19 % ; P<0.0001 ) , late-onset diarrhea grade 1/2 ( group A 21 % , group B 46 % ) and grade 3/4 ( group A 41 % , group B 66 % ; P<0.0001 ) , nausea and vomiting grade 1/2 ( group A 34 % , group B 59 % ) and grade 3/4 ( group A 30 % , group B 12 % ; P<0.0001 ) , neutropenia grade 3/4 ( group A 27 % , group B 28 % ; P<0.03 ) , with febrile neutropenia seen in only four patients in group A , anemia grade more than 2 ( group A 28 % , group B 12 % ; P<0.05 ) , asthenia grade more than 3 ( group A 24 % , group B 18 % ; P<0.001 ) , and alopecia grade more than 3 ( group A 40 % , group B 34 % ; P<0.2 ) . Conclusions The present study indicates that , in patients with ACC who have relapsed after 5-FU plus LV , the administration of irinotecan fractionated into two doses every 21 days yields a similar efficacy to , but a much lower incidence of toxicity than , the same total dose of irinotecan administered once every 21 days PURPOSE We evaluated the safety and efficacy of concurrent administration of two monoclonal antibodies , cetuximab and bevacizumab , in patients with metastatic colorectal cancer . PATIENTS AND METHODS This was a r and omized phase II study in patients with irinotecan-refractory colorectal cancer . All patients were naïve to both bevacizumab and cetuximab . Patients in arm A received irinotecan at the same dose and schedule as last received before study entry , plus cetuximab 400 mg/m2 loading dose , then weekly cetuximab 250 mg/m2 , plus bevacizumab 5 mg/kg administered every other week . Patients in arm B received the same cetuximab and bevacizumab as those in arm A but without irinotecan . RESULTS Forty-three patients received cetuximab , bevacizumab , and irinotecan ( CBI ) and 40 patients received cetuximab and bevacizumab alone ( CB ) . Toxicities were as would have been expected from the single agents . For the CBI arm , time to tumor progression ( TTP ) was 7.3 months and the response rate was 37 % ; for the CB arm , TTP was 4.9 months and the response rate was 20 % . The overall survival for the CBI arm was 14.5 months and the overall survival for the CB-alone arm was 11.4 months . CONCLUSION Cetuximab and bevacizumab can be administered concurrently , with a toxicity pattern that seems to be similar to that which would be expected from the two agents alone . This combination plus irinotecan also seems to be feasible . The activity seen with the addition of bevacizumab to cetuximab , or to cetuximab plus irinotecan , seems to be favorable when compared with historical controls of cetuximab or cetuximab/irinotecan in patients who are naïve to bevacizumab Summary Background Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer , but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain . Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer . Methods In this open-label , r and omised trial , we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK . From December , 2006 until June , 2008 , molecularly unselected patients were recruited to a three-arm design including irinotecan ( control ) , irinotecan plus ciclosporin , and irinotecan plus panitumumab ( IrPan ) groups . From June 10 , 2008 , in response to new data , the trial was amended to a prospect ively stratified design , restricting panitumumab r and omisation to patients with KRAS wild-type tumours ; the results of the comparison between the irinotcan and IrPan groups are reported here . We used a computer-generated r and omisation sequence ( stratified by previous EGFR targeted therapy and then minimised by centre , WHO performance status , previous oxaliplatin , previous bevacizumab , previous dose modifications , and best previous response ) to r and omly allocate patients to either irinotecan or IrPan . Patients in both groups received 350 mg/m2 intravenous irinotecan every 3 weeks ( 300 mg/m2 if aged ≥70 years or a performance status of 2 ) ; patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks . The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy , analysed by intention to treat . Tumour DNA was pyrosequenced for KRASc.146 , BRAF , NRAS , and PIK3CA mutations , and predefined molecular subgroups were analysed for interaction with the effect of panitumumab . This study is registered , number IS RCT N93248876 . Results Between Dec 4 , 2006 , and Aug 31 , 2010 , 1198 patients were enrolled , of whom 460 were included in the primary population of patients with KRASc.12–13,61 wild-type tumours and no previous EGFR targeted therapy . 230 patients were r and omly allocated to irinotecan and 230 to IrPan . There was no difference in overall survival between groups ( HR 1·01 , 95 % CI 0·83–1·23 ; p=0·91 ) , but individuals in the IrPan group had longer progression-free survival ( 0·78 , 0·64–0·95 ; p=0·015 ) and a greater number of responses ( 79 [ 34 % ] patients vs 27 [ 12 % ] ; p<0·0001 ) than did individuals in the irinotecan group . Grade 3 or worse diarrhoea ( 64 [ 29 % ] of 219 patients vs 39 [ 18 % ] of 218 patients ) , skin toxicity ( 41 [ 19 % ] vs none ) , lethargy ( 45 [21]% vs 24 [ 11 % ] ) , infection ( 42 [ 19 % ] vs 22 [ 10 % ] ) and haematological toxicity ( 48 [ 22 % ] vs 27 [ 12 % ] ) were reported more commonly in the IrPan group than in the irinotecan group . We recorded five treatment-related deaths , two in the IrPan group and three in the irinotecan group . Interpretation Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours . Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents . Funding Cancer Research UK , Amgen Summary Purpose To determine the efficacy of the addition of gefitinib to raltitrexed in patients with colorectal cancer ( CRC ) that have progressed after first line chemotherapy . The study also sought to explore the safety of the combination and to investigate biomarkers predictive outcome . Methods A total of 76 patients were r and omized to raltitrexed ( 3 mg/m2 i.v . ) every 21 days plus either daily gefitinib ( 250 mg p.o . ) or placebo . The primary endpoint of the study was progression free survival ( PFS ) . Tumor tissues were collected to determine the expression of EGFR , pEGFR , pMAPK , and pAkt . Results Both groups were well balanced with regard to prognostic factors . Treatment was well tolerated with no increased in toxicity except diarrhea and skin rash in the combination group . There were no differences in PFS between the combination arm [ 63 days ( 95 % CI : 57–84 ) ] compared to the raltitrexed alone arm [ 72 days ( 95 % CI : 59–132 ) ] , or overall survival 361 days ( 95 % CI : 283–533 days ) versus 291 days ( 95 % CI : 255–539 days ) respectively . The objective response rate was 7.9 % ( 3 patients ) ( CI 95 % : 1,66–21,38 ) versus 5.3 % ( 2 patients ) ( CI 0,64–17,75 ) , respectively . The biomarker studies were not conclusive . Conclusion The combination of raltitrexed and gefitinib was well tolerated although was not associated with improved progression free survival in patients with refractory CRC PURPOSE The purpose of this study was to compare the activity and toxicity of the combination of irinotecan ( IRI ) plus folinic acid (FA)-modulated 5-fluorouracil ( 5-FU ) i.v . bolus with a regimen of double modulation of 5-FU with methotrexate ( MTX ) and FA in patients with advanced colorectal carcinoma . PATIENTS AND METHODS Two-hundred and thirty-four patients were enrolled : 118 patients received IRI 200 mg/m2 ( 90-min i.v . infusion ) on day 1 , followed by levo-FA 250 mg/m2 ( 2-h i.v . infusion ) and 5-FU 850 mg/m2 ( i.v . bolus ) on day 2 ( IRIFAFU ) , and 116 patients received MTX 750 mg/m2 ( 2-h i.v . infusion ) on day 1 , followed by levo-FA 250 mg/m2 ( 2-h i.v . infusion ) and FU 800 mg/m2 ( i.v . bolus ) on day 2 ( MTXFAFU ) . Both cycles were repeated every 2 weeks until progression or to a maximum of 16 cycles . Response rate ( RR ) was the main end point of the study ; responses were assessed every four cycles and confirmed after 2 additional months of treatment . RESULTS RR was significantly greater with IRIFAFU ( 36 % ) than with MTXFAFU ( 20 % ) ( P < 0.001 ) . Multivariate analysis showed that IRIFAFU was significantly associated with a greater activity ( P = 0.028 ) . Median progression-free survival was longer with IRIFAFU than with MTXFAFU ( 7.2 months compared with 4.8 months ; P = 0.048 ) . Median survival time ( MST ) did not differ between the two arms ( 14.7 months compared with 14.8 months , respectively ) . Patients not receiving second-line chemotherapy , however , lived longer when treated in the first-line with IRIFAFU ( MST 11.9 months compared with 6.4 months ; P = 0.038 ) . IRIFAFU caused a significantly greater occurrence of grade 3 or 4 neutropenia ( 40 % compared with 9 % ; P = 0.001 ) and diarrhoea ( 13 % compared with 4 % ; P = 0.024 ) , but a significantly lower incidence of stomatitis ( 3 % compared with 12 % ; P = 0.007 ) , than the comparative regimen . CONCLUSIONS IRIFAFU appeared comparable in terms of activity and toxicity with other weekly or biweekly bolus or infusional combination regimens . IRIFAFU , however , seems easier to administer , because it does not require infusional catheter or pump devices , and it is less expensive . It may represent a new option for treating advanced colorectal carcinoma BACKGROUND In advanced colorectal cancer , chemotherapy is usually administered without pauses and until progression but patients can experience cumulative toxicity and can not tolerate a heavy therapeutic charge . AIM The aim of the present trial was to evaluate whether an intermittent chemotherapy with levo-leucovorin + 5-fluorouracil ( 5-FU ) + irinotecan ( CPT-11 ) was at least as effective as the same regimen given continuously , both administered until progression , in patients affected with advanced colorectal cancer and not previously exposed to chemotherapy for metastatic disease . PATIENTS , MATERIAL S AND METHODS A total of 337 patients from 27 institutions were r and omised between levo-leucovorin , 100/mg/m(2 ) i.v . + 5-FU ; 400 mg/m(2 ) i.v . bolus + 5-FU ; 600 mg/m(2 ) 22-h continuous infusion , days 1 and 2 + CPT-11 ; 180 mg/m(2 ) day 1 , administered every 2 weeks 2 months on and 2 months off ( arm A ) and the same regimen administered continuously ( arm B ) , until progression in both arms . The main end point was overall survival ( OS ) , the secondary progression-free survival ( PFS ) and toxicity . RESULTS At a median follow-up of 41 months , OS was 18 months in arm A and 17 months in arm B [ hazard ratio ( HR ) , 0.88 ] . Also PFS was comparable in the two groups ( 6 months in both , with HR , 1.03 ) , and even grade s 3 - 4 toxicity ( mainly myelosuppression , fever and diarrhoea ) was similar . Second-line oxaliplatin-based treatment was administered in a similar percentage ( 66 % ) in the two arms . The median chemotherapy-free period ( drug holiday ) in arm A was 3.5 months . CONCLUSION Reducing the charge of therapy in this population did not diminish the efficacy of treatment . Further studies with this strategy , including biologicals , are warranted BACKGROUND Policies of UK clinicians regarding the duration of chemotherapy for patients with advanced colorectal cancer are not consistent . We aim ed to compare effectiveness of continuous and intermittent chemotherapy in such patients . METHODS Patients who responded or had stable disease after receiving 12 weeks of the regimens described by de Gramont and Lokich , or raltitrexed chemotherapy , were r and omised to either intermittent ( a break in chemotherapy , re-starting on the same drug on progression ) , or continuous chemotherapy until progression . FINDINGS 354 patients ( 178 intermittent , 176 continuous ) were enrolled from 42 UK centres . At r and omisation , 41 % of participants had part or complete response ; 59 % were stable . Only 66 ( 37 % ) patients allocated to intermittent treatment restarted as planned , after a median of 130 days . Median time on treatment after restarting was 84 days . Patients in the continuous group remained on treatment for a median of a further 92 days . Similar proportions of patients in both groups received second-line therapy . Patients on intermittent chemotherapy had significantly fewer toxic effects and serious adverse events than those in the continuous group . There was no clear evidence of a difference in overall survival ( hazard ratio 0.87 favouring intermittent , 95 % CI 0.69 - 1.09 , p=0.23 ) . INTERPRETATION Our findings provided no clear evidence of a benefit in continuing therapy indefinitely until disease progression . They showed that it is safe to stop chemotherapy after 12 weeks and re-start the same treatment on progression in patients with chemosensitive advanced colorectal cancer Introduction : Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer . Based on pre clinical and clinical evidence that both drugs might act synergistically with mitomycin C , a r and omized study using a ‘ pick the winner ’ design was undertaken to determine the effectiveness and tolerance of these two combination schedules in patients with fluoropyrimidine/leucovorin-pretreated advanced colorectal cancer . Patients and Methods : Sixty-four patients with metastatic colorectal cancer , who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin were enrolled onto this study . They were r and omly assigned to treatment with irinotecan 120 mg/m2 on days 1 + 15 plus mitomycin C 8 mg/m2 on day 1 ( arm A ) or oxaliplatin 85 mg/m2 on days 1 + 15 plus mitomycin C 8 mg/m2 on day 1 ( arm B ) . In both treatment arms , courses were repeated every 4 weeks . Results : The objective response rate in arm A is 7/33 ( 21.2 % ; 95 % confidence interval , 9.0–38.9 % ) as compared to 5/31 in arm B ( 16.1 % ; 95 % CI , 5.5–34.7 % ) . Stable disease was noted in 48.5 vs. 45.2 % , whereas the tumor progressed in 30.3 vs. 38.7 % , respectively . Similar to the recorded response activities , the difference of the two combination regimens in terms of median time to progression ( 7.0 vs. 5.2 months ) and overall survival ( 12.0 vs. 11.2 months ) was only minor and clincally insignificant . The tolerance of treatment was acceptable in both arms , though severe adverse reactions requiring dose reductions ( 30 vs.16 % ) and treatment delays ( 22 vs. 13 % of courses ) were more commonly noted with irinotecan/mitomycin C. The most common toxicities in arm A were neutropenia ( 85 % ; WHO grade 3/4 in 33 % ) , thrombocytopenia ( 52 % ) , diarrhea ( 45 % ) , emesis ( 52 % ) and alopecia ( 92 % ) . In arm B , common toxicities included neutropenia ( 68 % ; grade 3/4 in 13 % ) , thrombocytopenia ( 81 % ) , emesis ( 52 % ) , and peripheral neutropathy ( 48 % ) . Conclusions : Both mitomycin C combination regimens seem to provide an acceptable therapeutic index in patients with fluoropyrimidine/leucovorin-pretreated metastatic colorectal cancer . In view of the increasing need for a broader chemotherapeutic armentarium for second-line therapy of this common malignant disease , both regimens may be worthwhile to undergo further clinical investigation 3505 Background : In ACC " FOLFIRI " is one of the st and ard regimens and is able to obtain about 40 % response rate ( RR ) with an overall survival ( OS ) of 17 - 18 months . Experimental studies ( Sobrero , 2000 ) indicate that an alternating chemotherapy could delay the appearance of cell resistance and reduce the therapeutic load for patients ( pts ) . METHODS In order to evaluate whether intermittent " FOLFIRI " ( CPT-11 : 180 mg/sqm d1 + l-folinic acid -FA : 100 mg/sqm in 2 hr + 5fluorouracil-5FU : 400 mg/sqm bolus + 600 mg/sqm 22 hr infusion , d 1 and 2 every 2 weeks , for 2 months on and 2 months off ) ( arm A ) was at least as effective as continuous " FOLFIRI " ( same regimen , every month ) ( arm B ) , until progression in both arms , 336 pts from 27 Centers were r and omised from 7/2001 to 6/2005 . The characteristics of pts were : median age 64 years ( r 29 - 75 ) , males 214 ( 63 % ) , PS 0 : 222 ( 66 % ) , liver mets only 166 ( 49 % ) , multiple mts including liver 80 ( 24 % ) . RESULTS RR was 29 % in arm A and 35 % in arm B , with a median progression-free survival ( PFS ) of 8.8 and 7.3 months respectively ( HR = 1.00 , 95 % CI : 0.74 - 1.36 ) . At a median follow-up of 27 months , median overall survival ( OS ) , the primary endpoint of the trial , was 16.9 months in arm A and 17.6 in arm B ( HR = 1.11 , 95 % CI : 0.83 - 1.48 ) . Toxicity was acceptable and similar in the 2 arms ( WHO grade 3 - 4 toxicity : neutropenia in 12 % pts , diarrhoea in 11 % , nausea/vomiting in 4 % and fatigue in 3 % ) . CONCLUSIONS Our results demonstrate that alternating " FOLFIRI " obtains the same survival as a continuous treatment , thus reducing the discomfort to pts and the economic costs . No significant financial relationships to disclose Purpose : The purpose of the present study was to evaluate the differences in the sequence of administration of 5-fluorouracil (5-FU)/leucovorin ( LV ) followed by irinotecan ( CPT-11 ) , or CPT-11 followed by 5-FU/LV in advanced colorectal cancer ( ACC ) . Patients and Methods : Chemotherapy-naïve patients with ACC were allocated to the following treatment groups : group A , a bolus of 20 mg/m2 LV and 425 mg/m2 5-FU for 5 days until progression/relapse , and upon progression treatment with weekly CPT-11 ( 100 mg/m2 ) , and group B , CPT-11 followed at progression/relapse by 5-FU/LV at the same doses and schedules as in group A. Results : 120 patients were r and omized to receive one of the two treatment sequences and their pretreatment characteristics were equally balanced between treatment arms . No statistically significant difference was found in the objective response rate to CPT-11 ( p = 0.45 ) ; partial response ( PR ) was 23.3 % for group A patients and 33.3 % for group B. Following documented progression and second line treatment there was a significant difference between the response rate in group A ( 23.3 % ) and group B where no patients were found to respond to second-line treatment with 5-FU/LV ( p = 0.024 ) . The median overall survival was 42.0 weeks ( range , 36.6–47.4 weeks ) for group A and 32.0 weeks ( range , 28.2–35.8 weeks ) for group B. The median time to progression for patients in group A following first-line 5-FU/LV was 18 weeks ( range , 10–36 weeks ) and 12 weeks ( range , 10–16 weeks ) for group B following first-line CPT-11 ( p = 0.0005 ) . Toxicity , according to WHO , was similar between groups . Conclusions : Treating patients with CPT-11 upon progression to 5-FU/LV treatment seems to be superior to the opposite sequence . We used these treatments as sequential monotherapies ( at progression/relapse ) , and the best results are gained when 5-FU/LV is followed by CPT-11 at disease progression or relapse Irinotecan is cytotoxic in patients with advanced colorectal cancer ( CRC ) . SN‐38 ( 10‐hydroxy‐7‐ethyl‐camptothecin ) is the active metabolite of irinotecan . Attachment of polyethylene glycol ( PEG ) polymer chains ( pegylation ) to SN‐38 ( EZN‐2208 ) increases the solubility , exposure , and half‐life of SN‐38 . Pre clinical studies demonstrated superior in vitro efficacy of EZN‐2208 when it was tested in irinotecan‐refractory human CRC cell lines PURPOSE The primary goal of this multicenter phase III trial was to determine whether overall survival ( OS ) of fluorouracil ( FU ) -refractory patients was noninferior when treated with second-line infusional fluorouracil , leucovorin , and oxaliplatin ( FOLFOX4 ; arm B ) versus irinotecan ( arm A ) . Cross-over to the other treatment on disease progression was m and ated . PATIENTS AND METHODS Patients who experienced treatment failure with one prior FU-based therapy and had not received prior irinotecan or oxaliplatin , either for metastatic disease or within 6 months of adjuvant FU therapy , were r and omly assigned to arm A ( irinotecan 350 or 300 mg/m(2 ) every 3 weeks ) or arm B ( FOLFOX4 ) . RESULTS A total of 491 patients were r and omly assigned ( arm A , n = 245 ; arm B , n = 246 ) ; 288 ( 59 % ) had experienced treatment failure with FU for metastatic colorectal cancer . Two hundred twenty-seven patients ( 46 % ) received protocol -m and ated third-line therapy ( arm A , 43 % ; arm B , 57 % ) . Median survival was 13.8 months ( 95 % CI , 12.2 to 15.0 months ) for initial treatment with FOLFOX4 and 14.3 months ( 95 % CI , 12.0 to 15.9 months ) for irinotecan ( P = .38 ; hazard ratio = 0.92 ; 95 % CI , 0.8 to 1.1 ) . Response rates ( RR ; 28 % v 15.5 % ; P = .0009 ) and time to progression ( TTP ; 6.2 v 4.4 months ; P = .0009 ) were significantly superior with FOLFOX4 . In the nonr and om subset of patients who crossed over , RR and TTP improvements with FOLFOX4 continued into third-line treatment . Irinotecan therapy was associated with more grade 3 nausea , vomiting , diarrhea , and febrile neutropenia ; FOLFOX4 was associated with more neutropenia and paresthesias . CONCLUSION In patients who experienced treatment failure with front-line FU therapy , OS does not significantly differ whether second-line therapy begins with irinotecan or FOLFOX4 . FOLFOX4 produces higher RR and longer TTP . Both arms had notable OS in patients who experienced treatment failure with first-line FU therapy |
13,769 | 30,083,458 | There was no evidence of a moderating effect of blinding index on pain .
For short-term and long-term pain assessment s pooled effects for inadequately blinded trials were statistically significant in favour of active dry needling , whereas there was no evidence of a difference between active and sham groups for adequately blinded trials .
However , with the caveats of small sample size , generally unclear risk of bias , statistical heterogeneity , potential publication bias , and the limitations of subgroup analyses , the available evidence suggests that inadequate blinding procedures could lead to exaggerated intervention effects in dry needling trials | Background Blinding is critical to clinical trials because it allows for separation of specific intervention effects from bias , by equalising all factors between groups except for the proposed mechanism of action .
Absent or inadequate blinding in clinical trials has consistently been shown in large meta-analyses to result in overestimation of intervention effects .
Blinding in dry needling trials , particularly blinding of participants and therapists , is a practical challenge ; therefore , specific effects of dry needling have yet to be determined .
Despite this , dry needling is widely used by health practitioners internationally for the treatment of pain .
This review presents the first empirical account of the influence of blinding on intervention effect estimates in dry needling trials .
The aim of this systematic review was to determine whether participant beliefs about group allocation relative to actual allocation ( blinding effectiveness ) , and /or adequacy of blinding procedures , moderated pain outcomes in dry needling trials . | Summary Nonspecific placebo factors such as patients ' perceptions of a treatment and expectations toward effect seem to be central to the clinical efficacy of acupuncture analgesia . ABSTRACT It is well known that acupuncture has pain‐relieving effects , but the contribution of specific and especially nonspecific factors to acupuncture analgesia is less clear . One hundred one patients who developed pain of ≥3 on a visual analog scale ( VAS , 0 to 10 ) after third molar surgery were r and omized to receive active acupuncture , placebo acupuncture , or no treatment for 30 min with acupuncture needles with potential for double‐blinding . Patients ' perception of the treatment ( active or placebo ) and expected pain levels ( VAS ) were assessed before and halfway through the treatment . Looking at actual treatment allocation , there was no specific effect of active acupuncture ( P = .240 ) , but there was a large and significant nonspecific effect of placebo acupuncture ( P < .001 ) , which increased over time . Interestingly , however , looking at perceived treatment allocation , there was a significant effect of acupuncture ( P < .001 ) , indicating that patients who believed they received active acupuncture had significantly lower pain levels than those who believed they received placebo acupuncture . Expected pain levels accounted for significant and progressively larger amounts of the variance in pain ratings after both active and placebo acupuncture ( up to 69.8 % ) . This is the first study to show that under optimized blinding conditions , nonspecific factors such as patients ' perception of and expectations toward treatment are central to the efficacy of acupuncture analgesia and that these factors may contribute to self‐reinforcing effects in acupuncture treatment . To obtain an effect of acupuncture in clinical practice , it may therefore be important to incorporate and optimize these factors Summary This multifactorial mixed‐ methods r and omized controlled trial quantified the specific and nonspecific factors of acupuncture , and found that the practitioner , not the treatment , has the strongest effect on outcome . Abstract The nonspecific effects of acupuncture are well documented ; we wished to quantify these factors in osteoarthritic ( OA ) pain , examining needling , the consultation , and the practitioner . In a prospect i ve r and omised , single‐blind , placebo‐controlled , multifactorial , mixed‐ methods trial , 221 patients with OA awaiting joint replacement surgery were recruited . Interventions were acupuncture , Streitberger placebo acupuncture , and mock electrical stimulation , each with empathic or nonempathic consultations . Interventions involved eight 30‐minute treatments over 4 weeks . The primary outcome was pain ( VAS ) at 1 week posttreatment . Face‐to‐face qualitative interviews were conducted ( purposive sample , 27 participants ) . Improvements occurred from baseline for all interventions with no significant differences between real and placebo acupuncture ( mean difference −2.7 mm , 95 % confidence intervals −9.0 to 3.6 ; P = .40 ) or mock stimulation ( −3.9 , −10.4 to 2.7 ; P = .25 ) . Empathic consultations did not affect pain ( 3.0 mm , −2.2 to 8.2 ; P = .26 ) but practitioner 3 achieved greater analgesia than practitioner 2 ( 10.9 , 3.9 to 18.0 ; P = .002 ) . Qualitative analysis indicated that patients ’ beliefs about treatment veracity and confidence in outcomes were reciprocally linked . The supportive nature of the trial attenuated differences between the different consultation styles . Improvements occurred from baseline , but acupuncture has no specific efficacy over either placebo . The individual practitioner and the patient ’s belief had a significant effect on outcome . The 2 placebos were equally as effective and credible as acupuncture . Needle and nonneedle placebos are equivalent . An unknown characteristic of the treating practitioner predicts outcome , as does the patient ’s belief ( independently ) . Beliefs about treatment veracity shape how patients self‐report outcome , complicating and confounding study interpretation The purpose of this study was to investigate the comparative effectiveness of early use of thrust ( TM ) and non-thrust manipulation ( NTM ) in sample of patients with mechanical low back pain ( LBP ) . The r and omized controlled trial included patients with mechanically reproducible LBP , ≥ age 18-years who were r and omized into two treatment groups . The main outcome measures were the Oswestry Disability Index ( ODI ) and a Numeric Pain Rating Scale ( NPRS ) , with secondary measures of Rate of Recovery , total visits and days in care , and the work subscale of the Fears Avoidance Beliefs Question naire work subscale ( FABQ-w ) . A two-way mixed model MANCOVA was used to compare ODI and pain , at baseline , after visit 2 , and at discharge and total visits , days in care , and rate of recovery ( while controlling for patient expectations and clinical equipoise ) . A total of 149 subjects completed the trial and received care over an average of 35 days . There were no significant differences between TM and NTM at the second visit follow-up or at discharge with any of the outcomes categories . Personal equipoise was significantly associated with ODI and pain . The findings suggest that there is no difference between early use of TM or NTM , and secondarily , that personal equipoise affects study outcome . Within-groups changes were significant for both groups Objectives To develop a sham needle device and test its credibility as a control for acupuncture when used in a r and omised controlled trial of myofascial trigger point needling in patients with whiplash associated pain . Methods Sham needles were developed by blunting true acupuncture needles . Whiplash injured patients ( < 16 weeks duration ) were r and omly allocated to receive either true acupuncture or the “ placebo ” sham needle control . The true and sham needling interventions were delivered using the same st and ardised procedure . Patients were informed that they would receive either real or placebo needles , and asked ( i ) to state which treatment they believed they had received ( treatment belief ) ; ( ii ) to complete the four item Borkovec and Nau self- assessment credibility scale . Results were compared between groups and the analysis explored whether a patient 's previous experience of acupuncture was related to their treatment belief . Other outcomes of the study will be reported elsewhere . Results 20 patients received the true acupuncture and 21 received the sham . There was no significant difference between the treatment beliefs of the two groups ( χ 2 = 1.51 ; p>0.2 ) nor in the mean item scores on the Borkovec and Nau credibility scale ( t test , p values ranged from 0.38 to 0.87 ) . Of the patients in the sham acupuncture group who had previous experience of acupuncture , none recorded receiving the sham intervention . Conclusion Within the context of this pilot study , the sham acupuncture intervention was found to be a credible control for acupuncture . This supports its use in a planned , definitive , r and omised controlled trial on a similar whiplash injured population Background Placebo needles that can mask acupuncture practitioners to the type of needle used have been considered almost impossible to develop until now . Methods We design ed a double-blind non-penetrating placebo needle , the needle tip of which simply presses against the skin , and a matched penetrating needle . The needles are encased inside an opaque guide tube and the appearance and feel of the pair are design ed to be indistinguishable . To vali date the masking effect for the practitioner , 10 acupuncturists each applied 23 non-penetrating needles and 17 penetrating needles to the Large Intestine-4 point . After removing each needle , they judged whether the needle was ' penetrating ' , ' non-penetrating ' or ' unidentifiable ' . For the validation of patient masking , an acupuncturist r and omly applied a non-penetrating/penetrating needle pair to the bilateral Sanjiao-5 points in 60 volunteers . When both applications were completed , we asked them to write down anything that they noticed regarding the needle application and associated sensations . Results The mean ± SD of correct/unidentifiable/incorrect answers given by the 10 acupuncturists were 17.0 ± 4.1/6.4 ± 3.6/16.6 ± 3.0 , respectively . Regarding patient masking , none of the subjects commented in the question naire that they had received a non-penetrating needle . Of 60 penetrating and 60 non-penetrating needle applications , 48 ( 80.0 % ) and 25 ( 41.7 % ) applications elicited skin penetration sensation and 48 ( 80.0 % ) and 20 ( 33.3 % ) applications elicited de qi , respectively . Conclusion These needles have the potential to mask both practitioners and patients from the type of needle used in acupuncture research Blinding protects against bias but the success of blinding is seldom assessed and reported in clinical trials including studies of acupuncture where blinding represents a major challenge . Recently , needles with the potential for double-blinding were developed , so we tested if acupuncture can be double-blinded in a r and omized study of sixty-seven patients with acute pain ≥ 3 ( 0 - 10 scale following third molar removal ) who received active acupuncture with a penetrating needle or placebo acupuncture with a non-penetrating needle . To test if acupuncture was administered double-blind , patients and acupuncturists were asked about perceived treatment allocation at the end of the study . To test if there were clues which led to identification of the treatment , deep dull pain associated with needle application and rotation ( termed “ de qi ” in East Asian medicine ) , and patients ’ pain levels were assessed . Perceived treatment allocation depended on actual group allocation ( p < 0.015 ) for both patients and acupuncturists , indicating that the needles were not successful in double-blinding . Up to 68 % of patients and 83 % of acupuncturists correctly identified the treatment , but for patients the distribution was not far from 50/50 . Also , there was a significant interaction between actual or perceived treatment and the experience of de qi ( p = 0.027 ) , suggesting that the experience of de qi and possible non-verbal clues contributed to correct identification of the treatment . Yet , of the patients who perceived the treatment as active or placebo , 50 % and 23 % , respectively , reported de qi . Patients ’ acute pain levels did not influence the perceived treatment . In conclusion , acupuncture treatment was not fully double-blinded which is similar to observations in pharmacological studies . Still , the non-penetrating needle is the only needle that allows some degree of practitioner blinding . The study raises questions about alternatives to double-blind r and omized clinical trials in the assessment of acupuncture treatment Clinicians cl aim that myofascial trigger points ( MTrPs ) are a primary cause of pain in whiplash injured patients . Pain from MTrPs is often treated by needling , with or without injection . We conducted a placebo controlled study to test the feasibility of a phase III r and omised controlled trial investigating the efficacy of MTrP needling in patients with whiplash associated pain . Forty-one patients referred for physiotherapy with a recent whiplash injury , were recruited . Patients were r and omised to receive st and ardised physiotherapy plus either acupuncture or a sham needle control . A trial was judged feasible if : i ) the majority of eligible patients were willing to participate ; ii ) the majority of patients had MTrPs ; iii ) at least 75 % of patients provided completed self- assessment data ; iv ) no serious adverse events were reported and v ) the end of treatment attrition rate was less than 20 % . 70 % of those patients eligible to participate volunteered to do so ; all participants had clinical ly identified MTrPs ; a 100 % completion rate was achieved for recorded self- assessment data ; no serious adverse events were reported as a result of either intervention ; and the end of treatment attrition rate was 17 % . A phase III study is both feasible and clinical ly relevant . This study is currently being planned Background Plantar heel pain can be managed with dry needling of myofascial trigger points ; however , there is only poor- quality evidence supporting its use . Objective The purpose of this study was to evaluate the effectiveness of dry needling for plantar heel pain . Design The study was a parallel-group , participant-blinded , r and omized controlled trial . Setting The study was conducted in a university health sciences clinic . Patients Study participants were 84 patients with plantar heel pain of at least 1 month 's duration . Intervention Participants were r and omly assigned to receive real or sham trigger point dry needling . The intervention consisted of 1 treatment per week for 6 weeks . Participants were followed for 12 weeks . Measurements Primary outcome measures included first-step pain , as measured with a visual analog scale ( VAS ) , and foot pain , as measured with the pain subscale of the Foot Health Status Question naire ( FHSQ ) . The primary end point for predicting the effectiveness of dry needling for plantar heel pain was 6 weeks . Results At the primary end point , significant effects favored real dry needling over sham dry needling for pain ( adjusted mean difference : VAS first-step pain=−14.4 mm , 95 % confidence interval [ 95 % CI]=−23.5 to −5.2 ; FHSQ foot pain=10.0 points , 95 % CI=1.0 to 19.1 ) , although the between-group difference was lower than the minimal important difference . The number needed to treat at 6 weeks was 4 ( 95 % CI=2 to 12 ) . The frequency of minor transitory adverse events was significantly greater in the real dry needling group ( 70 real dry needling appointments [ 32 % ] compared with only 1 sham dry needling appointment [ < 1 % ] ) . Limitations It was not possible to blind the therapist . Conclusion Dry needling provided statistically significant reductions in plantar heel pain , but the magnitude of this effect should be considered against the frequency of minor transitory adverse 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 In patients with myofascial pain , painful trigger points are often treated using dry needling and local anesthetic injections . However , the therapeutic effect of these treatments has been poorly quantified , and the mechanism underlying the effect is poorly understood . In a r and omized , double-blind , double-placebo clinical trial , a pressure algometer was used to measure pain-pressure thresholds in the masseter and temporalis muscles of 30 subjects aged 23 to 53 years with myofascial pain in the jaws , before and after a series of dry needling treatments , local anesthetic injections , and simulated dry needling and local anesthetic treatments ( treatment group A : Procaine + simulated dry needling ; treatment group B : dry needling + simulated local anesthetic ; control group C : simulated local anesthetic + simulated dry needling ) . Subjects rated pain intensity and unpleasantness using visual analogue scales , and the data were analyzed using analysis of variance . Pain pressure thresholds increased slightly after treatment , irrespective of the treatment modality . Pain intensity and unpleasantness scores decreased significantly at the end of treatment in all groups . There were no statistically significant between-group differences in pain pressure thresholds and visual analogue scale scores at the end of treatment . The findings suggest that the general improvement in pain symptoms was the result of nonspecific , placebo-related factors rather than a true treatment effect . Thus , the therapeutic value of dry needling and Procaine in the management of myofascial pain in the jaw muscles is question able Abstract Objective To investigate whether a sham device ( a vali date d sham acupuncture needle ) has a greater placebo effect than an inert pill in patients with persistent arm pain . Design A single blind r and omised controlled trial created from the two week placebo run-in periods for two nested trials that compared acupuncture and amitriptyline with their respective placebo controls . Comparison of participants who remained on placebo continued beyond the run-in period to the end of the study . Setting Academic medical centre . Participants 270 adults with arm pain due to repetitive use that had lasted at least three months despite treatment and who scored ≥3 on a 10 point pain scale . Interventions Acupuncture with sham device twice a week for six weeks or placebo pill once a day for eight weeks . Main outcome measures Arm pain measured on a 10 point pain scale . Secondary outcomes were symptoms measured by the Levine symptom severity scale , function measured by Pransky 's upper extremity function scale , and grip strength . Results Pain decreased during the two week placebo run-in period in both the sham device and placebo pill groups , but changes were not different between the groups ( −0.14 , 95 % confidence interval −0.52 to 0.25 , P = 0.49 ) . Changes in severity scores for arm symptoms and grip strength were similar between groups , but arm function improved more in the placebo pill group ( 2.0 , 0.06 to 3.92 , P = 0.04 ) . Longitudinal regression analyses that followed participants throughout the treatment period showed significantly greater downward slopes per week on the 10 point arm pain scale in the sham device group than in the placebo pill group ( −0.33 ( −0.40 to −0.26 ) v −0.15 ( −0.21 to −0.09 ) , P = 0.0001 ) and on the symptom severity scale ( −0.07 ( −0.09 to −0.05 ) v −0.05 ( −0.06 to −0.03 ) , P = 0.02 ) . Differences were not significant , however , on the function scale or for grip strength . Reported adverse effects were different in the two groups . Conclusions The sham device had greater effects than the placebo pill on self reported pain and severity of symptoms over the entire course of treatment but not during the two week placebo run in . Placebo effects seem to be malleable and depend on the behaviours embedded in medical rituals In this report , the authors explore the relationships of perceived treatment to outcome in a large , placebo-controlled trial of nicotine replacement treatment for smoking reduction . In the original study ( J. F. Etter , E. Laszlo , J. P. Zellweger , C. Perrot , & T. V. Perneger , 2002 ) , which was conducted in French-speaking Switzerl and , smokers were r and omly assigned to receive nicotine , matching placebo products , or no intervention . At the end of the 6-month study , participants were asked to guess whether they had received nicotine or placebo . In the present analysis , the authors examined the difference in smoking reduction between those who believed they had received nicotine and those who believed they had received placebo . Regardless of actual treatment , smokers who believed they had received nicotine had significantly better outcome than those who believed they had received placebo BACKGROUND Recently , dry needling has emerged as a popular treatment for muscular pain and impairments . While there are numerous studies detailing the benefits of dry needling for pain , few studies exist examining the effects on soft tissue mobility . PURPOSE The purpose of this study was to determine if the addition of hamstring dry needling to a st and ard stretching program results in greater improvements in hamstring flexibility compared to sham dry needling and stretching in subjects with atraumatic knee pain . Additionally , squat range of motion , knee pain , and the Lower Extremity Functional Scale were compared between the two groups . STUDY DESIGN Double blinded r and omized controlled trial . METHODS Thirty-nine subjects were r and omized to receive either dry needling ( n = 20 ) or sham ( n = 19 ) dry needling in addition to hamstring stretching , to all detected hamstring trigger points on two visits . All dependent variables were measured at baseline , immediately post intervention , and 1 , 3 , and 7 days after the initial treatment . Each subject also performed hamstring stretching three times daily for one week . RESULTS Significant improvements in hamstring range of motion and all other dependent variables were observed across time regardless of treatment group . However , the lack of significant time by group interactions indicated the improvements were not different between dry needling and sham dry needling groups . CONCLUSIONS The results of the current r and omized controlled trial suggest that two sessions of dry needling did not improve hamstring range of motion or other knee pain-related impairments more than sham dry needling in a young active population with atraumatic knee pain . LEVEL OF EVIDENCE Therapy , Level 2 Background Studies suggest that expectations powerfully shape clinical outcomes . For subjective outcomes in adequately blinded trials , health improvements are substantial and largely explained by non-specific factors . The objective of this study was to investigate if unblinding in r and omized controlled trials ( RCTs ) is associated with enhanced placebo effects for intervention groups and nocebo effects for placebo groups . For these effects , a secondary objective was to explore potential moderating factors . Methods We included RCTs that investigated the efficacy of phosphodiesterase-5 ( PDE-5 ) inhibitors for male erectile dysfunction by comparing one PDE-5 inhibitor to placebo . In addition , to be included studies must have reported scores for change from baseline , or baseline and final International Index of Erectile Functioning-Erectile Functioning domain score ( IIEF-EF ) , and be published in either English , French , Dutch , or German . We search ed for both published and unpublished relevant trials using PUBMED , EMBASE , the Cochrane Central Register of Controlled Trials , a clinical trials register ( clinical trials.gov ) and the Food and Drug Administration clinical review s through March 2012.We evaluated the blinding status of trials with the Cochrane Risk of Bias Tool , using the domains of allocation sequence concealment , blinding of participants , healthcare providers and outcome assessors . Across these four domains , studies that scored low risk of bias were judged to be adequately blinded and studies that scored unclear or high risk of bias were judged to be inadequately blinded . Results We included 110 studies ( 205 journal publications and 2 unpublished sources ) that involved 23,877 participants ; 93 ( 85 % ) , 51 ( 46 % ) , 93 ( 85 % ) and 93 ( 85 % ) studies were assessed with an unclear risk of bias for allocation concealment , blinding of participant , blinding of caregiver and blinding of outcome assessor , respectively . None of the studies reported testing of blinding . None of the 205 journal publications provided sufficient details to assess allocation concealment , blinding of participants , caregivers and outcome assessors . After contacting authors for additional information , we judged five studies to be adequately ( n = 1,202 ) and 16 to be inadequately ( n = 3,006 ) blinded . The IIEF-EF score for placebo groups in adequately blinded trials versus inadequately blinded trials was 1.92 points ( 95 % CI , 0.64 to 3.20 ) versus 1.56 ( 95 % CI , 0.93 to 2.20 ) , respectively . The IIEF-EF score for intervention groups in adequately blinded trials versus inadequately blinded trials was 9.40 ( 95 % CI , 6.96 to 11.83 ) versus 8.33 ( 95 % CI , 7.29 to 9.37 ) , respectively . In a secondary analysis , prior experience with the drug affected the scores ; in placebo groups with participants naïve to the intervention the score was 2.89 ( 95 % CI , 2.33 to 3.45 ) versus -0.11 ( 95 % CI , -2.06 to 1.84 ) with participants having prior experience . In the intervention groups , these scores were 7.99 ( 95 % CI , 6.85 to 9.14 ) versus 8.33 ( 95 % CI , 7.51 to 9.16 ) , respectively . Unblinding lowered placebo scores ( creating a nocebo effect ) by 19 % ( 0.33 points ; 95 % CI , -0.96 to 1.62 ) . Unblinding lowered intervention scores by 11 % ( 1.0 ; 95 % CI , -1.35 to 3.47 ) . The results provided no conclusive evidence for nocebo or enhanced placebo effects . Patients taking a PDE-5 inhibitor for the first time experience a larger placebo effect that accounts for 35 % of the total effect . Conclusions Given the overall poor reporting of blinding in clinical trial reports and the small number of trials that could be rated as adequately or inadequately blinded , we could not draw any robust conclusions about the existence or absence of nocebo and enhanced placebo effects . A large placebo effect was found for patients taking PDE-5 inhibitors for the first time . It was not clear if previous exposure to the drug impacted trial blinding . We found clear evidence that studies assessing a subjective continuous outcome fail to report on measures taken to secure double blinding . Although we observed a trend for the presence of a nocebo effect , there was insufficient evidence to quantify its impact on expectations . RCTs with patients with no prior experience with PDE-5 inhibitors reported larger placebo effects and possibly these studies were better blinded . Future research should further investigate the factors that contribute to blinding and their impact on health outcomes in r and omized trials of subjectively assessed conditions . This research is part of a PhD project and has no external funding . The authors have no competing interests to declare CONTEXT This study was part of a large double-blind sham surgery-controlled trial design ed to determine the effectiveness of transplantation of human embryonic dopamine neurons into the brains of persons with advanced Parkinson 's disease . This portion of the study investigated the quality of life ( QOL ) of participants during the 1 year of double-blind follow-up . OBJECTIVES To determine whether QOL improved more in the transplant group than in the sham surgery group and to investigate outcomes at 1 year based on perceived treatment ( the type of surgery patients thought they received ) . DESIGN Participants were r and omly assigned to receive either the transplant or sham surgery . Reported results are from the 1-year double-blind period . SETTING Participants were recruited from across the United States and Canada . Assessment and surgery were conducted at 2 separate university medical centers . PARTICIPANTS A volunteer sample of 40 persons with idiopathic Parkinson 's disease participated in the transplant ( " parent " ) study , and 30 agreed to participate in the related QOL study : 12 received the transplant and 18 received sham surgery . INTERVENTIONS Interventions in the parent study were transplantation and sham brain surgery . Assessment s of QOL were made at baseline and 4 , 8 , and 12 months after surgery . MAIN OUTCOME MEASURES Comparison of the actual transplant and sham surgery groups and the perceived treatment groups on QOL and medical outcomes . We also investigated change over time . RESULTS There were 2 differences or changes over time in the transplant and sham surgery groups . Based on perceived treatment , or treatment patients thought they received , there were numerous differences and changes over time . In all cases , those who thought they received the transplant reported better scores . Blind ratings by medical staff showed similar results . CONCLUSIONS The placebo effect was very strong in this study , demonstrating the value of placebo-controlled surgical trials OBJECTIVES To use a r and omised , double blind , placebo controlled trial to establish the effect on straight leg raise , hip internal rotation , and muscle pain of dry needling treatment to the gluteal muscles in athletes with posterior thigh pain referred from gluteal trigger points . METHODS A r and omised , double blind , placebo controlled trial of 59 male runners was performed during the 2002 Australian Rules football season . Subjects were thoroughly screened and had magnetic resonance imaging of their hamstring muscles to exclude local pathology . The inclusion criterion was reproduction of recognisable posterior thigh pain with the application of digital pressure to the gluteal trigger points . Subjects r and omly received either therapeutic or placebo needle treatment on one occasion at their gluteal trigger points . Range of motion and visual analogue scale data were collected immediately before , immediately after , 24 hours after , and 72 hours after the intervention . Range of motion was measured with passive straight leg raise and hip internal rotation . Visual analogue scales were completed for hamstring and gluteal pain and tightness at rest and during a running task . RESULTS Magnetic resonance imaging scans revealed normal hamstring musculature in most subjects . Straight leg raise and hip internal rotation remained unchanged in both groups at all times . Visual analogue scale assessment of hamstring pain and tightness and gluteal tightness after running showed improvements immediately after the intervention in both groups ( p = 0.001 ) , which were maintained at 24 and 72 hours . The magnitude of this improvement was the same for therapeutic and placebo interventions . Resting muscle pain and tightness were unaffected . CONCLUSIONS Neither dry needling nor placebo needling of the gluteal muscles result ed in any change in straight leg raise or hip internal rotation . Both interventions result ed in subjective improvement in activity related muscle pain and tightness . Despite being commonly used clinical tests in this situation , straight leg raise and hip internal rotation are not likely to help the therapist assess response to treatment . Patient reports of response to such treatment are better indicators of its success . The mechanisms by which these responses occur and the reasons for the success of the placebo needling treatment are areas for further investigation BACKGROUND Blinding can reduce bias in r and omized clinical trials , but blinding procedures may be unsuccessful . Our aim was to assess how often r and omized clinical trials test the success of blinding , the methods involved and how often blinding is reported as being successful . METHODS We analysed a r and om sample of blinded r and omized clinical trials indexed in the The Cochrane Central Register of Controlled Trials and published in 2001 . We identified 1599 blinded trials , and noted if they had conducted any test for the success of blinding . We also selected 200 trials r and omly that did not report any such test , and sent a question naire to the corresponding authors asking them if they had conducted any tests . RESULTS Thirty-one out of 1599 trials ( 2 % ) reported tests for the success of blinding . Test methods varied , and reporting was generally incomplete . Blinding was considered successful in 14 out of the 31 trials ( 45 % ) and unclear in 10 ( 32 % ) . Of the seven trials ( 23 % ) reporting unsuccessful blinding the risk of a biased trial result was either not addressed or was discounted in six cases . We received 130 question naires from trial authors ( 65 % ) of which 15 ( 12 % ) informed that they had conducted , but not published , tests . CONCLUSIONS Blinding is rarely tested . Test methods vary , and the reporting of tests , and test results , is incomplete . There is a considerable method ological uncertainty how best to assess blinding , and an urgent need for improved methodology and improved reporting R and omised controlled trials ( RCTs ) of acupuncture often find equivalent responses to real and placebo acupuncture despite both appearing superior to no treatment . This raises questions regarding the mechanisms of acupuncture , especially the contribution of patient expectancies . We systematic ally review ed previous research assessing the relationship between expectancy and treatment responses following acupuncture , whether real or placebo . To be included , studies needed to assess and /or manipulate expectancies about acupuncture and relate these to at least one health-relevant outcome . Nine such independent studies were identified through systematic search es of Medline , PsycInfo , PubMed , and Cochrane Clinical Trials Register . The methodology and reporting of these studies were quite heterogeneous , meaning that meta- analysis was not possible . A descriptive review revealed that five studies found statistically significant effects of expectancy on a least one outcome , with three also finding evidence suggestive of an interaction between expectancy and type of acupuncture ( real or placebo ) . While there were some trends in significant effects in terms of study characteristics , their generality is limited by the heterogeneity of study design s. The differences in design across studies highlight some important method ological considerations for future research in this area , particularly regarding whether to assess or manipulate expectancies and how best to assess expectancies The aim of this study was to determine whether the dry needling of myofascial trigger points ( MTrPs ) is superior to placebo in the prevention of pain after total knee arthroplasty . Forty subjects were r and omised to a true dry needling group ( T ) or to a sham group ( S ) . All were examined for MTrPs by an experienced physical therapist 4–5 hours before surgery . Immediately following anesthesiology and before surgery started , subjects in the T group were dry needled in all previously diagnosed MTrPs , while the S group received no treatment in their MTrPs . Subjects were blinded to group allocation as well as the examiner in presurgical and follow-up examinations performed 1 , 3 , and 6 months after arthroplasty . Subjects in the T group had less pain after intervention , with statistically significant differences in the variation rate of the visual analogue scale ( VAS ) measurements 1 month after intervention and in the need for immediate postsurgery analgesics . Differences were not significant at 3- and 6-month follow-up examinations . In conclusion , a single dry needling treatment of MTrP under anaesthesia reduced pain in the first month after knee arthroplasty , when pain was the most severe . Results show a superiority of dry needling versus placebo . An interesting novel placebo methodology for dry needling , with a real blinding procedure , is presented Background In relation to Myofascial Triggerpoints ( MFTrPs ) of the upper Trapezius , this study explored muscle contractility characteristics , the occurrence of post-intervention muscle soreness and the effect of dry needling on muscle contractile characteristics and clinical outcomes . Methods Seventy-seven female office workers ( 25 - 46yrs ) with and without neck/shoulder pain were observed with respect to self-reported pain ( NRS-101 ) , pressure-pain threshold ( PPT ) , maximum voluntary contraction ( Fmax ) and rate of force development ( RFD ) at baseline ( pre-intervention ) , immediately post-intervention and 48 hours post-intervention . Symptomatic and asymptomatic participant groups were each r and omized into two treatment sub-groups ( superficial ( SDN ) and deep dry needling ( DDN ) ) after baseline testing . At 48 hours post-intervention participants were asked whether delayed onset muscle soreness ( DOMS ) and /or post-needling soreness had developed . Results Muscle contractile characteristics did not differ between groups at baseline . Forty-six individuals developed muscle soreness ( 39 from mechanical testing and seven from needling ) . No inter-group differences were observed post-intervention for Fmax or RFD for the four sub-groups . Over the observation period , symptomatic participants reported less pain from both SDN ( p= 0.003 ) and DDN ( p=0.011 ) . However , PPT levels were reduced for all participants ( p=0.029 ) . Those reporting DOMS experienced significant decreases in PPT , irrespective of symptom state or intervention ( p=0.001 ) . Conclusions In selected female neck/shoulder pain sufferers , maximum voluntary contraction and rapid force generation of the upper Trapezius was not influenced by clinical ly relevant self-reported pain or the presence of diagnostically relevant MFTrPs . Dry needling , deep or superficial , did not affect measured functional outcomes over the 48-hour observation period . DOMS affected participants uniformly irrespective of pain , MFTrP status or intervention type and therefore is like to act as a modifier . Trial registration Clinical Trials.gov- NCT01710735 Significance and InnovationsThe present investigation is one of the first to examine the hypothesis of gross muscle contractile inhibition due to the presence of diagnostically relevant MFTrPs . Individuals suffering from clinical ly relevant levels of self-reported pain are able to tolerate maximum voluntary contraction testing , but delayed onset muscle soreness ( DOMS ) is a likely side-effect irrespective of symptom status . As a consequence , its confounding effect during subsequent testing must be taken into account Background The masking properties of a new , non-penetrating , double-blind placebo acupuncture needle were demonstrated . Practitioners correctly identified some of the needles ; if they were confident in this opinion , they would be unblinded . Objective To investigate the clues that led to correct identification , and the confidence in this decision . Methods Ten acupuncture practitioners , blindly and r and omly , applied 10 each of three types of needle to the shoulder : blunt , non-penetrating needles that pressed the skin ( ‘ skin-touch placebo needle ’ ) ; new non-penetrating needles that penetrated soft material ( stuffing ) but did not reach the skin ( ‘ non-touch control needle ’ ) ; matching penetrating needles . Afterwards , practitioners were asked to judge the type of needle , their confidence in their decision and what clues led them to their judgements . Results Of the 30 judgements made by each practitioner , the mean number of correct , incorrect and unidentifiable answers were 10.4 ( SD 3.7 ) , 15.2 ( SD 4.9 ) and 4.4 ( SD 6.1 ) , respectively . There was no significant difference in the confidence scores for 104 correct ( mean , 54.0 ( SD 20.2)% ) and 152 incorrect ( mean , 50.3 ( SD 24.3)% ) judgements . Twelve needles were identified with 100 % confidence — three correct , and nine incorrect . For needles correctly identified , the proportions of non-touch ( p = 0.14 ) and skin-touch ( p = 0.17 ) , needles were no greater than chance , but the proportion of penetrating needles correctly identified exceeded chance ( p < 0.01 ) . 53 % of judgements were made from the “ feeling of needle insertion ” , but 57 % of these were wrong . Conclusion Practitioners had a slight tendency to guess the penetrating needles correctly , but were uncertain about most of their judgments , posing only a very small risk to double blinding There is evidence for the efficacy of acupuncture treatment for chronic shoulder pain , but it remains unclear which acupuncture modes are most effective . We compared the effect of trigger point acupuncture ( TrP ) , with that of sham ( SH ) acupuncture treatments , on pain and shoulder function in patients with chronic shoulder pain . The participants were 18 patients ( 15 women , 3 men ; aged 42 - 65 years ) with nonradiating shoulder pain for at least 6 months and normal neurological findings . The participants were r and omized into two groups , each receiving five treatment sessions . The TrP group received treatment at trigger points for the muscle , while the other group received SH acupuncture treatment on the same muscle . Outcome measures were pain intensity ( visual analogue scale , VAS ) and shoulder function ( Constant-Murley Score : CMS ) . After treatment , pain intensity between pretreatment and 5 weeks after TrP decreased significantly ( p<0.001 ) . Shoulder function also increased significantly between pretreatment and 5 weeks after TrP ( p<0.001 ) . A comparison using the area under the outcome curves demonstrated a significant difference between groups ( p=0.024 ) . Compared with SH acupuncture therapy , TrP therapy appears more effective for chronic shoulder pain Double-blinded trials are often considered the gold st and ard for research , but significant bias may result from unblinding of participants and investigators . Although the CONSORT guidelines discuss the importance of reporting " evidence that blinding was successful " , it is unclear what constitutes appropriate evidence . Among studies reporting methods to evaluate blinding effectiveness , many have compared groups with respect to the proportions correctly identifying their intervention at the end of the trial . Instead , we reasoned that participants ' beliefs , and not their correctness , are more directly associated with potential bias , especially in relation to self-reported health outcomes . During the Water Evaluation Trial performed in northern California in 1999 , we investigated blinding effectiveness by sequential interrogation of participants about their " blinded " intervention assignment ( active or placebo ) . Irrespective of group , participants showed a strong tendency to believe they had been assigned to the active intervention ; this translated into a statistically significant intergroup difference in the correctness of participants ' beliefs , even at the start of the trial before unblinding had a chance to occur . In addition , many participants ( 31 % ) changed their belief during the trial , suggesting that assessment of belief at a single time does not capture unblinding . Sequential measures based on either two or all eight question naires identified significant group-related differences in belief patterns that were not identified by the single , cross-sectional measure . In view of the relative insensitivity of cross-sectional measures , the minimal additional information in more than two assessment s of beliefs and the risk of modifying participants ' beliefs by repeated question ing , we conclude that the optimal means of assessing unblinding is an intergroup comparison of the change in beliefs ( and not their correctness ) between the start and end of a r and omized controlled trial We compared the effects of trigger point acupuncture with that of sham acupuncture treatments on pain and oral function in patients with temporom and ibular disorders ( TMDs ) . This 10-week study included 16 volunteers from an acupuncture school with complaints of chronic temporom and ibular joint myofascial pain for at least 6 months . The participants were r and omized to one of two groups , each receiving five acupuncture treatment sessions . The trigger point acupuncture group received treatment at trigger points for the same muscle , while the other acupuncture group received sham treatment on the trigger points . Outcome measures were pain intensity ( visual analogue scale ) and oral function ( maximal mouth opening ) . After treatment , pain intensity was less in the trigger point acupuncture group than in the sham treatment group , but oral function remained unchanged in both groups . Pain intensity decreased significantly between pretreatment and 5 weeks after trigger point ( p<0.001 ) and sham acupunctures ( p<0.050 ) . Group comparison using the area under the curve demonstrated a significant difference between groups ( p=0.0152 ) . Compared with sham acupuncture therapy , trigger point acupuncture therapy may be more effective for chronic temporom and ibular joint myofascial pain Objective To investigate whether placebo effects can experimentally be separated into the response to three components— assessment and observation , a therapeutic ritual ( placebo treatment ) , and a supportive patient-practitioner relationship— and then progressively combined to produce incremental clinical improvement in patients with irritable bowel syndrome . To assess the relative magnitude of these components . Design A six week single blind three arm r and omised controlled trial . Setting Academic medical centre . Participants 262 adults ( 76 % women ) , mean ( SD ) age 39 ( 14 ) , diagnosed by Rome II criteria for and with a score of ≥150 on the symptom severity scale . Interventions For three weeks either waiting list ( observation ) , placebo acupuncture alone ( “ limited ” ) , or placebo acupuncture with a patient-practitioner relationship augmented by warmth , attention , and confidence ( “ augmented ” ) . At three weeks , half of the patients were r and omly assigned to continue in their originally assigned group for an additional three weeks . Main outcome measures Global improvement scale ( range 1 - 7 ) , adequate relief of symptoms , symptom severity score , and quality of life . Results At three weeks , scores on the global improvement scale were 3.8 ( SD 1.0 ) v 4.3 ( SD 1.4 ) v 5.0 ( SD 1.3 ) for waiting list versus “ limited ” versus “ augmented , ” respectively ( P<0.001 for trend ) . The proportion of patients reporting adequate relief showed a similar pattern : 28 % on waiting list , 44 % in limited group , and 62 % in augmented group ( P<0.001 for trend ) . The same trend in response existed in symptom severity score ( 30 ( 63 ) v 42 ( 67 ) v 82 ( 89 ) , P<0.001 ) and quality of life ( 3.6 ( 8.1 ) v 4.1 ( 9.4 ) v 9.3 ( 14.0 ) , P<0.001 ) . All pairwise comparisons between augmented and limited patient-practitioner relationship were significant : global improvement scale ( P<0.001 ) , adequate relief of symptoms ( P<0.001 ) , symptom severity score ( P=0.007 ) , quality of life ( P=0.01 ) . Results were similar at six week follow-up . Conclusion Factors contributing to the placebo effect can be progressively combined in a manner resembling a grade d dose escalation of component parts . Non-specific effects can produce statistically and clinical ly significant outcomes and the patient-practitioner relationship is the most robust component . Trial registration Clinical Trials NCT00065403 This purpose of this article is to contrast the analgesic efficacy of acupuncture following dental surgery with the analgesic effects based on the expectation of benefit in two independently conducted placebo-controlled trials evaluating acupuncture as an adjunctive therapy for dental surgery . Both trials used pain following dental surgery as the outcome variable , and both included a blinding check to ascertain patients ’ beliefs regarding which treatment they were receiving . Although no statistically significant analgesic effect was observed between the acupuncture and placebo groups , participants in both experiments who believed they received real acupuncture reported significantly less pain than patients who believed that they received a placebo . Patients ’ beliefs regarding the receipt of acupuncture bore a stronger relationship to pain than any specific action possessed by acupuncture . These results also support the importance of both employing credible controls for the placebo effect in clinical trials and evaluating the credibility of those controls The objective of this study was to test the hypothesis that dry needling is more effective than sham dry needling in the treatment of myofascial pain syndrome ( MPS ) . This was a prospect i ve , double-blinded , r and omized-controlled study conducted in an outpatient clinic . Thirty-nine subjects with established myofascial trigger points were r and omized into two groups : study group ( N = 22 ) and placebo group ( N = 17 ) . Dry needling was applied using acupuncture needles , and sham dry needling was applied in the placebo group . The treatment was composed of six sessions which were performed in 4 weeks ; the first four sessions were performed twice a week ( for 2 weeks ) and the last two , once a week ( for 2 weeks ) . The visual analog scale ( VAS ) and Short Form-36 ( SF-36 ) were used . When compared with the initial values , VAS scores of the dry needling group following the first and sixth sessions were significantly lower ( p = 0.000 and p < 0.000 , respectively ) . When VAS scores were compared between the groups , the first assessment scores were found to be similar , but the second and third assessment scores were found to be significantly lower in the dry needling group ( p = 0.034 and p < 0.001 , respectively ) . When SF-36 scores of the groups were compared , both the physical and mental component scores were found to be significantly increased in the dry needling group , whereas only those of vitality scores were found to be increased significantly in the placebo ( sham needling ) group . The present study shows that the dry needling treatment is effective in relieving the pain and in improving the quality of life of patients with MPS Introduction There is some evidence for the efficacy of acupuncture , but it remains unclear whether trigger point acupuncture is effective . Our objective was to evaluate the effects of trigger point acupuncture on pain and quality of life in chronic low back pain patients compared with sham acupuncture . Methods Twenty-six consecutive out- patients ( 17 women , 9 men ; age range : 65–91 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating low back pain for at least six months and normal neurological examination , were r and omised to two groups . Each group received one phase of trigger point acupuncture and one of sham acupuncture with a three week washout period between them , over 12 weeks . Group A ( n=13 ) received trigger point acupuncture in the first phase and sham acupuncture in the second . Group B ( n=13 ) received the same interventions in the reverse order . Outcome measures were pain intensity ( visual analogue scale , VAS ) and Rol and Morris Question naire . Results Nineteen patients were included in the analysis . At the end of the first treatment phase , group A receiving trigger point acupuncture scored significantly lower VAS ( P<0.001 ) and Rol and Morris Question naire scores ( P<0.01 ) than the sham control group . There were significant within-group reductions in pain in both groups during the trigger point acupuncture phase but not in the sham treatment phase . However , the beneficial effects were not sustained . Conclusion These results suggest that trigger point acupuncture may have greater short term effects on low back pain in elderly patients than sham acupuncture Objective There is some evidence for the efficacy of acupuncture in chronic low back pain , but it remains unclear which acupuncture modes are most effective . Our objective was to evaluate the effects of two different modes of trigger point acupuncture on pain and quality of life in chronic low back pain patients compared to st and ard acupuncture treatment . Methods Thirty five consecutive out- patients ( 25 women , 10 men ; age range : 65–81 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating low back pain for at least six months and normal neurological examination , were r and omised to one of three groups over 12 weeks . Each group received two phases of acupuncture treatment with an interval between them . Nine patients dropped out during the course of the study . The st and ard acupuncture group ( n=9 ) received treatment at traditional acupuncture points for low back pain , while the other acupuncture groups received superficial ( n=9 ) or deep ( n=9 ) treatments on trigger points . Outcome measures were VAS pain intensity and Rol and Morris Question naire . Results After treatment , the group that received deep needling to trigger points reported less pain intensity and improved quality of life compared to the st and ard acupuncture group or the group that received superficial needling to trigger points , but the differences were not statistically significant . There was a significant reduction in pain intensity between the treatment and interval in the group that received deep needling to trigger points ( P<0.01 ) , but not in the st and ard acupuncture group or the group that received superficial needling to trigger points . Conclusion These results suggest that deep needling to trigger points may be more effective in the treatment of low back pain in elderly patients than either st and ard acupuncture therapy , or superficial needling to trigger points Abstract This r and omized controlled trial investigated the effectiveness and cost-effectiveness of dry-needling and exercise compared with sham dry-needling and exercise for chronic whiplash-associated disorders ( WAD ) . The setting was a single university centre and 4 physiotherapy practice s in Queensl and , Australia . Eighty patients with chronic WAD ( > 3 months ) were enrolled between June 2009 and August 2012 with 1-year follow-up completed in August 2013 . The interventions were 6 weeks of dry-needling to posterior neck muscles ( n = 40 ) and exercise or sham dry-needling and exercise ( n = 40 ) . The primary outcomes of the Neck Disability Index ( NDI ) and self-rated recovery were measured at baseline , 6 and 12 weeks , 6 and 12 months by a blinded assessor . Analysis was intention to treat . An economic evaluation was planned but missing data deemed further analysis unwarranted . Seventy-nine patients ( 99 % ) were followed up at 6 weeks , 78 ( 98 % ) at 12 weeks , 74 ( 93 % ) at 6 months , and 73 ( 91 % ) at 12 months . The dry-needling and exercise intervention was more effective than sham dry-needling and exercise in reducing disability at 6 and 12 months but not at 6 and 12 weeks . The treatment effects were small and not clinical ly worthwhile . At 6 weeks , the treatment effect on the 0 - 100 NDI was −0.3 ( 95 % confidence interval −5.4 to 4.7 ) , 12 weeks −0.3 ( −5.2 to 4.9 ) , 6 months −4.4 ( −9.6 to −0.74 ) , and 12 months −3.8 ( −9.1 to −0.5 ) . There was no effect for self-rated recovery . In patients with chronic WAD , dry-needling and exercise has no clinical ly worthwhile effects over sham dry-needling and exercise Tsai C-T , Hsieh L-F , Kuan T-S , Kao MJ , Chou L-W , Hong C-Z : Remote effects of dry needling on the irritability of the myofascial trigger point in the upper trapezius muscle . Objective : To investigate the remote effect of dry needling on the irritability of a myofascial trigger point in the upper trapezius muscle . Design : Thirty-five patients with active myofascial trigger points in upper trapezius muscles were r and omly divided into two groups : 18 patients in the control group received sham needling , and 17 patients in the dry-needling group received dry needling into the myofascial trigger point in the extensor carpi radialis longus muscle . The subjective pain intensity , pressure pain threshold , and range of motion of the neck were assessed before and immediately after the treatment . Results : Immediately after dry needling in the experimental group , the mean pain intensity was significantly reduced , but the mean pressure threshold and the mean range of motion of cervical spine were significantly increased . There were significantly larger changes in all three parameters of measurement in the dry-needling group than that in the control group . Conclusions : This study demonstrated the remote effectiveness of dry needling . Dry needling of a distal myofascial trigger point can provide a remote effect to reduce the irritability of a proximal myofascial trigger point Abstract In a pooled analysis of four r and omized controlled trials of acupuncture in patients with migraine , tension‐type headache , chronic low back pain , and osteoarthritis of the knee we investigated the influence of expectations on clinical outcome . The 864 patients included in the analysis received either 12 sessions of acupuncture or minimal ( i.e. sham ) acupuncture ( superficial needling of non‐acupuncture points ) over an 8 week period . Patients were asked at baseline whether they considered acupuncture to be an effective therapy in general and what they personally expected from the treatment . After three acupuncture sessions patients were asked how confident they were that they would benefit from the treatment strategy they were receiving . Patients were classified as responders if the respective main outcome measure improved by at least fifty percent . Both univariate and multivariate analyses adjusted for potential confounders ( such as condition , intervention group , age , sex , duration of complaints , etc . ) consistently showed a significant influence of attitudes and expectations on outcome . After completion of treatment , the odds ratio for response between patients considering acupuncture an effective or highly effective therapy and patients who were more sceptical was 1.67 ( 95 % confidence interval 1.20–2.32 ) . For personal expectations and confidence after the third session , odds ratios were 2.03 ( 1.26–3.26 ) and 2.35 ( 1.68–3.30 ) , respectively . Results from the 6‐month follow‐up were similar . In conclusion , in our trials a significant association was shown between better improvement and higher outcome expectations Background The purpose of this study was to examine the immediate effect of single acupuncture stimulation to the most painful point in patients with low back pain . Method A r and omised , evaluator-blinded , sham controlled clinical trial was conducted in which 31 patients with low back pain were r and omly allocated to either an acupuncture group ( n=15 ) or a sham acupuncture group ( n=16 ) . Both acupuncture and sham acupuncture were performed at the most painful point on the lower back of the subjects . For the acupuncture group , a stainless steel needle was inserted to a depth of 20 mm and manually stimulated ( sparrow pecking method ) for 20 seconds , while for the sham treatment a guide tube without a needle was placed at the point and tapped on the skin . Changes in low back pain were evaluated with a visual analogue scale ( VAS ) and the Schober test . Participants were also asked if they felt the needling sensation or not . The therapy and the evaluation were independently performed by two different acupuncturists . Results VAS score and the Schober test score showed significant improvement after treatment as compared with the sham group ( P=0.02 , 0.001 , respectively ) . There were no significant differences in the needling sensation between the acupuncture and sham group . Conclusion These results suggest that acupuncture at the most painful point gives immediate relief of low back pain OBJECTIVES To compare the effects of real acupuncture to tender points for neck and shoulder pain and stiffness ( Japanese : katakori ) with those of sham acupuncture . DESIGN R and omized-controlled trial . METHODS Thirty-four volunteers from an acupuncture school with complaints of chronic pain and stiffness , who had no arm symptoms and gave informed consent , were r and omly allocated to acupuncture or sham groups . Acupuncture or sham acupuncture was applied to the tender points once a week for 3 weeks . In the acupuncture group the acupuncture needle was inserted to the muscle , then the sparrow pecking technique was applied five times . Sham acupuncture was done without insertion of the needle . Dull pain and stiffness were evaluated by visual analog scale ( VAS ) before , and every 2 days after the first needling for 1 month . Pressure pain threshold on the tender points was measured before and after each treatment . RESULTS There was no statistical difference of VAS scores between acupuncture and sham groups 9 days after the last treatment . However , the acupuncture group showed significant reduction of VAS scores immediately after and /or 1 day after the real acupuncture treatments ( P<0.01 ) . The effect tended to be prolonged after repeated treatment . Pressure pain thresholds tended to increase after real acupuncture treatment but not after sham acupuncture . CONCLUSIONS Acupuncture applied to tender points appears to have short-term effects on neck and shoulder pain and stiffness , but this study was unable to demonstrate any long-term superiority over sham acupuncture Background There is evidence for the efficacy of acupuncture treatment in knee osteoarthritis , but it remains unclear which acupuncture modes are most effective . We evaluated the effects of trigger point acupuncture on pain and quality of life in knee osteoarthritis patients , compared with acupuncture at st and ard points , and sham acupuncture . Methods Thirty patients ( 27 women , 3 men ; aged 61–82 years ) with non-radiating knee osteoarthritis pain for at least six months and normal neurological examination were r and omised to one of three groups for the study period of 21 weeks . Each group received five acupuncture treatment sessions . The st and ard acupuncture point group ( n=10 ) received treatment at traditional acupuncture points for knee pain ; the trigger point acupuncture group ( n=10 ) received treatment at trigger points ; and the third group ( n=10 ) received sham acupuncture treatment at the trigger points . Outcome measures were pain intensity ( visual analogue scale , VAS ) and WOMAC index ( Western Ontario and McMaster Universities Arthritis Index ) . The groups were compared by the area under the curve method . Results Five patients dropped out of the study because of lack of improvement , and one patient ( in the trigger point acupuncture group ) dropped out because of deterioration of symptoms ; the remaining 24 patients were included in the analysis . After treatment , the trigger point acupuncture group reported less pain intensity on VAS than the st and ard acupuncture or sham treatment group , but both the trigger point acupuncture and st and ard acupuncture groups reported improvement of function of knee . There was a significant reduction in pain intensity between pre-treatment and five weeks after treatment for the trigger point acupuncture ( P<0.01 ) and st and ard acupuncture groups ( P<0.01 ) included in the analysis , but not for the sham treatment group . Group comparison using the area under the curves demonstrated a significant difference only between trigger point acupuncture and sham treatment groups analysed ( P<0.025 for VAS , and P<0.031 for WOMAC ) . Conclusion These results suggest that trigger point acupuncture therapy may be more effective for osteoarthritis of the knee in some elderly patients than st and ard acupuncture therapy INTRODUCTION There is some evidence for the efficacy of acupuncture in chronic neck pain ( CNP ) treatment , but it remains unclear which acupuncture modes are most effective . Objective was to evaluate the effects of trigger point acupuncture on pain and quality of life ( QOL ) in CNP patients compared to three other acupuncture treatments ( acupoints , non-trigger point and sham treatment ) . METHODS Forty out- patients ( 29 women , 11 men ; age range : 47 - 80 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating CNP for at least 6 months and normal neurological examination were r and omised to one of four groups over 13 weeks . Each group received two phases of acupuncture treatment with an interval between them . The acupoint group ( st and ard acupuncture ; SA , n=10 ) received treatment at traditional acupoints for neck pain , the trigger point ( TrP , n=10 ) and non-trigger point ( non-TrP , n=10 ) groups received treatment at tenderness points for the same muscle , while the other acupuncture group received sham treatments on the trigger point ( SH , n=10 ) . Outcome measures were pain intensity ( visual analogue scale ; VAS 0 - 100 mm ) and disease specific question naire ( neck disability index ; NDI , 60-point scale ) . RESULTS After treatment , the TrP group reported less pain intensity and improved QOL compared to the SA or non-TrP group . There was significant reduction in pain intensity between the treatment and the interval for the TrP group ( p<0.01 , Dunnett 's multiple test ) , but not for the SA or non-TrP group . CONCLUSION These results suggest that trigger point acupuncture therapy may be more effective on chronic neck pain in aged patients than the st and ard acupuncture therapy OBJECTIVE To evaluate the effect of dry needling into a myofascial trigger point ( MTrP ) in the lower trapezius muscle of patients with mechanical idiopathic neck pain . DESIGN A single-center , r and omized , double-blinded controlled study . SETTING Patients were recruited from the student population of a local hospital by advertisement in the university clinic from January 2010 to December 2011 . PARTICIPANTS Patients ( N=72 ) with unilateral neck pain , neck pain for ≥3 months , and active trigger points in the lower trapezius muscle were r and omly assigned to 1 of 2 treatment groups . All the patients completed the study . INTERVENTIONS Dry needling in an MTrP in the lower trapezius muscle , or dry needling in the lower trapezius muscle but not at an MTrP. MAIN OUTCOME MEASURES The visual analog scale ( VAS ) , Neck Pain Question naire ( NPQ ) , and pressure-pain threshold ( PPT ) were assessed before the intervention and 1 week and 1 month postintervention . RESULTS Treatment with dry needling of the lower trapezius muscle close to the MTrP showed decreases in pain and PPT as well as an improvement in the degree of disability ( P<.001 ) compared with the baseline and control group measurements ( P<.001 ) . The dry-needling technique performed in the MTrP showed more significant therapeutic effects ( P<.001 ) . CONCLUSIONS The application of dry needling into an active MTrP of the lower trapezius muscle induces significant changes in the VAS , NPQ , and PPT levels compared with the application of dry needling in other locations of the same muscle in patients with mechanical neck pain OBJECTIVE To compare the feasibility of blinding and the perceived risk of unblinding in trials evaluating pharmacologic ( PT ) and nonpharmacologic treatments ( NPT ) of hip or knee osteoarthritis . STUDY DESIGN AND SETTING Two independent review ers assessed the feasibility of blinding patients , care providers , and outcome assessors , the perceived risk of unblinding , and whether blinding was reported in 110 reports of r and omized controlled trials ( RCTs ) evaluating PT and NPT in patients with hip or knee osteoarthritis . RESULTS Blinding was considered to be possible less often in NPT trials than in PT trials for patients ( 42 vs. 96 % ; P < .001 ) , care providers ( 12 vs. 96 % ; P < .001 ) , and outcome assessors ( 34 vs. 98 % ; P < .001 ) . When blinding was judged feasible , the perceived risk of unblinding was more often considered moderate or important in NPT than PT trials for patients ( 35 vs. 14 % , P=.02 ) and outcome assessors ( 44 vs. 10 % , P=.0004 ) . When blinding was judged feasible , it was reported less often in NPT reports than in PT reports for patients ( 46 vs. 98 % , P < .001 ) , care providers ( 43 vs. 83 % , P=.03 ) , and outcome assessors ( 72 vs. 98 % , P=.0006 ) . CONCLUSION Blinding appears to be more difficult to achieve and unblinding may occur more often in NPT than PT trials 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 |
13,770 | 30,152,733 | This study demonstrates that hypnotherapy and relaxation techniques are effective in reducing short- and long-term headache activity in migraine sufferers | Abstract Migraine is a complex neurological condition that causes a range of symptoms , the most common of which is a severe headache .
The aim of this systematic review of the literature is to determine the efficacy of hypnosis in the treatment of migraine . | Evidence -based practice involves the use of evidence from systematic review s and r and omised controlled trials , but the extent of this evidence in physiotherapy has not previously been surveyed . The aim of this survey is to describe the quantity and quality of r and omised controlled trials and the quantity of systematic review s relevant to physiotherapy . The Physiotherapy Evidence Data base ( PEDro ) was search ed . The quality of trials was assessed with the PEDro scale . The search identified a total of 2,376 r and omised controlled trials and 332 systematic review s. The first trial was published in 1955 and the first review was published in 1982 . Since that time , the number of trials and review s has grown exponentially . The mean PEDro quality score has increased from 2.8 in trials published between 1955 and 1959 to 5.0 for trials published between 1995 and 1999 . There is a substantial body of evidence about the effects of physiotherapy . However , there remains scope for improvements in the quality of the conduct and reporting of clinical trials Abstract Thirty-seven adults with spinal-cord injury and chronic pain were r and omly assigned to receive 10 sessions of self-hypnosis ( HYP ) or EMG biofeedback relaxation ( BIO ) training for pain management . Participants in both treatment conditions reported substantial , but similar , decreases in pain intensity from before to after the treatment sessions . However , participants in the HYP condition , but not the BIO condition , reported statistically significant decreases in daily average pain pre- to posttreatment . These pre- to posttreatment decreases in pain reported by the HYP participants were maintained at 3-month follow-up . Participants in the HYP condition , but not the BIO condition , also reported significant pre- to posttreatment increases in perceived control over pain , but this change was not maintained at the 3-month follow-up Sickle cell disease ( SCD ) is the most common genetic disease in African-Americans , characterized by recurrent painful vaso-occlusive crises . Medical therapies for controlling or preventing crises are limited because of efficacy and /or toxicity . This is a r and omized , controlled , single-crossover protocol of hypnosis for managing pain in SCD patients . Participants receive hypnosis from a trained hypnosis therapist followed by six weeks of self-hypnosis using digital media . Those in the control arm receive SCD education followed by a six-week waiting period before crossing over to the hypnosis arm of the study . Outcome measures include assessment s of pain ( frequency , intensity and quality ) , anxiety , coping strategies , sleep , depression , and health care utilization . To date , there are no published r and omized , controlled trials evaluating the efficacy of hypnosis on SCD pain modulation in adults . Self-hypnosis for pain management may be helpful in modulating chronic pain , improving sleep quality , and decreasing use of narcotics in patients with SCD . TRIAL REGISTRATION Clinical Trials.gov : Tension headaches can form a chronic ( very long duration ) condition . EMG biofeedback , relaxation training and analgesia by hypnotic suggestion can reduce the pain . So far , no differences have been demonstrated between the effects of various psychological treatments . In a constructively design ed study , we firstly compared an abbreviated form of autogenic training to a form of hypnotherapy ( future oriented hypnotic imagery ) which was not presented as hypnosis and secondly we compared both treatments to the same future oriented hypnotic imagery , but this time explicitly presented as hypnosis . The three treatments were equally effective at post-treatment , but after a 6-month follow-up period , the future oriented hypnotic imagery which had been explicitly presented as hypnosis was superior to autogenic training . Contrary to common belief , it could be demonstrated that the therapists were as effective with the treatment modality they preferred as with the treatment modality they felt to be less remedial Objective Postpr and ial symptoms in irritable bowel syndrome are common and relate to an exaggerated motor and sensory component of the gastrocolonic response . We investigated whether this response can be affected by hypnotherapy . Methods We included 28 patients with irritable bowel syndrome refractory to other treatments . They were r and omized to receive gut-directed hypnotherapy 1 hour per week for 12 weeks ( N = 14 ) or were provided with supportive therapy ( control group ; N = 14 ) . Before r and omization and after 3 months , all patients underwent a colonic distension trial before and after a 1-hour duodenal lipid infusion . Colonic sensory thresholds and tonic and phasic motor activity were assessed . Results Before r and omization , reduced thresholds after vs. before lipid infusion were seen in both groups for all studied sensations . At 3 months , the colonic sensitivity before duodenal lipids did not differ between groups . Controls reduced their thresholds after duodenal lipids for gas ( 22 ± 1.7 mm Hg vs. 16 ± 1.6 mm Hg , p < .01 ) , discomfort ( 29 ± 2.9 mm Hg vs. 22 ± 2.6 mm Hg , p < .01 ) , and pain ( 33 ± 2.7 mm Hg vs. 26 ± 3.3 mm Hg , p < .01 ) , whereas the hypnotherapy group reduced their thresholds after lipids only for pain ( 35 ± 4.0 mm Hg vs. 29 ± 4.7 mm Hg , p < .01 ) . The colonic balloon volumes and tone response at r and omization were similar in both groups . At 3 months , baseline balloon volumes were lower in the hypnotherapy group than in controls ( 83 ± 14 ml vs. 141 ± 15 ml , p < .01 ) . In the control group , reduced balloon volumes during lipid infusion were seen ( 141 ± 15 ml vs. 111 ± 19 ml , p < .05 ) , but not after hypnotherapy ( 83 ± 14 ml vs. 80 ± 16 ml , p > .20 ) . Conclusion Hypnotherapy reduces the sensory and motor component of the gastrocolonic response in patients with irritable bowel syndrome . These effects may be involved in the clinical efficacy of hypnotherapy in IBS The main aims of this experimental study are : ( 1 ) to compare the relative effects of analgesia suggestions and relaxation suggestions on clinical pain , and ( 2 ) to compare the relative effect of relaxation suggestions when they are presented as “ hypnosis ” and as “ relaxation training ” . Forty‐five patients with fibromyalgia were r and omly assigned to one of the following experimental conditions : ( a ) hypnosis with relaxation suggestions ; ( b ) hypnosis with analgesia suggestions ; ( c ) relaxation . Before and after the experimental session , the pain intensity was measured using a visual analogue scale ( VAS ) and the sensory and affective dimensions were measured with the McGill Pain Question naire . The results showed : ( 1 ) that hypnosis followed by analgesia suggestions has a greater effect on the intensity of pain and on the sensory dimension of pain than hypnosis followed by relaxation suggestions ; ( 2 ) that the effect of hypnosis followed by relaxation suggestions is not greater than relaxation . We discuss the implication s of the study on our underst and ing of the importance of suggestions used in hypnosis and of the differences and similarities between hypnotic relaxation and relaxation training In a controlled study , 40 patients with refractory fibromyalgia were r and omly allocated to treatment with either hypnotherapy or physical therapy for 12 weeks with followup at 24 weeks . Compared with the patients in the physical therapy group , the patients in the hypnotherapy group showed a significantly better outcome with respect to their pain experience , fatigue on awakening , sleep pattern and global assessment at 12 and 24 weeks , but this was not reflected in an improvement of the total myalgic score measured by a dolorimeter . At baseline most patients in both groups had strong feelings of somatic and psychic discomfort as measured by the Hopkins Symptom Checklist . These feelings showed a significant decrease in patients treated by hypnotherapy compared with physical therapy , but they remained abnormally strong in many cases . We conclude hypnotherapy may be useful in relieving symptoms in patients with refractory fibromyalgia BACKGROUND In western population s irritable bowel syndrome ( IBS ) affects between 10 % and 30 % of the population and has a significant effect on quality of life . It generates a substantial workload in both primary and secondary care and has significant cost implication s. Gut-directed hypnotherapy has been demonstrated to alleviate symptoms and improve quality of life but has not been assessed outside of secondary and tertiary referral centres . AIM To assess the effectiveness of gut-directed hypnotherapy as a complementary therapy in the management of IBS . DESIGN OF STUDY R and omised controlled trial . SETTING Primary care patients aged 18 - 65 years inclusive , with a diagnosis of IBS of greater than 6 weeks ' duration and having failed conventional management , located in South Staffordshire and North Birmingham , UK . METHOD Intervention patients received five sessions of hypnotherapy in addition to their usual management . Control patients received usual management alone . Data regarding symptoms and quality of life were collected at baseline and again 3 , 6 , and 12 months post-r and omisation . RESULTS Both groups demonstrated a significant improvement in all symptom dimensions and quality of life over 12 months . At 3 months the intervention group had significantly greater improvements in pain , diarrhoea and overall symptom scores ( P<0.05 ) . No significant differences between groups in quality of life were identified . No differences were maintained over time . Intervention patients , however , were significantly less likely to require medication , and the majority described an improvement in their condition . CONCLUSIONS Gut-directed hypnotherapy benefits patients via symptom reduction and reduced medication usage , although the lack of significant difference between groups beyond 3 months prohibits its general introduction without additional evidence . A large trial incorporating robust economic analysis is , therefore , urgently recommended This article both summarizes the previous review s of r and omized , controlled trials of hypnotic analgesia for the treatment of chronic and acute pain in adults , and review s similar trials which have recently been published in the scientific literature . The results indicate that for both chronic and acute pain conditions : ( 1 ) hypnotic analgesia consistently results in greater decreases in a variety of pain outcomes compared to no treatment/st and ard care ; ( 2 ) hypnosis frequently out-performs non-hypnotic interventions ( e.g. education , supportive therapy ) in terms of reductions in pain-related outcomes ; and ( 3 ) hypnosis performs similarly to treatments that contain hypnotic elements ( such as progressive muscle relaxation ) , but is not surpassed in efficacy by these alternative treatments . Factors that may influence the efficacy of hypnotic analgesia interventions are discussed , including , but not limited to , the patient 's level of suggestibility , treatment outcome expectancy , and provider expertise . Based upon this body of literature , suggestions are offered for practitioners who are using , or would like to use , hypnosis for the amelioration of pain problems in their patients or clients We investigated the effectiveness of a special hypnotherapy technique in the treatment of chronic tension-type headache . A waitinglist control group was used to control for the changes in headache activity due to the passage of time . The results showed significant reductions in the number of headache days ( p less than 0.05 ) , the number of headache hours ( p less than 0.05 ) and headache intensity ( p less than 0.05 ) . The improvement was confirmed by the subjective evaluation data gathered with the use of a question naire and by a significant reduction in anxiety scores ( p less than 0.01 ) & NA ; The aims of this study were to(a ) investigate the efficacy of autogenic training ( AT ) and cognitive self‐hypnosis training ( CSH ) for the treatment of chronic headaches in comparison with a waiting‐list control ( WLC ) condition,(b ) investigate the influence of subject recruitment on treatment outcome ( c ) explore whether the level of hypnotizability is related to therapy outcome . Three different subjects groups ( group 1 , patients ( n = 58 ) who were referred by a neurological outpatient clinic ; group 2 , members ( n = 48 ) of the community who responded to an advertisement in a newspaper ; and group 3 , students ( n = 40 ) who responded to an advertisement in a university newspaper ) were allocated at r and om to a therapy or WLC condition . During treatment , there was a significant reduction in the Headache Index scores of the subjects in contrast with the controls . At post‐treatment and follow‐up almost no significant differences were observed between the 2 treatment conditions or the 3 referral sources regarding the Headache Index , psychological distress ( SCL‐90 ) scores and medication use . Follow‐up measurements indicated that therapeutic improvement was maintained . In both treatment conditions , the high‐hypnotizable subjects achieved a greater reduction in headache pain at post‐treatment and follow‐up than did the low‐hypnotizable subjects . It is concluded that a relatively simple and highly structured relaxation technique for the treatment of chronic headache subjects may be preferable to more complex cognitive hypnotherapeutic procedures , irrespective of the source of recruitment . The level of hypnotic susceptibility seems to be a subject characteristic which is associated with a more favourable outcome in subjects treated with AT or CSH Abstract Twenty-two patients with multiple sclerosis ( MS ) and chronic pain we recruited into a quasi-experimental trial comparing the effects of self-hypnosis training ( HYP ) with progressive muscle relaxation ( PMR ) on pain intensity and pain interference ; 8 received HYP and the remaining 14 participants were r and omly assigned to receive either HYP or PMR . HYP-condition participants reported significantly greater pre- to postsession as well as pre- to posttreatment decreases in pain and pain interference than PMR-condition participants , and gains were maintained at 3-month follow-up . Most of the participants in both conditions reported that they continued to use the skills they learned in treatment and experienced pain relief when they did so . General hypnotizability was not significantly related to treatment outcome , but treatment- outcome expectancy assessed before and after the first session was . The results support the efficacy of self-hypnosis training for the management of chronic pain in persons with MS |
13,771 | 31,431,982 | Conclusion The one adaptive design review ed here , and a simulation study found in the search , both indicate that adaptive design s can be applied to early phase trials in RA . | Objective Adaptive design s can enable highly sophisticated and efficient early phase trials , but the clinical inference from these trials is surrounded by complexity , and currently there is a paucity but steadily increasing amount of use of these design s in all fields of medicine .
We aim to review early phase trials in RA to discover those that have used adaptive design s and benchmark trial characteristics . | Background Methotrexate is the most efficient anticancer drug in osteosarcoma . It requires individual exposure monitoring because of the high doses used , its wide interpatient pharmacokinetic variability and the existence of demonstrated relationships between efficacy , toxicity and serum drug concentrations . Objective To develop a maximum a posteriori ( MAP ) Bayesian estimator able to predict individual pharmacokinetic parameters and exposure indices such as area under the curve ( AUC ) for methotrexate from a few blood sample s , in order to prevent toxicity and facilitate further studies of the relationships between efficacy and exposure . Methods Methotrexate population pharmacokinetics were estimated by a retrospective analysis of concentration data from 40 children and young adults by using the nonparametric expectation maximisation method NPEM . A linear two-compartment model with elimination from the central compartment was assumed . Individual pharmacokinetic parameters and AUC were subsequently estimated in 30 other young patients , using MAP Bayesian estimation as implemented in two programs , ADAPT II and an inhouse program Winphar ® . Results The pharmacokinetic parameters used in the model were the volume of the central compartment ( V1 ) and the transfer constants ( k10 , k12 and k21 ) . The mean values ( with percentage coefficient of variation ) obtained were : 18.24L ( 54.1 % ) and 0.41 ( 42.3 % ) , 0.0168 ( 68.7 % ) , and 0.1069 ( 61.3 % ) h-1 , respectively . Bayesian forecasting enabled nonbiased estimation of AUC and systemic clearance using a schedule with two sampling times ( 6 and 24 hours after the beginning of the infusion ) and either program . Collection of a third sample at 4 hours improved the precision . Conclusion The Bayesian adaptive method developed herein allows accurate estimation of individual exposure to methotrexate and can easily be used in clinical practice OBJECTIVE To evaluate the safety and activity of an immunoconjugate of ricin A chain and anti-CD5 monoclonal antibody ( anti-CD5 IC ) , with and without concomitant methotrexate and /or azathioprine , in the treatment of rheumatoid arthritis ( RA ) . METHODS Seventy-nine patients with active RA were enrolled in 2 prospect i ve open-label protocol s. RESULTS Using composite criteria , response rates were 50 - 68 % at 1 month and 22 - 25 % at 6 months . Transient depletion of CD3/CD5 T cells was observed on days 2 and 5 of treatment , with reconstitution on day 15 or day 29 . Treatment-associated adverse effects were common but resolved rapidly without sequelae . CONCLUSION These findings suggest activity of anti-CD5 IC in active RA and warrant confirmation in a multicenter r and omized study ( currently underway ) Objectives The aim of this 12-week Phase IIb study was to assess the efficacy and safety of olokizumab ( OKZ ) , a humanised anti-IL6 monoclonal antibody , in patients with rheumatoid arthritis ( RA ) with moderate-to-severe disease activity who had previously failed tumour necrosis factor ( TNF ) inhibitor therapy . The dose-exposure-response relationship for OKZ was also investigated . Methods Patients were r and omised to one of nine treatment arms receiving placebo ( PBO ) or OKZ ( 60 , 120 or 240 mg ) every 4 weeks ( Q4W ) or every 2 weeks ( Q2W ) , or 8 mg/kg tocilizumab ( TCZ ) Q4W . The primary endpoint was change from baseline in DAS28(C-reactive protein , CRP ) at Week 12 . Secondary efficacy endpoints were American College of Rheumatology 20 ( ACR20 ) , ACR50 and ACR70 response rates at Week 12 . Exploratory analyses included comparisons of OKZ efficacy with TCZ . Results Across 221 r and omised patients , OKZ treatment produced significantly greater reductions in DAS28(CRP ) from baseline levels at Week 12 , compared to PBO ( p<0.001 ) , at all the OKZ doses tested ( 60 mg OKZ p=0.0001 , 120 and 240 mg OKZ p<0.0001 ) . Additionally , ACR20 and ACR50 responses were numerically higher for OKZ than PBO ( ACR20 : PBO=17.1–29.9 % , OKZ=32.5–60.7 % ; ACR50 : PBO=1.3–4.9 % , OKZ=11.5–33.2 % ) . OKZ treatment , at several doses , demonstrated similar efficacy to TCZ across multiple endpoints . Most adverse events were mild or moderate and comparable between OKZ and TCZ treatment groups . Pharmacokinetic/pharmacodynamic modelling demonstrated a shallow dose/exposure response relationship in terms of percentage of patients with DAS28(CRP ) < 2.6 . Conclusions OKZ produced significantly greater reductions in DAS28(CRP ) from baseline at Week 12 compared with PBO . Reported AEs were consistent with the safety profile expected of this class of drug , with no new safety signals identified . Trial register number : NCT01242488 OBJECTIVE To investigate the safety , tolerability , pharmacokinetics , and efficacy of apilimod mesylate , an oral interleukin-12 (IL-12)/IL-23 inhibitor , in patients with rheumatoid arthritis ( RA ) . METHODS We performed a phase IIa , r and omized , double-blind , placebo-controlled proof-of-concept study of apilimod , in combination with methotrexate , in 29 patients with active RA ( 3:1 ratio of apilimod-treated to placebo-treated patients ) in 3 stages . Patients received apilimod 100 mg/day or placebo for 4 weeks ( stage 1 ) or 8 weeks ( stage 2 ) . In stage 3 , patients received apilimod 100 mg twice a day or placebo for 8 weeks , with an optional extension of 4 weeks . Clinical response ( Disease Activity Score in 28 joints [ DAS28 ] and American College of Rheumatology [ ACR ] criteria ) was assessed throughout ; synovial tissue sample s collected at baseline and on day 29 ( stages 1 and 2 ) or day 57 ( stage 3 ) were stained for cellular markers and cytokines for immunohistochemistry analysis . RESULTS While only mild adverse events were observed in stages 1 and 2 , in stage 3 , all patients experienced headache and /or nausea . Among apilimod-treated patients ( 100 mg/day ) , there was a small , but significant , reduction in the DAS28 on day 29 and day 57 compared with baseline . ACR20 response was reached in only 6 % of patients on day 29 and 25 % of patients on day 57 , similar to the percentage of responders in the placebo group . Increasing the dosage ( 100 mg twice a day ) did not improve clinical efficacy . Consistent with clinical results , apilimod did not have an effect on expression of synovial biomarkers . Of importance , we also did not observe an effect of apilimod on synovial IL-12 and IL-23 expression . CONCLUSION Our results do not support the notion that IL-12/IL-23 inhibition by apilimod is able to induce robust clinical improvement in RA Objective To evaluate the efficacy and safety of golimumab 50 and 100 mg monotherapy in Japanese patients with active rheumatoid arthritis ( RA ) despite treatment with disease-modifying antirheumatic drugs ( DMARDs ) . Methods A total of 316 patients were r and omised to receive subcutaneous injections every 4 weeks of placebo ( group 1 ) , golimumab 50 mg ( group 2 ) or golimumab 100 mg ( group 3 ) ; group 1 crossed over to golimumab 50 mg at week 16 . The primary end point was the proportion of patients achieving ≥20 % improvement in the American College of Rheumatology criteria ( ACR20 ) at week 14 . ACR50 and ACR70 response rates were also measured . Adverse events ( AEs ) were monitored throughout the study . Results Demographics were similar across groups ; the mean age was 52 years and 81.8 % of patients ( 252/308 ) were female . Week 14 ACR20 response rates were significantly greater in groups 2 ( 51/101 ( 50.5 % ) ) and 3 ( 60/102 ( 58.8 % ) ) than in group 1 ( 20/105 ( 19.0 % ) ; p<0.0001 for both ) , as were ACR50 and ACR70 response rates . After placebo crossover at week 16 , week 24 ACR response rates were similar in groups 1 and 2 . Through week 16 , 63.8 % of patients in group 1 , 62.4 % in group 2 and 60.8 % in group 3 had AEs and 1.9 % , 1.0 % and 2.0 % had serious AEs . After week 16 , one malignancy was reported ( breast cancer , group 3 ) . Infections were the most common AEs . No deaths or cases of tuberculosis were reported through week 24 . Conclusions Golimumab monotherapy ( 50 and 100 mg ) was effective in reducing the signs and symptoms of RA in Japanese patients with active disease despite DMARD treatment Infliximab , a chimeric anti-TNF alpha antibody , showed in two double-blind placebo-controlled trials efficacy in combination with methotrexate ( MTX ) in patients with severe rheumatoid arthritis ( RA ) . Whereas in the first trial low-dose MTX or placebo was compared to infliximab alone and in combination , the second trial compared infliximab to placebo in patients with active RA despite maximal tolerated MTX treatment . Infliximab showed synergistic effects in combination with MTX . The immunogenicity of infliximab was reduced by the combination . Infliximab in combination with high-dose MTX is effective and safe in long-term treatment up to 54 weeks BACKGROUND Tumor necrosis factor ( TNF ) is an important mediator of cachexia , and its blockade prevents catabolism in animal models . However , little evidence shows that anti-TNF therapy is effective in treating cachexia in humans . OBJECTIVE The main aim of this study was to investigate the effect of etanercept , a synthetic soluble TNF receptor , on body composition in patients with early rheumatoid arthritis ( RA ) . DESIGN Twenty-six patients were r and omly assigned to 24 wk of treatment with etanercept or methotrexate ; the latter is the first-line therapy for RA . Body composition , physical function , disease activity , systemic inflammation , and the circulating insulin-like growth factor ( IGF ) system were measured at baseline ( week 0 ) and at follow-up ( weeks 12 and 24 ) . Twelve patients in each treatment group ( 9 F , 3 M ) completed the study . RESULTS Overall , no important changes in body composition were observed , despite a transient increase in IGF-I at week 12 ( P < 0.01 ) . However , the secondary analysis of those patients ( 6/treatment group ) who gained weight during follow-up showed a significant effect of etanercept on the composition of the weight gained : 44 % of weight gained in the etanercept group was fat-free mass , as compared with only 14 % in the methotrexate group ( P = 0.04 ) . Etanercept and methotrexate were equally effective in controlling the disease and improving physical function . CONCLUSIONS Anti-TNF therapy with etanercept is not superior to that with methotrexate for the treatment of rheumatoid cachexia over a period of 6 mo . However , TNF blockade seems to normalize the anabolic response to overfeeding and , if these findings are confirmed , may be useful in conditions characterized by anorexia and weight loss OBJECTIVE Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis ( RA ) . Accordingly , we are developing a tolerization approach to dnaJP1 , a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA . We undertook this study to test 2 hypotheses : 1 ) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype , and 2 ) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement . METHODS One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial . They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months . RESULTS The dnaJP1 peptide was safe and well-tolerated . In response to treatment with dnaJP1 , there was a significant reduction in the percentage of T cells producing tumor necrosis factor alpha and a corresponding trend toward an increased percentage of T cells producing interleukin-10 . Coexpression of a cluster of molecules ( programmed death 1 and its lig and s ) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders . Analysis of the primary efficacy end point ( meeting the American College of Rheumatology 20 % improvement criteria at least once on day 112 , 140 , or 168 ) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations . Differences in clinical responses were also found between treatment groups on day 140 and at followup . Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine ( HCQ ) was superior to the combination of HCQ and placebo . CONCLUSION Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy . Susceptibility to treatment relies on the coexpression of molecules that can down-regulate adaptive immunity A composite index for estimating improvement in individual rheumatoid arthritis ( RA ) patients during trials of slow-acting , disease-modifying antirheumatic drugs ( DMARDs ) was developed by analyzing the responses of 130 placebo-treated participants in Cooperative Systematic Studies of Rheumatic Diseases studies . If responses in 4 of 6 selected measures were required for improvement ( by greater than or equal to 20 % for morning stiffness , Westergren erythrocyte sedimentation rate , joint pain/tenderness score , and joint swelling score , and by greater than or equal to 2 grade s on a 5- grade scale , or from grade 2 to grade 1 for patient 's and physician 's overall assessment s of current disease severity ) , few placebo-treated patients qualified as improved , whereas significantly more DMARD-treated patients demonstrated improvement . The proposed index appears to be useful in estimating the probability that an RA patient will improve if taking a placebo during a DMARD trial , and may be a useful tool for analysis of DMARD studies OBJECTIVE Human cartilage glycoprotein 39 ( HC gp-39 ) appears to be a relevant autoantigen in patients with rheumatoid arthritis ( RA ) . Administration of major histocompatibility complex ( MHC ) Class II complexed antigens without requisite costimulatory signals can induce immunologic tolerance . We evaluated the safety , pharmacokinetics , and preliminary efficacy of AG4263 in patients with RA . AG4263 is a soluble complex of native HLA-DR4 ( beta*0401 ) complexed to Org 36601 , a 13-mer peptide derived from HC gp-39 ( also referred to as CDP263 ) . METHODS Thirty-one HLA-DRB1 * 0401 positive patients with persistent RA disease activity despite concurrent methotrexate were r and omized to 7 infusions of AG4263 ( n = 24 ) or placebo ( n = 7 ) over 6 weeks . The initial dose of 0.5 micro g/kg was escalated in subsequent cohorts to a maximum of 150 micro g/kg . Safety analyses included recording of adverse events and measurement of CD4/CD8 counts , reactivity to recall antigens , and development of antibodies to HLA-DR4 . Efficacy was assessed using the Paulus 20 criteria . RESULTS Treatment was well tolerated , with injection site reaction the most common adverse event . There was no loss of reactivity to recall antigens , change in cell counts , or antibodies to HLA-DR . The mean half-life of AG4263 was 12.5 h. Some evidence of clinical response was seen ; responses were more common among patients receiving the highest doses of AG4263 and among those with baseline T cell reactivity to CDP263 . CONCLUSION AG4263 was safe , well tolerated , and without evidence of generalized immune suppression . Along with the observed trend toward clinical efficacy , the results suggest that this therapeutic approach warrants further investigation in patients with RA Objectives To evaluate safety and efficacy of weekly ( qw ) and every other week ( q2w ) dosing of sarilumab , a fully human anti-interleukin 6 receptor α ( anti-IL-6Rα ) monoclonal antibody , for moderate-to-severe rheumatoid arthritis ( RA ) . Methods In this dose-ranging study , patients ( n=306 ) with active RA , despite methotrexate , were r and omly assigned to placebo or one of five subcutaneous doses/regimens of sarilumab : 100 mg q2w , 150 mg q2w , 100 mg qw , 200 mg q2w , 150 mg qw for 12 weeks , plus methotrexate . The primary end point was ACR20 at Week 12 . Secondary endpoints included ACR50 , ACR70 , Disease Activity Score in 28 joints ( C reactive protein ) . Safety , pharmacokinetics , pharmacodynamics and efficacy in population subgroups were assessed . Results The proportion of patients achieving an ACR20 response compared with placebo was significantly higher for sarilumab 150 mg qw ( 72.0 % vs 46.2 % , multiplicity adjusted p=0.0203 ) . Higher ACR20 responses were also attained with 150 mg q2w ( 67 % ; unadjusted ( nominal ) p=0.0363 ) and 200 mg q2w ( 65 % ; unadjusted p=0.0426 ) versus placebo . Sarilumab ≥150 mg q2w reduced C reactive protein , which did not return to baseline between dosing intervals . Infections were the most common adverse event ; none were serious . Changes in laboratory values ( neutropenia , transaminases and lipids ) were consistent with reports with other IL-6Rα inhibitors . Conclusions Sarilumab improved signs and symptoms of RA over 12 weeks in patients with moderate-to-severe RA with a safety profile similar to reports with other IL-6 inhibitors . Sarilumab 150 mg and sarilumab 200 mg q2w had the most favourable efficacy , safety and dosing convenience and are being further evaluated in Phase III R and omized clinical trials remain the gold st and ard to establish efficacy and safety of new treatments . In acute myeloid leukemia , large trials have been associated with gradual improvement in outcome over 2 decades in younger patients without major differences emerging between treatments . By contrast , in older patients , improvement has been minimal , which justifies a new approach to identifying effective treatments . Given the urgent unmet need , and with the emergence of several novel agents or combinations that are likely to be expensive , large benefits are probably required to change clinical practice . To address this issue , we have evolved a " Pick a Winner " r and omized progressive design with a rolling incorporation of novel treatments ( drug X ) , which has been tested in older patients with acute myeloid leukemia . The rationale , operational characteristics , and initial experience of such an approach in the context of the United Kingdom National Cancer Research Institute AML16 trial are presented OBJECTIVE To evaluate the efficacy , pharmacokinetics , immunogenicity , and safety of multiple infusions of a chimeric monoclonal anti-tumor necrosis factor alpha antibody ( cA2 ) ( infliximab ; Remicade , Centocor , Malvern , PA ) given alone or in combination with low-dose methotrexate ( MTX ) in rheumatoid arthritis ( RA ) patients . METHODS In a 26-week , double-blind , placebo-controlled , multicenter trial , 101 patients with active RA exhibiting an incomplete response or flare of disease activity while receiving low-dose MTX were r and omized to 1 of 7 groups of 14 - 15 patients each . The patients received either intravenous cA2 at 1 , 3 , or 10 mg/kg , with or without MTX 7.5 mg/week , or intravenous placebo plus MTX 7.5 mg/week at weeks 0 , 2 , 6 , 10 , and 14 and were followed up through week 26 . RESULTS Approximately 60 % of patients receiving cA2 at 3 or 10 mg/kg with or without MTX achieved the 20 % Paulus criteria for response to treatment , for a median duration of 10.4 to > 18.1 weeks ( P < 0.001 versus placebo ) . Patients receiving cA2 at 1 mg/kg without MTX became unresponsive to repeated infusions of cA2 ( median duration 2.6 weeks ; P=0.126 versus placebo ) . However , coadministration of cA2 at 1 mg/kg with MTX appeared to be synergistic , prolonging the duration of the 20 % response in > 60 % of patients to a median of 16.5 weeks ( P < 0.001 versus placebo ; P=0.006 versus no MTX ) and the 50 % response to 12.2 weeks ( P < 0.001 versus placebo ; P=0.002 versus no MTX ) . Patients receiving placebo infusions plus suboptimal low-dose MTX continued to have active disease , with a Paulus response lasting a median of 0 weeks . A 70 - 90 % reduction in the swollen joint count , tender joint count , and C-reactive protein level was maintained for the entire 26 weeks in patients receiving 10 mg/kg of cA2 with MTX . In general , treatment was well tolerated and stable blood levels of cA2 were achieved in all groups , except for the group receiving 1 mg/kg of cA2 alone , at which dosage antibodies to cA2 were observed in approximately 50 % of the patients . CONCLUSION Multiple infusions of cA2 were effective and well tolerated , with the best results occurring at 3 and 10 mg/kg either alone or in combination with MTX in approximately 60 % of patients with active RA despite therapy with low-dose MTX . When cA2 at 1 mg/kg was given with low-dose MTX , synergy was observed . The results of the trial provide a strategy for further evaluation of the efficacy and safety of longer-term treatment with cA2 Rituximab is a B cell-depleting anti-CD20 chimeric IgGkappa monoclonal antibody being investigated for the treatment of rheumatoid arthritis . The purpose of this study was to develop a population pharmacokinetic model in rheumatoid arthritis patients . In addition , the final pharmacokinetic model was used to assess the variability in drug exposure ( AUC0-infinity ) for fixed versus body surface area-based dosing . A total of 102 patients were included in this population pharmacokinetic analysis . A 2-compartment pharmacokinetic model described the data reasonably well . Body surface area and gender were the most significant covariates for both CL and Vc . Body surface area alone only explained about 19.7 % of the total interindividual variability of CL . In a simulation study , body surface area-based dosing normalized drug exposure over a wide range of body surface area but did not seem to improve the predictability of rituximab AUC0-infinity in rheumatoid arthritis patients . Therefore , no rationale for body surface area-based dosing for rituximab in rheumatoid arthritis patients was found OBJECTIVE Tabalumab , a fully human IgG4 monoclonal antibody , neutralizes soluble and membrane-bound BAFF . The aim of this study was to examine the tolerability and efficacy of tabalumab in patients with active rheumatoid arthritis receiving methotrexate . METHODS In this r and omized , double-blind , placebo-controlled , parallel , multiple-dose study , patients who were naive to biologic therapy received infusions of tabalumab ( 30 , 60 , or 160 mg ) or placebo at weeks 0 , 3 , and 6 in combination with methotrexate and were evaluated for 24 weeks . The primary efficacy end point was the percentage of patients meeting American College of Rheumatology 20 % improvement criteria ( achieving an ACR20 response ) at week 16 . RESULTS At week 16 , the percentages of patients achieving an ACR20 response in the 30-mg ( 57.6 % ) , 60-mg ( 67.6 % ) , and 160-mg ( 51.5 % ) groups were significantly greater than the percentage of patients achieving an ACR20 response in the placebo group ( 29.4 % ; P<0.05 ) . There were initial transient increases from baseline in the frequency of CD20 + and IgD+/CD27- B cells , followed by reductions , although B cells were not completely depleted . Also , the frequency of IgD-/CD27 + B cells increased in all tabalumab groups compared with the placebo group and returned toward baseline levels by the end of the study . The incidence of adverse events was similar across all treatment groups ; no deaths occurred . Serum IgM levels decreased significantly in all tabalumab groups combined compared with the placebo group . There were no significant decreases in serum IgG or IgA levels in the tabalumab groups compared with the placebo group . CONCLUSION Tabalumab treatment significantly reduces the signs and symptoms of rheumatoid arthritis and has a safety profile similar to that seen with placebo treatment Background Publication bias is generally ascribed to authors and sponsors failing to su bmi t studies with negative results , but may also occur after su bmi ssion . We evaluated whether su bmi tted manuscripts on r and omized controlled trials ( RCTs ) with drugs are more likely to be accepted if they report positive results . Methods Manuscripts su bmi tted from January 2010 through April 2012 to one general medical journal ( BMJ ) and seven specialty journals ( Annals of the Rheumatic Diseases , British Journal of Ophthalmology , Gut , Heart , Thorax , Diabetologia , and Journal of Hepatology ) were included , if at least one study arm assessed the efficacy or safety of a drug and a statistical test was used to evaluate treatment effects . Publication status was retrospectively retrieved from su bmi ssion systems or provided by journals . Sponsorship and trial results were extracted from manuscripts and classified according to predefined criteria . Main outcome measure was acceptance for publication . Results Of 15,972 manuscripts su bmi tted , 472 ( 3.0 % ) were drug RCTs , of which 98 ( 20.8 % ) were published . Among su bmi tted drug RCTs , 287 ( 60.8 % ) had positive and 185 ( 39.2 % ) negative results . Of these , 60 ( 20.9 % ) and 38 ( 20.5 % ) , respectively , were published . Manuscripts on non-industry trials ( n = 213 ) reported positive results in 138 ( 64.8 % ) manuscripts , compared to 71 ( 47.7 % ) on industry-supported trials ( n = 149 ) , and 78 ( 70.9 % ) on industry-sponsored trials ( n = 110 ) . Twenty-seven ( 12.7 % ) non-industry trials were published , compared to 27 ( 18.1 % ) industry-supported and 44 ( 40.0 % ) industry-sponsored trials . After adjustment for other trial characteristics , manuscripts reporting positive results were not more likely to be published ( OR , 1.00 ; 95 % CI , 0.61 to 1.66 ) . Su bmi ssion to specialty journals , sample size , multicentre status , journal impact factor , and corresponding authors from Europe or US were significantly associated with publication . Conclusions For the selected journals , there was no tendency to preferably publish manuscripts on drug RCTs that reported positive results , suggesting that publication bias may occur mainly prior to su bmi ssion Interleukin-11 ( IL-11 ) is a pleiotropic cytokine that regulates the growth and development of hematopoietic stem cells and decreases the proinflammatory mediators of cytokine and nitric oxide production . In animal models of arthritis , treatment with recombinant human IL-11 ( rhIL-11 ) reduces both the level of synovitis and the histologic lesion scores in the joints . The goal of this phase-I/II study in adults with rheumatoid arthritis ( RA ) was to evaluate the safety and clinical activity of different doses and schedules of rhIL-11 in patients with active RA for whom treatment with at least one disease-modifying antirheumatic drug had failed . This was a multicenter , r and omized , placebo-controlled trial that evaluated the safety and tolerability of rhIL-11 in 91 patients with active RA . rhIL-11 was administered subcutaneously ; patients were r and omized into one of five treatment groups ( ratio of rhIL-11 to placebo , 4:1 ) . Patients were treated for 12 weeks with either 2.5 or 7.5 μg/kg of rhIL-11 or placebo twice per week or 5 or 15 μg/kg of rhIL-11 or placebo once per week . The status of each subject 's disease activity in accordance with the American College of Rheumatology ( ACR ) criteria was assessed before , during , and after completion of administration of the study drug . Administration of rhIL-11 was well tolerated at all doses and schedules . The most frequent adverse event was a reaction at the injection site . The data suggest a statistically significant reduction in the number of tender joints ( P < 0.008 ) at the 15 μg/kg once-weekly dose schedule but showed no overall significant benefit at the ACR criterion of a 20 % response . The trial showed rhIL-11 to be safe and well tolerated at a variety of doses and schedules over a 12-week treatment period in patients with active RA . The only adverse event clearly associated with rhIL-11 administration was reaction at the injection site OBJECTIVE Adenosine exerts antiinflammatory effects via activation of the A3 adenosine receptor ( A3AR ) , a Gi protein-associated cell-surface receptor , overexpressed in synovial tissue and peripheral blood mononuclear cells ( P BMC ) in patients with active rheumatoid arthritis ( RA ) . CF101 is a highly specific orally bioavailable A3AR agonist . METHODS This was a multicenter study , blinded to dose , design ed to assess the clinical activity and safety of CF101 in active RA . Seventy-four patients were r and omized to receive 0.1 , 1.0 , or 4.0 mg CF101 bid for 12 weeks . The primary efficacy endpoint was American College of Rheumatology 20 % response ( ACR20 ) at Week 12 . A3AR expression levels were analyzed in P BMC from 18 patients . RESULTS . Maximal responses were observed with 1.0 mg bid , lower at 0.1 and 4.0 mg bid . At 12 weeks , 55.6 % , 33.3 % , and 11.5 % of the patients receiving 1.0 mg CF101 achieved ACR20 % , 50 % , and 70 % responses , respectively . CF101 was generally well tolerated , with mild headache ( 4.1 % ) , nausea ( 2.7 % ) , and rash ( 2.7 % ) being the most common treatment-related adverse events . Statistically significant correlations between A3AR overexpression at baseline and ACR50 and ACR70 responses were observed . CONCLUSION CF101 administered bid for 12 weeks result ed in improvement in signs and symptoms of RA that did not achieve statistical significance , and was safe and well tolerated . The expression level of A3AR was directly correlated with patient responses to CF101 , suggesting its utilization as a biomarker for the pharmacodynamic and therapeutic effects of this novel agent . These findings require confirmation in a double-blind r and omized placebo-controlled trial , currently under way Introduction Oncostatin M ( OSM ) has been implicated in the pathophysiology of rheumatoid arthritis ( RA ) through its effect on inflammation and joint damage . GSK315234 is a humanised anti-OSM Immunoglobulin G1 ( IgG1 ) monoclonal antibody ( mAb ) . This 3-part study examines the safety , tolerability and efficacy of GSK315234 in patients with active RA . Method This was a 3-part ( Parts A , B and C ) , multicenter study . Part A and Part B were r and omised , double-blind , placebo-controlled , Bayesian adaptive dose finding studies to investigate the safety , tolerability , efficacy , pharmacokinetics and pharmacodynamics of single ( Part A ) and 3 repeat ( Part B ) intravenous infusions of GSK315234 in patients with active RA on a background of methotrexate ( MTX ) . Part C was a single dose , r and omised , single-blind , placebo-controlled study to assess subcutaneously administered GSK315234 to patients with active RA on a background of MTX . Result The primary endpoint of the study was mean change in DAS28 at Day 28 in Part A and Day 56 in Part B and C. All patients receiving at least one dose of GSK315234 were included in safety analysis . In Part A , there were statistically significant differences in DAS28 between 3 mg/kg and placebo at Day 56 , 84 and 91 . There was also a statistically significant difference in DAS28 between 0.3 mg/kg , 3 mg/kg and 10 mg/kg , as compared to placebo , at Day 84 . Although these changes were small and occurred late , they supported progression to Part B and C to determine the therapeutic potential of GSK315234 . For Part B , no significant difference was observed between 6 mg/kg and placebo . For Part C , a statistically significant difference in DAS28 was observed at Day 40 , Day 84 and Day 100 between the 500 mg subcutaneous group , as compared to placebo . No significant findings were observed at any of the time points for EULAR response criteria , ACR20 , ACR50 or ACR70 . An exploratory analysis of clinical , pharmacokinetic and pharmacodynamics data suggests the lack of efficacy may be due to moderate binding affinity and rapid off-rate of GSK315234 as compared to the higher affinity OSM receptor causing a protein carrier effect prolonging the half life of OSM due to accumulation of the OSM/antibody complex in the serum and synovial fluid . Conclusion Our data highlighted the importance of binding affinity and off-rate effect of a mAb to fully neutralize the target and how this may influence its efficacy and potentially worsen disease activity . Using an anti-OSM mAb with high affinity should test this hypothesis and examine the potential of OSM as a therapeutic target in RA.Trial registration Clinical Trials.gov no : The treatment of older patients with acute myeloid leukaemia , who are not considered suitable for conventional intensive therapy , is unsatisfactory . Low-dose Ara-C(LDAC ) has been established as superior to best supportive care , but only benefits the few patients who enter complete remission . Alternative or additional treatments are required to improve the situation . This r and omised trial compared the addition of the immunoconjugate , gemtuzumab ozogamicin ( GO ) , at a dose of 5 mg on day 1 of each course of LDAC , with the intention of improving the remission rate and consequently survival . Between June 2004 and June 2010 , 495 patients entered the r and omisation . The addition of GO significantly improved the remission rate ( 30 % vs 17 % ; odds ratio(OR ) 0.48 ( 0.32–0.73 ) ; P=0.006 ) , but not the 12 month overall survival ( 25 % vs 27 % ) . The reason for the induction benefit failing to improve OS was two-fold : survival of patients in the LDAC arm who did not enter remission and survival after relapse were both superior in the LDAC arm . Although the addition of GO to LDAC doubled the remission rate it did not improve overall survival . Maintaining remission in older patients remains elusive Background Hip and knee osteoarthritis is a common cause of pain and disability , which can be improved by exercise interventions . However , regular exercise is uncommon in this group because the low physical activity level in the general population is probably reduced even further by pain related fear of movement . The best method of encouraging increased activity in this patient group is not known . A booklet has been developed for patients with hip or knee osteoarthritis . It focuses on changing disadvantageous beliefs and encouraging increased physical activity . Methods / Design This paper describes the design of a Phase II r and omised controlled trial ( RCT ) to test the effectiveness of this new booklet for patients with hip and knee osteoarthritis in influencing illness and treatment beliefs , and to assess the feasibility of conducting a larger definitive RCT in terms of health status and exercise behaviour . A computerised search of four general medical practice patients ' record data bases will identify patients older than 50 years of age who have consulted with hip or knee pain in the previous twelve months . A r and om sample of 120 will be invited to participate in the RCT comparing the new booklet with a control booklet , and we expect 100 to return final question naires . This trial will assess the feasibility of recruitment and r and omisation , the suitability of the control intervention and outcome measurement tools , and will provide an estimate of effect size . Outcomes will include beliefs about hip and knee pain , beliefs about exercise , fear avoidance , level of physical activity , health status and health service costs . They will be measured at baseline , one month and three months . Discussion We discuss the merits of testing effectiveness in a phase II trial , in terms of intermediate outcome measures , whilst testing the processes for a larger definitive trial . We also discuss the advantages and disadvantages of testing the psychometric properties of the primary outcome measures concurrently with the trial . Trial registration Current Controlled Trials IS RCT OBJECTIVE RANKL is essential for osteoclast development , activation , and survival . Denosumab is a fully human monoclonal IgG2 antibody that binds RANKL , inhibiting its activity . The aim of this multicenter , r and omized , double-blind , placebo-controlled , phase II study was to evaluate the effects of denosumab on structural damage in patients with rheumatoid arthritis ( RA ) receiving methotrexate treatment . METHODS RA patients received subcutaneous placebo ( n = 75 ) , denosumab 60 mg ( n = 71 ) , or denosumab 180 mg ( n = 72 ) injections every 6 months for 12 months . The primary end point was the change from baseline in the magnetic resonance imaging ( MRI ) erosion score at 6 months . RESULTS At 6 months , the increase in the MRI erosion score from baseline was lower in the 60-mg denosumab group ( mean change 0.13 ; P = 0.118 ) and significantly lower in the 180-mg denosumab group ( mean change 0.06 ; P = 0.007 ) than in the placebo group ( mean change 1.75 ) . A significant difference in the modified Sharp erosion score was observed as early as 6 months in the 180-mg denosumab group ( P = 0.019 ) as compared with placebo , and at 12 months , both the 60-mg ( P = 0.012 ) and the 180-mg ( P = 0.007 ) denosumab groups were significantly different from the placebo group . Denosumab caused sustained suppression of markers of bone turnover . There was no evidence of an effect of denosumab on joint space narrowing or on measures of RA disease activity . Rates of adverse events were comparable between the denosumab and placebo groups . CONCLUSION Addition of twice-yearly injections of denosumab to ongoing methotrexate treatment inhibited structural damage in patients with RA for up to 12 months , with no increase in the rates of adverse events as compared with placebo Objective : To assess the efficacy of interferon beta ( IFNβ ) in combination with methotrexate in treatment of patients with rheumatoid arthritis . Methods : 209 patients with active rheumatoid arthritis , who had been on methotrexate for at least six months and at a stable dose for four weeks before study entry , were r and omised in double blind fashion to receive placebo ( 0.05 ml or 0.5 ml ) , IFNβ 2.2 μg ( 0.05 ml ) , or IFNβ 44 μg ( 0.5 ml ) , given subcutaneously three times weekly for 24 weeks . The primary efficacy measure was a change in radiological scores at week 24 . The secondary endpoint was the proportion of patients who met the ACR 20 % improvement criteria at the end of the study . Synovial biopsy specimens were obtained before and after treatment from a subset of patients . Immunohistochemistry was used to detect the presence of inflammatory cells and the results were measured by digital image analysis . Collagen crosslinks were measured in urine at different times throughout the study . Results : Analysis of radiological scores and clinical variable showed no changes in any of the groups , and there were no differences between the groups . On microscopic analysis of synovial tissue there was no significant change in the scores for infiltration by inflammatory cells after IFNβ treatment . Urinary levels of collagen crosslinks were unchanged between the treatment groups . Conclusions : At the doses tested , treatment with IFNβ three times weekly in combination with methotrexate did not have a clinical or radiological effect in patients with rheumatoid arthritis Background and Objectives GLPG0259 is a small-molecule inhibitor of mitogen-activated protein kinase-activated protein kinase 5 ( MAPKAPK5 ) , a kinase enzyme that plays a role in important inflammatory pathways . The main objectives of the phase I clinical studies in early development were to characterize the pharmacokinetics , tolerability , and safety of GLPG0259 in healthy subjects , including the development of a solid dosage form ( free-base pellets and fumarate salt capsules ) and the potential for interaction of GLPG0259 with methotrexate . Subjects and Methods Four phase I studies were initiated . Study 1 was a r and omized , double-blind , placebo-controlled study to evaluate the safety , tolerability , and pharmacokinetics of single ascending doses ( 1.5–150 mg ) and multiple oral doses ( 20 and 50 mg once daily ) of GLPG0259 in healthy male subjects ( n = 34 ) . Study 2 was a r and omized , double-blind , placebo-controlled study to evaluate the safety , tolerability , and pharmacokinetics of oral multiple ascending doses of GLPG0259 ( 25–75 mg once daily ) given for 14 days to healthy male subjects , and to get preliminary information on the potential pharmacokinetic interaction between GLPG0259 and methotrexate ( n = 24 ) . Studies 3 and 4 were open-label , r and omized , crossover studies to compare the oral bioavailability of two solid dosage forms of GLPG0259 ( a capsule ) relative to an oral solution after a 100 mg or 50 mg single dose and to evaluate the effect of food on these formulations ( n = 12 for each study ) .Main Outcome Measures The non-compartmental pharmacokinetic parameters for plasma concentrations of GLPG0259 were determined , and a population pharmacokinetic model of GLPG0259 was developed to support the planning of the number and timing of the sparse sample s to be taken per patient in the phase II study . Safety and tolerability data are also summarized . Results The absorption of GLPG0259 was slow , with a decrease in the absorption rate with increasing dose , and there was decreased elimination , with an apparent terminal elimination half-life of 26.0 hours . On the basis of statistical analysis of variance , the exposure to GLPG0259 increased in proportion to the dose over a 30–150 mg single-dose range and a 25–75 mg repeated-dose range . Between- and within-subject variability in GLPG0259 pharmacokinetics was low/moderate ( coefficient of variation [ CV ] 16–30 % ) . After once-daily repeated dosing , steady-state plasma concentrations were reached at between 5 and 8 dosing days , which is consistent with the long apparent elimination half-life of GLPG0259 . Food increased the bioavailability of GLPG0259 given in a solid dosage form . Co-administration of GLPG0259 with a single dose of methotrexate 7.5 mg did not result in any change in the pharmacokinetic profiles of either GLPG0259 or methotrexate . Conclusion In summary , the investigation of safety/tolerability and pharmacokinetics in the early development phase showed that single and repeated doses of GLPG0259 were safe and well tolerated . The most common adverse event reported was mild gastrointestinal discomfort . The pharmacokinetics characterized in healthy male subjects showed no major obstacles and supports a once-daily oral regimen in patients Abstract background The pace of novel medical treatments and approaches to therapy has accelerated in recent years . Unfortunately , many potential therapeutic advances do not fulfil their promise when subjected to r and omized controlled trials . It is therefore highly desirable to speed up the process of evaluating new treatment options , particularly in phase II and phase III trials . To help realize such an aim , in 2003 , Royston and colleagues proposed a class of multi-arm , two-stage trial design s intended to eliminate poorly performing contenders at a first stage ( point in time ) . Only treatments showing a predefined degree of advantage against a control treatment were allowed through to a second stage . Arms that survived the first-stage comparison on an intermediate outcome measure entered a second stage of patient accrual , culminating in comparisons against control on the definitive outcome measure . The intermediate outcome is typically on the causal pathway to the definitive outcome ( i.e. the features that cause an intermediate event also tend to cause a definitive event ) , an example in cancer being progression-free and overall survival . Although the 2003 paper alluded to multi-arm trials , most of the essential design features concerned only two-arm trials . Here , we extend the two-arm design s to allow an arbitrary number of stages , thereby increasing flexibility by building in several ' looks ' at the accumulating data . Such trials can terminate at any of the intermediate stages or the final stage . Methods We describe the trial design and the mathematics required to obtain the timing of the ' looks ' and the overall significance level and power of the design . We support our results by extensive simulation studies . As an example , we discuss the design of the STAMPEDE trial in prostate cancer . Results The mathematical results on significance level and power are confirmed by the computer simulations . Our approach compares favourably with methodology based on beta spending functions and on monitoring only a primary outcome measure for lack of benefit of the new treatment . Conclusions The new design s are practical and are supported by theory . They hold considerable promise for speeding up the evaluation of new treatments in phase II and III trials OBJECTIVE T cells are involved in the pathogenesis of rheumatoid arthritis ( RA ) . In animal models of autoimmune diseases , blockade of costimulatory molecules on antigen-presenting cells has been demonstrated to be effective in preventing or treating this disease by preventing T cell activation . To date , the effect of costimulatory blockade in patients with RA is unknown . The goal of this multicenter , multinational study was to determine the safety and preliminary efficacy of costimulatory blockade using CTLA-4Ig and LEA29Y in RA patients who have been treated unsuccessfully with at least 1 disease-modifying agent . METHODS CTLA-4Ig , LEA29Y ( 0.5 , 2 , or 10 mg/kg ) , or placebo was administered intravenously to 214 patients with RA . Patients received 4 infusions of study medication , on days 1 , 15 , 29 , and 57 , and were evaluated on day 85 . The primary end point was the proportion of patients meeting the American College of Rheumatology 20 % improvement criteria ( ACR20 ) . All patients were monitored for treatment safety and tolerability . RESULTS CTLA-4Ig and LEA29Y infusions were well tolerated at all dose levels . Peri-infusional adverse events were carefully monitored , and showed similar incidence across all dose groups with the exception of headaches , which were slightly more frequent in the 2 treatment groups . The incidence of discontinuations due to worsening of RA was 19 % , 12 % , and 9 % at 0.5 , 2 , and 10 mg/kg , respectively , in the CTLA-4Ig-treated patients and 3 % , 3 % , and 6 % at 0.5 , 2 , and 10 mg/kg , respectively , in the LEA29Y-treated patients ( versus 31 % in the placebo group ) . ACR20 responses on day 85 had increased in a dose-dependent manner ( 23 % , 44 % , and 53 % of CTLA-4Ig-treated patients and 34 % , 45 % , and 61 % of LEA29Y-treated patients at 0.5 , 2.0 , and 10 mg/kg , respectively , versus 31 % of placebo-treated patients ) . CONCLUSION Both of the costimulatory blocking molecules studied were generally safe and well tolerated . As compared with placebo , both CTLA-4Ig and LEA29Y demonstrated efficacy in the treatment of RA OBJECTIVE To establish the safety and efficacy of repeat infusions of tocilizumab ( previously known as MRA ) , a humanized anti-interleukin-6 ( IL-6 ) receptor antibody , alone and in combination with methotrexate ( MTX ) , for the treatment of rheumatoid arthritis ( RA ) . METHODS The study group comprised 359 patients with active RA in whom the response to MTX was inadequate . During a stabilization period , these patients received their current dose of MTX for at least 4 weeks . Following stabilization , they were r and omized to 1 of 7 treatment arms , as follows : tocilizumab at doses of 2 mg/kg , 4 mg/kg , or 8 mg/kg either as monotherapy or in combination with MTX , or MTX plus placebo . RESULTS A 20 % response ( improvement ) according to the American College of Rheumatology criteria ( ACR20 response ) was achieved by 61 % and 63 % of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy , respectively , and by 63 % and 74 % of patients receiving those doses of tocilizumab plus MTX , respectively , compared with 41 % of patients receiving placebo plus MTX . Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX ( P < 0.05 ) . A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward , in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab . In the majority of patients who received 8 mg/kg of tocilizumab , the C-reactive protein level/erythrocyte sedimentation rate normalized , while placebo plus MTX had little effect on these laboratory parameters . Tocilizumab was mostly well tolerated , with a safety profile similar to that of other biologic and immunosuppressive therapies . Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern ( rising and falling between infusions ) . There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels . There were 2 cases of sepsis , both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX . CONCLUSION These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA Summary In an open , non-r and omized clinical trial conducted at multiple centres , 49 patients with rheumatoid arthritis were treated with recombinant interferon-gamma for 20 days . The study was carried out in two sub- studies . In the first , the total daily dose of interferon-gamma was 50 μg ; in the second , 100 μg . Of the 49 cases , 40 were evaluable for statistical analysis ; 24 of these patients ( 60 % ) responded to therapy , according to the criteria of a successful outcome laid down in the study protocol , and were classified as responders . In responders , the clinical parameters investigated improved with both dosages . The lower dosage differed from the higher one in having a markedly lower incidence of side-effects . The results lead to the conclusion that a r and omized double-blind phase-III clinical trial should be performed Background Adaptive dose-ranging trials are more efficient than traditional approaches and may be design ed to explicitly address the goals and decisions inherent in learn-phase drug development . We report the design , implementation , and outcome of an innovative Bayesian , response-adaptive , dose-ranging trial of an investigational drug in patients with diabetes , incorporating a dose expansion approach to flexibly address both efficacy and safety . Purpose The design was developed to assess whether one or more doses of an investigational drug demonstrated superior efficacy to an active control while maintaining an acceptable safety profile . Methods The trial used a two-stage design , in which patients were initially allocated equally to placebo , investigational drug at a low and a medium dose , and an active control . Movement to the second stage was contingent upon evidence of efficacy ( measured by change in fasting blood glucose ) to add a very low dose of the investigational drug and of safety ( measured by weight gain ) to add a high dose of the investigational drug . The design incorporated a longitudinal model to maximize use of incomplete data , predictive probabilities to guide the decisions to terminate the trial for futility or move on to Stage 2 , and a dose-response model in Stage 2 to borrow information across adjacent doses . Extensive simulations were used to fine tune trial parameters , to define operating characteristics , and to determine the required sample sizes . A data monitoring committee was provided with frequent reports to aid in trial oversight . Results In Stage 1 , as trial data accrued , the predictive probability that either the low or medium dose of the investigational drug was superior to the active control fell to low values . Stage 1 termination was recommended after 199 subjects were r and omized , out of a maximum trial size of 500 subjects , and the final sample size was 218 . Thus the trial did not progress to Stage 2 . Limitations Because of the relatively narrow dose range to be assessed , and the inability to utilize the highest dose at the beginning of the trial , a fully responsive-adaptive design incorporating dose-response modeling was not considered a viable option . This limited the efficiency gains possible with a full set of adaptive design elements . Conclusions The two-stage dose-expansion design functioned as design ed , recommending early termination based on a low probability that the tested doses had efficacy greater than the active control . Clinical Trials 2010 ; 7 : 121—135 . OBJECTIVE To assess the efficacy , safety , and biologic activity of atacicept in patients with rheumatoid arthritis ( RA ) in whom the response to treatment with tumor necrosis factor antagonists was inadequate . METHODS The Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial ( AUGUST I ) was a multicenter , phase II , double-blind , placebo-controlled dose-finding study involving 256 patients r and omized 1:1:1:1 to receive atacicept ( 25 mg , 75 mg , or 150 mg ) or placebo twice weekly for 4 weeks , then weekly for 21 weeks , with a 13-week treatment-free followup period ( week 38 ) . The primary end point was a response at week 26 according to the American College of Rheumatology criteria for 20 % improvement in disease severity , using the C-reactive protein level . RESULTS No statistically significant differences were observed in the efficacy end points at week 26 ( P = 0.410 for overall treatment effect ) . However , atacicept significantly reduced immunoglobulin and rheumatoid factor ( RF ) levels , but not anti-citrullinated protein antibody levels , in a dose-dependent manner , with levels returning toward baseline values during followup . The effects of treatment on IgG-RF and IgA-RF were more pronounced than the effects on total IgG and IgA. Adverse events ( AEs ) , including serious AEs , leading to withdrawal were more common among patients treated with atacicept compared with placebo . AEs were variable in nature , and no dose-dependent trends were observed . The frequency of infection-related AEs was similar across treatments . No notable effect of treatment on immunization status ( protective versus nonprotective titer ) was observed after initiation of treatment . CONCLUSION This study did not meet the primary efficacy end point . However , clear biologic activity consistent with the proposed mechanism of action was observed . The results suggest that decreasing the expression of RF may not be sufficient to induce clinical improvement in RA . The safety of atacicept was considered acceptable in this patient population OBJECTIVE To examine the efficacy and safety of different rituximab doses plus methotrexate ( MTX ) , with or without glucocorticoids , in patients with active rheumatoid arthritis ( RA ) resistant to disease-modifying antirheumatic drugs ( DMARDs ) , including biologic agents . METHODS A total of 465 patients were r and omized into 9 treatment groups : 3 rituximab groups ( placebo [ n = 149 ] , 500 mg [ n = 124 ] , or 1,000 mg [ n = 192 ] on days 1 and 15 ) each also taking either placebo glucocorticoids , intravenous methylprednisolone premedication , or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks . All patients received MTX ( 10 - 25 mg/week ) ; no other DMARDs were permitted . RESULTS Significantly more patients who received 2 500-mg or 2 1,000-mg infusions of rituximab met the American College of Rheumatology 20 % improvement criteria ( achieved an ACR20 response ) at week 24 ( 55 % and 54 % , respectively ) compared with placebo ( 28 % ; P < 0.0001 ) . ACR50 responses were achieved by 33 % , 34 % , and 13 % of patients , respectively ( P < 0.001 ) , and ACR70 responses were achieved by 13 % , 20 % , and 5 % of patients ( P < 0.05 ) . Changes in the Disease Activity Score in 28 joints ( -1.79 , -2.05 , -0.67 ; P < 0.0001 ) and moderate to good responses on the European League Against Rheumatism criteria ( P < 0.0001 ) reflected the ACR criteria responses . Glucocorticoids did not contribute significantly to the primary efficacy end point , ACR20 response at 24 weeks . Intravenous glucocorticoid premedication reduced the frequency and intensity of first infusion-associated events ; oral glucocorticoids conferred no additional safety benefit . Rituximab was well tolerated ; the type and severity of infections was similar to those for placebo . CONCLUSION Both rituximab doses were effective and well tolerated when added to MTX therapy in patients with active RA . The primary end point ( ACR20 response ) was independent of glucocorticoids , although intravenous glucocorticoid premedication improved tolerability during the first rituximab infusion OBJECTIVE To investigate safety and tolerability and pilot efficacy of repeated single doses of Org39141 in patients with active rheumatoid arthritis ( RA ) . Org 39141 is recombinant human cartilage glycoprotein-39 , intended to induce mucosal tolerance upon intranasal administration . METHODS RA patients with moderate disease activity were treated for 4 weeks and followed for another 8 weeks . The trial had a sequential cohort design : RA patients in the first cohort received 4 intranasal doses ( one per week ) of either 25 microg Org 39141 or placebo ; in subsequent cohorts , treatment with 125microg , 625 microg , or 3125 microg Org39141 was compared to placebo . Safety was evaluated by means of reporting adverse events , st and ard laboratory testing , and nose examination . The primary efficacy endpoint was RA disease activity as measured by the Disease Activity Score 28 ( DAS28 ) . RESULTS A total of 36 patients were r and omized . Org39141 was well tolerated , and no severe or serious adverse events ( AE ) were reported . In the pooled placebo group , a decrease in DAS28 was observed , but to a lesser extent than in the Org 39141 treatment groups . After 4 weeks of treatment , the mean decrease in DAS in the 625 microg Org 39141 treatment group ( -24 % ) was statistically ( p = 0.02 ) and clinical ly ( EULAR criteria ) significantly larger than in the pooled placebo group ( -3 % ) . Once-weekly intranasal treatment with Org39141 was well tolerated , and no serious or severe AE were reported . A trend towards efficacy was observed . Our results are encouraging for further clinical development of Org39141 To compare the efficacy , safety , and tolerability of 4 doses of oral tofacitinib ( CP‐690,550 ) with placebo in Japanese patients with active rheumatoid arthritis ( RA ) receiving stable background methotrexate ( MTX ) who had an inadequate response to MTX alone BACKGROUND The Hip & Knee Book : Helping you cope with osteoarthritis was developed to change disadvantageous beliefs and encourage physical activity in people with hip or knee osteoarthritis . AIM To assess the feasibility of conducting a definitive r and omised controlled trial ( RCT ) of this evidence -based booklet in people with hip or knee osteoarthritis . DESIGN Phase II feasibility r and omised controlled trial ( RCT ) . METHOD Computerised search es of patients ' record data bases identified people with osteoarthritis of the hip or knee , who were invited to participate in the RCT comparing the new booklet with a control booklet . Outcomes were measured at baseline , 1 month , and 3 months , and included : beliefs about hip and knee pain , exercise , and fear avoidance ; level of physical activity ; and health service use . RESULTS The trial methods were feasible in terms of recruitment , r and omisation , and follow-up , but most participants recruited had longst and ing established symptoms . After one and 3 months , there was a small relative improvement in illness , exercise , and fear-avoidance beliefs and physical activity level in The Hip & Knee Book group ( n = 59 ) compared with the control group ( n = 60 ) , which provides some proof of principle for using these outcomes in future trials . CONCLUSION This feasibility study provided proof of principle for testing The Hip & Knee Book in a larger definitive RCT Tumour necrosis factor alpha ( TNF alpha ) is a critical inflammatory mediator in rheumatoid arthritis , and may therefore be a useful target for specific immunotherapy . In support of this hypothesis , we previously observed beneficial responses in patients with active rheumatoid arthritis after open-label administration of a chimeric monoclonal antibody to TNF alpha ( cA2 ) . We now report the results of a four-centre , r and omised double-blind trial of a single infusion of 1 or 10 mg/kg cA2 compared with placebo in 73 patients with active rheumatoid arthritis . The primary endpoint of the study was the achievement at week 4 of a Paulus 20 % response , an amalgam of six clinical , observational , and laboratory variables . Intention-to-treat analysis of data from individual patients showed only 2 of 24 placebo recipients responding at this time , compared with 11 of 25 patients treated with low-dose cA2 ( p = 0.0083 ) and 19 of 24 patients treated with high-dose cA2 ( p < 0.0001 ) . Over half of the high-dose cA2 patients responded by the more stringent 50 % Paulus criteria at this time ( p = 0.0005 ) . The magnitude of these responses was impressive , with maximum mean improvements in individual disease-activity assessment s , such as tender or swollen-joint counts and in serum C-reactive protein , exceeding 60 % for patients on high-dose treatment . There were two severe adverse events . 1 patient on 1 mg/kg cA2 developed pneumonia ( " possibly " treatment-related ) and 1 on 10 mg/kg had a fracture ( " probably not " treatment-related ) . The results provide the first good evidence that specific cytokine blockade can be effective in human inflammatory disease and define a new direction for the treatment of rheumatoid arthritis OBJECTIVES To test the sensitivity to change of ultrasonographic endpoints in early phase clinical trials in subjects with active rheumatoid arthritis ( RA ) . METHODS A double-blind , placebo and comparator controlled , r and omised , two-centre study investigated the effect on synovial thickness and vascularity of 28 days repeat daily oral dosing of 60 mg of the inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA . Fifty patients with DAS28 scores ≥4.0 were assigned to 3 treatment arms of 17 , 19 and 14 ( on placebo , GW274150 and prednisolone respectively ) . Synovial thickness and vascularity of all 10 metacarpophalangeal joints were assessed by ultrasonography using a semi-quantitative scale at baseline ( Day 1 ) , Day 15 and Day 28 . Vascularity was also measured quantitatively by power Doppler area . RESULTS At Day 28 , the GW274150 group showed a trend towards reduction in synovial thickness compared with placebo , with an adjusted mean decrease of 33 % ( p=0.072 ) ; the prednisolone group decreased significantly by 44 % ( p=0.011 ) . Similarly , there was a trend to reduced synovial vascularity with GW274150 by 42 % compared with placebo ( p=0.075 ) ; prednisolone result ed in a statistically significant decrease of 55 % ( p=0.012 ) . There was a 55 % decrease in power Doppler area for GW274150 , compared with placebo although the result was not statistically significant ( p=0.375 ) . Prednisolone 7.5 mg result ed in a highly statistically significant decrease of 95 % ( p=0.003 ) . CONCLUSIONS This study advocates the use of ultrasonographic measures of metacarpophalangeal joint synovitis as an endpoint for clinical studies assessing therapeutic potential of new compounds in small patient cohorts over 28 days OBJECTIVE To evaluate the clinical response to and safety of single and repeat doses of a chimeric anti-CD4 monoclonal antibody , cM-T412 , in patients with rheumatoid arthritis ( RA ) concomitantly treated with a stable regimen of low-dose methotrexate . METHODS Sixty-four patients with refractory RA , who were already receiving stable doses of methotrexate , were r and omized into a multicenter , double-blind , placebo-controlled trial to receive 3 monthly treatments with either a placebo , or 5 , 10 , or 50 mg cM-T412 , given intravenously . RESULTS Using > or = 50 % improvement in swollen joint counts as a criterion for clinical response , 13 % , 13 % , 18 % , and 13 % of patients receiving 50 , 10 , or 5 mg cM-T412 , or the placebo , respectively , exhibited a clinical response at 3 months of therapy . Using > or = 50 % improvement in tender joint counts as a measure of clinical efficacy at 3 months , 19 % , 13 % , 12 % , and 6 % of patients receiving 50 , 10 , or 5 mg cM-T412 , or the placebo , respectively , exhibited a clinical response . " Flu-like " symptoms ( fever , chills , rigor ) within 24 hours of the infusion occurred more frequently in the groups receiving 50-mg ( 29 % ) and 10-mg ( 31 % ) doses of cM-T412 than those receiving 5 mg cM-T412 ( 12 % ) or the placebo ( 13 % ) . Significant CD4 + T cell depletion occurred in the 50-mg group ( mean of 353 CD4 + T cells/mm3 at 6 months versus 856 CD4 + T cells/mm3 at baseline ) . All patients were followed up for 12 months after the final treatment ; no opportunistic infectious complications occurred . CONCLUSION Treatment with cM-T412 in this cohort of RA patients who were also taking methotrexate was not associated with clinical efficacy or enhanced toxicity from infectious complications , despite significant peripheral CD4 + T cell depletion OBJECTIVE To assess the safety and efficacy of abatacept , a selective T cell costimulation modulator , in patients with psoriatic arthritis ( PsA ) . METHODS In this 6-month , multicenter , r and omized , double-blind , placebo-controlled , phase II study , 170 PsA patients with a psoriasis target lesion ( TL ) ≥2 cm who had previously taken disease-modifying antirheumatic drugs ( DMARDs ) , including anti-tumor necrosis factor ( anti-TNF ) agents , were r and omized ( 1:1:1:1 ) to receive placebo or abatacept at doses of 3 mg/kg , 10 mg/kg , or 30/10 mg/kg ( 2 initial doses of 30 mg/kg , followed by 10 mg/kg ) on days 1 , 15 , and 29 and then once every 28 days thereafter . The primary end point was the American College of Rheumatology 20 % criteria for improvement ( ACR20 response ) on day 169 . Other key end points were magnetic resonance imaging ( MRI ) scores for joint erosion , osteitis , and synovitis , scores on the Health Assessment Question naire ( HAQ ) and the Short Form-36 ( SF-36 ) health survey , the investigator 's global assessment of psoriasis , the TL score , and the Psoriasis Area and Severity Index ( PASI ) score . RESULTS Proportions of patients achieving an ACR20 response were 19 % , 33 % , 48 % , and 42 % in the placebo , the abatacept 3 mg/kg , the abatacept 10 mg/kg , and the abatacept 30/10 mg/kg groups , respectively . Compared with placebo , improvements were significantly higher for the abatacept 10 mg/kg ( P = 0.006 ) and 30/10 mg/kg ( P = 0.022 ) groups , but not for 3 mg/kg group ( P = 0.121 ) . All abatacept regimens result ed in improved MRI , HAQ , and SF-36 scores , with 10 mg/kg showing the greatest improvements . Improvements in the TL and PASI scores were observed in all abatacept arms ; a response according to the investigator 's global assessment was seen only with 3 mg/kg of abatacept . The safety profiles were similar among the treatment arms . CONCLUSION The results of this study suggest that 10 mg/kg of abatacept , the approved dosage for rheumatoid arthritis and juvenile idiopathic arthritis , may be an effective treatment option for OBJECTIVE To compare the efficacy , safety , and tolerability of 5 doses of oral tofacitinib ( CP-690,550 ) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis ( RA ) in patients with an inadequate response to disease-modifying antirheumatic drugs . METHODS In this 24-week , double-blind , phase IIb study , patients with RA ( n = 384 ) were r and omized to receive placebo , tofacitinib at 1 , 3 , 5 , 10 , or 15 mg administered orally twice a day , or adalimumab at 40 mg injected subcutaneously every 2 weeks ( total of 6 injections ) followed by oral tofacitinib at 5 mg twice a day for 12 weeks . The primary end point was the responder rate according to the American College of Rheumatology 20 % improvement criteria ( ACR20 ) at week 12 . RESULTS Treatment with tofacitinib at a dose of ≥3 mg twice a day result ed in a rapid response with significant efficacy when compared to placebo , as indicated by the primary end point ( ACR20 response at week 12 ) , achieved in 39.2 % ( 3 mg ; P ≤ 0.05 ) , 59.2 % ( 5 mg ; P < 0.0001 ) , 70.5 % ( 10 mg ; P < 0.0001 ) , and 71.9 % ( 15 mg ; P < 0.0001 ) in the tofacitinib group and 35.9 % of patients in the adalimumab group ( P = 0.105 ) , compared with 22.0 % of patients receiving placebo . Improvements were sustained at week 24 , according to the ACR20 , ACR50 , and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints ( DAS28 ) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate . The most common treatment-emergent adverse events ( AEs ) in patients across all tofacitinib treatment arms ( n = 272 ) were urinary tract infection ( 7.7 % ) , diarrhea ( 4.8 % ) , headache ( 4.8 % ) , and bronchitis ( 4.8 % ) . CONCLUSION Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile BACKGROUND In a phase II study , etanercept ( recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein ) safely produced rapid , dose-dependent improvement in rheumatoid arthritis over 3 months . OBJECTIVE To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis . DESIGN R and omized , double-blind , placebo-controlled trial with blinded joint assessors . SETTING 13 North American centers . PATIENTS 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs . INTERVENTION Twice-weekly subcutaneous injections of etanercept , 10 or 25 mg , or placebo for 6 months . MEASUREMENTS The primary end points were 20 % and 50 % improvement in disease activity according to American College of Rheumatology ( ACR ) responses at 3 and 6 months . Other end points were 70 % ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months . RESULTS Etanercept significantly reduced disease activity in a dose-related fashion . At 3 months , 62 % of the patients receiving 25 mg of etanercept and 23 % of the placebo recipients achieved 20 % ACR response ( P < 0.001 ) . At 6 months , 59 % of the 25-mg group and 11 % of the placebo group achieved a 20 % ACR response ( P < 0.001 ) ; 40 % and 5 % , respectively , achieved a 50 % ACR response ( P < 0.01 ) . The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56 % and 47 % in the 25-mg group and 6 % and -7 % in the placebo group ( P < 0.05 ) . Significantly more etanercept recipients achieved a 70 % ACR response , minimal disease status ( 0 to 5 affected joints ) , and improved quality of life . Etanercept was well tolerated , with no dose-limiting toxic effects . CONCLUSIONS Etanercept can safely provide rapid , significant , and sustained benefit in patients with active rheumatoid arthritis Background Interleukin 6 ( IL-6 ) plays a key role in the inflammatory cascade in rheumatoid arthritis . BMS945429 is a humanised , monoclonal antibody that potently binds IL-6 . Objective To conduct aphase II study to determine the efficacy and safety of BMS945429 in patients with active rheumatoid arthritis and an inadequate response to methotrexate . Methods Patients were r and omised 1:1:1:1 to BMS945429 ( 80 , 160 or 320 mg ; administered intravenously ) or placebo plus methotrexate during this 16-week , double-blind trial . The primary efficacy end point was the proportion of patients with a 20 % improvement in American College of Rheumatology responses ( ACR20 ) at week 12 . Additional end points included ACR50 and ACR70 responses and 28-joint Disease Activity Scores ( DAS28 ) . Results Of 127 r and omised and treated patients , 116 completed the trial . ACR20 responders at week 12 were 81 % ( 80 mg ; p<0.0001 vs placebo ) , 71 % ( 160 mg ; p=0.0005 vs placebo ) , 82 % ( 320 mg ; p<0.0001 vs placebo ) and 27 % ( placebo ) , respectively . By week 16 , 14 % ( 80 mg ) , 28 % ( 160 mg ) and 44 % ( 320 mg ) of BMS945429 patients were in DAS28 remission ( DAS28 score < 2.6 ) . Statistically significant and clinical ly meaningful improvements in health-related quality of life ( HRQoL ) were reported in all active treatment groups . Administration of BMS945429 was associated with increases in liver enzymes and in serum cholesterol . There were no serious infections , infusion reactions or apparent immunogenicity . Conclusions In this phase II study , BMS945429 was associated with rapid and significant improvements in disease activity and HRQoL in patients with active rheumatoid arthritis and an inadequate response to methotrexate OBJECTIVE To compare the efficacy , safety , and tolerability of 6 dosages of oral tofacitinib ( CP-690,550 ) with placebo for the treatment of active rheumatoid arthritis ( RA ) in patients receiving a stable background regimen of methotrexate ( MTX ) who have an inadequate response to MTX monotherapy . METHODS In this 24-week , double-blind , phase IIb study , patients with active RA ( n = 507 ) were r and omized to receive placebo or tofacitinib ( 20 mg/day , 1 mg twice daily , 3 mg twice daily , 5 mg twice daily , 10 mg twice daily , or 15 mg twice daily ) . All patients continued to receive a stable dosage of MTX . The primary end point was the American College of Rheumatology 20 % improvement criteria ( ACR20 ) response rate at week 12 . RESULTS At week 12 , ACR20 response rates for patients receiving all tofacitinib dosages ≥3 mg twice daily ( 52.9 % for 3 mg twice daily , 50.7 % for 5 mg twice daily , 58.1 % for 10 mg twice daily , 56.0 % for 15 mg twice daily , and 53.8 % for 20 mg/day ) were significantly ( P ≤ 0.05 ) greater than those for placebo ( 33.3 % ) . Improvements were sustained at week 24 for the ACR20 , ACR50 , and ACR70 responses , scores for the Health Assessment Question naire disability index , the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level ( DAS28-CRP ) , and a 3-variable DAS28-CRP of < 2.6 . The most common treatment-emergent adverse events occurring in > 10 % of patients in any tofacitinib group were diarrhea , upper respiratory tract infection , and headache ; 21 patients ( 4.1 % ) experienced serious adverse events . Sporadic increases in transaminase levels , increases in cholesterol and serum creatinine levels , and decreases in neutrophil and hemoglobin levels were observed . CONCLUSION In patients with active RA in whom the response to MTX has been inadequate , the addition of tofacitinib at a dosage ≥3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks With the increasing pace of drug development , it is not unusual for several promising treatment regimens to be ready simultaneously for testing in a r and omized phase III setting . Various limiting factors , including the time needed to transfer research results to clinical practice and a narrow ' window of opportunity ' , may make it unfeasible to perform trials to test such regimens sequentially against a control treatment in a traditional two-arm parallel group design . We present an approach to trial design based on eliminating inferior contenders at an early stage , allowing through to a second stage only treatments that show a predefined degree of advantage against a control treatment . The first stage of testing utilizes a marker known to be a valid intermediate outcome measure or surrogate for the definitive outcome . The experimental arms are compared pairwise with control according to this intermediate outcome measure . Arms that survive the comparison enter a second stage of patient accrual culminating in comparisons against control on the outcome measure of primary interest . We show how the design may be realized in practice by considering hypothetically distinct trials at stages 1 and 2 , each with their own operating characteristics . The overall operating characteristics are computed from the stage 1 and 2 size and power and the correlation between the treatment effects on the intermediate and primary outcome measures according to a bivariate Normal approximation . The correlation is estimated by bootstrapping individual patient data from previous trials . We illustrate the general approach in a design of a real trial of four new chemotherapy regimens for advanced ovarian cancer . The intermediate outcome measure is progression-free survival . An international r and omized controlled trial using the new design is already under way OBJECTIVE Treatment of autoimmune diseases with therapies that tolerize pathogenic lymphocytes may obviate the need for longterm global immunosuppression . In vitro , non-Fc receptor binding derivatives of anti-murine CD3 monoclonal antibodies tolerize type 1 T cells and stimulate type 2 T cells . Recently , a humanized non-FcR binding derivative of the anti-human CD3 Mab OKT3 , huOKT3gamma1(ala-ala ) , has been described . We hypothesized that this Mab may be safe and efficacious in the treatment of type 1 T lymphocyte mediated chronic autoimmune diseases such as psoriatic arthritis ( PsA ) . METHODS In a Phase I/II trial , 7 patients with PsA were treated with escalating daily doses of huOKT3gamma1(ala-ala ) for 12 to 14 days . Number of tender and swollen joints and a visual analog pain scale were used to rate disease activity at entry and Day 30 and Day 90 after treatment . RESULTS At Day 30 , 6 of 7 patients had > or = 75 % improvement in the number of inflamed joints and an average 63 % improvement on the patient pain scale . Two of 6 responders had sustained improvement at Day 90 . No patient treated with an initial dose < or = 1 mg had significant side effects , nor did they have detectable increases in serum cytokines . One patient treated with 4 mg without escalation developed mild cytokine release symptoms associated with elevation of interleukin 10 . Transient T cell depletion occurred following treatment with the maximum dose of 4 mg , which resolved by Day 30 . Antiidiotypic antibodies developed in 2 patients ; however , there was no concurrent decrease in efficacy . CONCLUSION These data indicate that huOKT3gamma1(ala-ala ) may be useful in treating BACKGROUND The pharmacokinetics of golimumab , a human monoclonal antibody that inhibits the activity of tumor necrosis factor α , after a single subcutaneous ( SC ) or intravenous ( IV ) administration have been previously studied . OBJECTIVES The purpose of this study was to assess the pharmacokinetics of golimumab after multiple SC or IV administrations in patients with active rheumatoid arthritis ( RA ) . The effect of concomitant methotrexate ( MTX ) use on golimumab pharmacokinetics was evaluated . METHODS In this open-label , r and omized , Phase I study , 49 adult patients with RA received SC golimumab 100 mg ( n = 33 ) every 4 weeks through week 20 or IV golimumab 2 mg/kg ( n = 16 ) at weeks 0 and 12 . Serial blood sample s were collected , and serum golimumab concentration was measured with an electrochemiluminescent immunoassay . Golimumab pharmacokinetic parameters were derived with the use of a noncompartmental analysis . Adverse events were monitored at every visit . RESULTS The population was predominantly Caucasian ( 84 % ) and female ( 76 % ) , and the median age was 57 years . After SC golimumab administration , the serum golimumab concentration achieved steady state by ∼12 weeks with mean trough serum concentrations ranging from 1.15 to 1.24 μg/mL. After the final 30-minute IV infusion of golimumab 2 mg/kg , the mean ( SD ) clearance ( CL ) was 7.5 ( 2.6 ) mL/d/kg . The mean terminal half-life after SC and IV administrations was ∼13 days . The mean absolute bioavailability for SC golimumab was estimated to be 53 % . The geometric mean of golimumab CL/F in patients with and without concomitant MTX use was 13.9 and 21.2 mL/d/kg , respectively , and the geometric mean ratio of CL/F was 65.5 % ( 90 % CI : 45.2%-94.9 % , P = 0.06 ) . Golimumab was generally well tolerated . No malignancies or deaths occurred during the study . CONCLUSIONS Pharmacokinetics of golimumab were consistent after SC or IV administration in this population of patients with RA . Golimumab was well tolerated and no unexpected adverse events were observed in this trial The purpose of this phase II clinical trial was to examine safety of elk velvet antler taken concurrently with rheumatoid arthritis medications and to determine efficacy by dose to enable sample size estimation and dose st and ardization for a larger study . Forty patients with stage II rheumatoid arthritis were r and omly assigned to 1 of 4 arms of 10 patients each . One group received placebo and the other 3 groups received 2 , 4 , or 6 capsules ( 215 mg ) of elk velvet antler with appropriate placebos to total 6 capsules daily . All subjects continued to take their arthritis medications . Outcome variables were reported adverse events and health status . At 1 month , there were no significant differences between groups in number of adverse events or health status . The greatest improvement was in the 6 elk velvet antler group , the least was in the placebo group . Differences were not statistically significant . It was concluded that elk velvet antler can be taken safely in conjunction with a number of rheumatoid arthritis medications and should be studied further to assess efficacy OBJECTIVE The goal of this single infusion , dose escalation study was to evaluate the safety of the PRIMATIZED anti-CD4 monoclonal antibody ( Mab ) , IDEC-CE9.1 , in patients with rheumatoid arthritis ( RA ) . METHODS Twenty-five patients received single infusions of IDEC-CE9.1 in dose escalation form ( 0.03 to 4 mg/kg ) . Cohorts consisted of 3 patients each with seropositive RA . Following treatment , patients were monitored for 2 weeks before initiation of treatment of the next cohort . Peripheral blood sample s were taken during and after treatment to measure immune function . Flow cytometry of peripheral blood mononuclear cells and in vitro proliferative responses to antigens and recall antigens were assessed pre and post-treatment . Cell surface markers CD3 , CD4 ( OKT4 and Leu 3a ) , CD8 , CD20 , CD25 , CD45Ro , CD45Ra and DR were analyzed , and proliferation to mitogens and recall antigens was measured . RESULTS No infusion related adverse events were noted and other drug related adverse events were mild . Reduction in peripheral CD4 T cell number was brief ( 3 to 7 days ) and not associated with infection . CD4 cell surface antigen downmodulation was observed postinfusion . Suppression of CD25 expression was associated with a positive clinical response . In vitro proliferative responses to mitogens and antigen were inhibited for up to one month with no association to positive clinical response . CONCLUSION IDEC-CE9.1 appears to have a benign safety profile and may modulate immune function rather than deplete CD4 + T cells OBJECTIVE This pilot phase II , double-blind , placebo-controlled trial of 1 month duration , with a 2 - 3-month open-label extension , evaluated the safety , tolerability , biologic effects , and efficacy of interleukin-2 diphtheria fusion protein ( DAB486IL-2 ) in refractory rheumatoid arthritis ( RA ) . METHODS Forty-five RA patients were enrolled in the trial , and were r and omized , after a 3 - 4-week disease-modifying antirheumatic drug washout , to receive a daily intravenous dose of either DAB486IL-2 or placebo ( saline ) for 5 days . A blinded , third-party observer evaluated arthritis activity . Clinical response was defined as > or = 25 % improvement in swollen and tender joints and > or = 25 % improvement in at least 2 of 6 additional parameters . The double-blind phase was 4 weeks ; placebo patients could cross over to receive open-label treatment for a maximum of 3 monthly DAB486IL-2 cycles . RESULTS In the double-blind phase , 4 of 22 patients ( 18 % ) in the treated group and none in the placebo group ( P = 0.05 ) met the criteria for clinical response . During the open-label treatment phase , 11 of 36 patients ( 31 % ) and 11 of 33 patients ( 33 % ) had a clinical response after completing 2 and 3 courses of DAB486IL-2 , respectively . Adverse events included transient fever/chills ( 45 % ) , nausea/vomiting ( 50 % ) , elevated ( < or = 3 x normal ) transaminases ( 55 % ) , and increased joint pain ( 45 % ) . Twelve patients ( 8 placebo , 4 DAB486IL-2 ) did not complete 3 treatment cycles . No apparent differences were noted in CD4 + CD25 + cells of responders versus nonresponders , or of DAB486IL-2-treated versus placebo-treated patients . CONCLUSION Clinical responses were noted in patients treated with DAB486IL-2 ( 18 % ) compared with placebo ( 0 % ) in the double-blind phase . In the open-label phase , 33 % of patients completing 3 monthly DAB486IL-2 cycles had improvement in arthritis activity . Further studies of IL-2 diphtheria fusion proteins are warranted to eluci date factors that may predict clinical response and define mechanism(s ) of action OBJECTIVE Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation-inducing lig and . The purpose of this study was to investigate the tolerability , pharmacokinetics , and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis ( RA ) and to collect exploratory data on clinical outcomes . METHODS In this multicenter , phase Ib , r and omized , placebo-controlled , dose-escalating trial , 73 patients were enrolled into 6 escalating-dose cohorts . Patients received atacicept or placebo as single doses ( 70 , 210 , or 630 mg ) or as repeated doses given at 2-week intervals ( 3 doses of 70 mg , 3 doses of 210 mg , or 7 doses of 420 mg ) , followed by 10 weeks of trial assessment s , with a followup assessment at 3 months after the final dose . RESULTS Atacicept was well tolerated , with few differences between treatment groups and no obvious safety concerns . The pharmacokinetics profile was nonlinear , but was consistent and predictable across all doses and regimens . Treatment-related decreases in immunoglobulin ( particularly IgM ) and rheumatoid factor levels were evident , and a clear decrease in anti-citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg . The B cell response was biphasic , with an initial transient increase ( dominated by memory B cells ) followed by a dose-related decrease ( dominated by mature B cells ) . Clinical assessment s showed trends toward improvement with the 3-month treatment . Little effect on the erythrocyte sedimentation rate or C-reactive protein levels was seen . CONCLUSION Atacicept was well tolerated both systemically and locally . The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action OBJECTIVE To assess the efficacy , safety , and biologic activity of atacicept in tumor necrosis factor antagonist-naive patients with rheumatoid arthritis ( RA ) in whom the response to methotrexate treatment was inadequate . METHODS In this phase II study , patients with active RA ( n = 311 ) were r and omized 1:1:1:1 to receive placebo , atacicept 150 mg weekly with or without a 4-week loading period ( twice-weekly dosing ) , or open-label adalimumab 40 mg every other week , for 25 weeks . The primary end point was 20 % improvement in disease severity according to the American College of Rheumatology criteria , assessed using the C-reactive protein level ( ACR20-CRP ) , at week 26 . Secondary end points included additional assessment s of efficacy , biologic activity , and safety . RESULTS The proportion of patients meeting the primary end point ( ACR20-CRP response ) did not differ significantly in the atacicept groups and the placebo group ( 46 % in the placebo group , 45 % in the atacicept loading group , and 58 % in the atacicept nonloading group ) . In contrast , an ACR20-CRP response was observed in 71 % of patients in the adalimumab group ( P < 0.001 versus placebo ) . ACR50-CRP response rates were significantly higher in all active-treatment groups compared with placebo , but ACR70-CRP response rates were superior only in the adalimumab group . Atacicept treatment reduced the levels of serum IgG , IgA , and IgM rheumatoid factor and the levels of circulating mature B cells and plasma cells . The effects of treatment were similar with and without loading . Immunoglobulin levels returned toward baseline values during the treatment-free followup period ( week 38 ) . The most frequent adverse events associated with atacicept represented common illnesses . No serious infections occurred among patients treated with atacicept . CONCLUSION The primary end point ( ACR20-CRP response ) was not met despite significant biologic effects of atacicept that were consistent with its proposed mechanism of action . Modest effects of atacicept were seen for some secondary efficacy end points . Treatment with atacicept raised no new safety concerns We describe a dose escalation procedure for a combined phase I/II clinical trial . The procedure is based on a Bayesian model for the joint distribution of the occurrence of a dose limiting event and of some indicator of efficacy ( both considered binary variables ) , making no assumptions other than monotonicity . Thus , the chances of each outcome are assumed to be non-decreasing in dose level . We applied the procedure to the design of a placebo-controlled , sequential trial in rheumatoid arthritis , in each stage of which patients were r and omized between placebo and all dose levels that currently appeared safe and non-futile . On the basis of data from a pilot study , we constructed five different scenarios for the dose-response relationships under which we simulated the trial and assessed the performance of the procedure . The new design appears to have satisfactory operating characteristics and can be adapted to the requirements of a range of trial situations OBJECTIVE Multiple lines of evidence suggest that sex hormones may play a role in the pathogenesis or clinical expression of rheumatoid arthritis ( RA ) . Studies on the effects of exogenous estrogens in RA patients have yielded contradictory results . We undertook this study to determine the effects of the selective estrogen receptor alpha ( ERalpha ) agonist Org 37663 in patients with RA , in terms of both its estrogenic effects and its ability to ameliorate disease activity . METHODS A 10-week , multicenter , r and omized , double-blind , placebo-controlled , parallel group , dose-finding , proof-of-concept trial was initiated to obtain data on the efficacy and safety of Org 37663 in postmenopausal female patients with RA who were receiving background treatment with either methotrexate or sulfasalazine . Patients were r and omized to receive placebo or Org 37663 at doses of 4 mg/day , 15 mg/day , or 50 mg/week . The primary efficacy variable was the Disease Activity Score in 28 joints ( DAS28 ) . RESULTS Org 37663 induced a clear biologic , estrogenic response in several organ systems , including a dose-related increase in levels of sex hormone binding globulin . However , the DAS28 decreased similarly for all treatment groups including placebo , indicating lack of clinical efficacy of Org 37663 in this trial . CONCLUSION The observed lack of clinical benefit in RA patients treated with an ERalpha agonist , in association with a clear biologic response to the study drug , provides evidence that a biologically relevant ERalpha-mediated estrogenic effect is not associated with a clinical ly relevant effect on RA symptoms and signs OBJECTIVE Biological products that neutralize tumour necrosis factor alpha ( TNF-alpha ) are beneficial in rheumatoid arthritis ( RA ) . We studied the effects of CDP870 , a novel anti-TNF-alpha antibody fragment modified to obtain a prolonged plasma half-life ( approximately 14 days ) . METHODS Thirty-six patients were r and omized in a double-blind , ascending-dose group study to a single intravenous infusion of placebo ( n = 12 ) or 1 , 5 or 20 mg/kg CDP870 ( each n = 8) . The patients were predominantly female ( 30/36 ) , had a mean age of 56 yr and a mean duration of RA of 13 years . They had received a mean of five DMARDs or experimental therapies ( with 1 month washout before the study started ) and had active disease . Continuation of NSAIDs and up to 7.5 mg prednisolone daily was allowed . Following the blinded dosing period , 32 patients received a single open-label infusion of either 5 or 20 mg/kg CDP870 . RESULTS In the blinded dosing period , 6/12 placebo patients withdrew from the study ( for deteriorating RA < or = 4 weeks after dosing ) . Two of 24 CDP870-treated patients withdrew , both in the 1 mg/kg group ( for deteriorating RA or lost to follow up > 4 weeks after dosing ) . The proportion of patients with ACR20 improvement for the per- protocol population with the last observation carried forward was 16.7 , 50 , 87.5 and 62.5 % after 0 , 1 , 5 and 20 mg/kg CDP870 respectively ( combined treatment effect , P = 0.012 , primary analysis ) at 4 weeks and 16.7 , 25 , 75 and 75 % ( P = 0.032 ) at 8 weeks . The proportion of patients with ACR50 improvement for the per- protocol population with the last observation carried forward was 0 , 12.5 , 12.5 and 50 % after 0 , 1 , 5 and 20 mg/kg CDP870 respectively ( combined treatment effect , P = 0.079 ) at 4 weeks and 0 , 12.5 , 12.5 and 50 % ( P = 0.079 ) at 8 weeks . Following the open-label dose of CDP870 , similar beneficial effects were achieved . CONCLUSION CDP870 is effective , was very well tolerated in this small study , and has an extended duration of action following one or more intravenous doses OBJECTIVE To evaluate the effects of the anti-TNF-α monoclonal antibody golimumab , administered by s.c . injection or i.v . infusion , on markers of inflammation in patients with RA . METHODS In this phase 1 , open-label study , patients with active RA were r and omized to receive s.c . golimumab 100 mg at baseline and every 4 weeks through week 20 ( n = 33 ; group 1 ) or i.v . golimumab 2 mg/kg at baseline and week 12 ( n = 16 ; group 2 ) . Serum levels of CRP , IL-6 , serum amyloid A ( SAA ) , TNF receptor II ( TNFRII ) , MMP-3 , hyaluronic acid , haptoglobin , ferritin and haemoglobin and serum/urine hepcidin were measured at various time points . Associations between the biomarkers were assessed with Spearman 's correlations . RESULTS In both groups 1 and 2 , decreases in mean serum levels of CRP , IL-6 , SAA , TNFRII , MMP-3 , haptoglobin , ferritin and hepcidin , and mean urine levels of hepcidin occurred within 1 week and were sustained through week 8 . Decreases in concentrations of serum CRP , IL-6 , SAA , MMP-3 , hepcidin , ferritin and haptoglobin and urine hepcidin were maintained through week 24 in group 1 , but began to reverse after week 8 in group 2 . Among all patients , decreases in serum hepcidin correlated significantly with decreases in serum CRP and ferritin . CONCLUSION Decreases in serum and urine concentrations of markers of inflammation occurred as early as 24 h after treatment with golimumab , and most of these improvements were sustained through week 24 in group 1 OBJECTIVE To evaluate the efficacy and safety of leflunomide in comparison with methotrexate ( MTX ) on patients with rheumatoid arthritis ( RA ) in China . METHODS Five hundred and sixty-six patients with active rheumatoid arthritis were r and omly assigned to receive leflunomide at 20 mg once daily or MTX at 15 mg once weekly in a controlled trial . Five hundred and four patients completed the 12-week treatment and some patients continued the treatment for 24 weeks . RESULTS Both leflunomide and MTX could improve the symptoms , signs , and joint function , but there were no changes in X-ray observations of patients with rheumatoid arthritis . In the leflunomide group , the overall rates of effectiveness at 12 weeks and 24 weeks were 86.94 % and 92.31 % respectively ; the rates of remarkable improvement were 64.95 % and 79.81 % respectively . In the MTX group , the overall rates of effectiveness at 12 weeks and 24 weeks were 84.04 % and 83.15 % respectively ; the rates of remarkable improvement were 56.81 % and 75.28 % respectively . According to intent-to-treat analysis , the ACR 20 % response rates at 12 weeks and 24 weeks in the leflunomide group were 62.54 % and 67.18 % respectively , compared with 60.08 % and 61.32 % respectively in MTX group . No statistical differences were shown in the efficacy between the two groups ( P > 0.05 ) . The adverse events in the leflunomide group were gastrointestinal symptoms , skin rash , alopecia , nervous system symptoms , decreased leukocyte count , and elevation of alanine aminotransferase ( ALT ) . Most of these side effects were mild and transient . The incidence of adverse events in the leflunomide group was 16.84 % , significantly lower than that in MTX group ( 28.17 % , P = 0.002 ) . CONCLUSIONS Leflunomide is effective in the treatment of RA with less adverse events than MTX . Its efficacy is similar to MTX , but the incidence of adverse events and the rate of withdrawal due to adverse events were lower in the leflunomide group than in MTX group OBJECTIVE To investigate the safety and efficacy of MRA , a recombinant human anti-interleukin-6 ( anti-IL-6 ) receptor monoclonal antibody of the IgG1 subclass that inhibits the function of IL-6 , in patients with established rheumatoid arthritis ( RA ) . METHODS A r and omized , double-blind , placebo-controlled , dose-escalation trial was conducted in 45 patients with active RA , as defined by the American College of Rheumatology ( ACR ) revised criteria . Patients were sequentially allocated to receive a single intravenous dose of either 0.1 , 1 , 5 , or 10 mg/kg of MRA or placebo . The primary efficacy end point was meeting the ACR 20 % response criteria at week 2 after treatment . RESULTS Demographic features were similar between treatment groups . At week 2 , a significant treatment difference was observed between the 5 mg/kg of MRA and placebo , with 5 patients ( 55.6 % ) in the MRA cohort and none in the placebo cohort achieving ACR 20 % improvement . There was no statistically significant difference in the ACR 20 % response between the other 3 MRA cohorts and placebo at week 2 . The mean disease activity score at week 2 in those who received 5 mg/kg and 10 mg/kg of MRA was 4.8 and 4.7 ( P < 0.001 and P < 0.001 by analysis of variance ) , respectively . These mean scores were statistically significantly lower than those in the 0.1- and 1-mg/kg MRA and the placebo cohorts ( 6.4 , 6.2 , and 7.0 , respectively ) . The erythrocyte sedimentation rate and C-reactive protein values fell significantly in the 5- and 10-mg/kg MRA cohorts and normalized 2 weeks after treatment . Seventeen patients ( 5 , 4 , 6 , 2 , and 0 patients in the placebo , 0.1- , 1- , 5- , and 10-mg/kg MRA cohorts , respectively ) required corticosteroid or disease-modifying antirheumatic drug treatment because of active disease before study end . They were regarded as nonresponders from the time they received these treatments . Diarrhea was the most common adverse event , occurring in 8 % of patients . Seven patients ( 15.6 % ) reported a severe adverse event ( 3 , 1 , 2 , and 2 patients in the placebo , 0.1- , 1- , and 10-mg/kg MRA cohorts ) . There were no serious adverse events that were thought to be related to the study drug . CONCLUSION This is the first r and omized controlled trial showing that inhibition of IL-6 significantly improved the signs and symptoms of RA and normalized the acute-phase reactants . Further research with multiple dosing is necessary to define the most appropriate therapeutic regimen of MRA in RA OBJECTIVE To assess the pharmacokinetics , safety profile , and efficacy of the fully human anti-tumor necrosis factor-alpha ( anti-TNF-alpha ) monoclonal antibody adalimumab ( D2E7 ) in patients with long-st and ing , active rheumatoid arthritis ( RA ) . METHODS This was a r and omized , double blind , placebo controlled study of single intravenous injections of ascending doses ( 0.5 to 10 mg/kg ) of adalimumab in 5 cohorts of 24 patients each ( 18 adalimumab and 6 placebo in all cohorts except the 0.5 mg/kg cohort of 17 adalimumab , 7 placebo ) . A total of 120 patients participated ( adalimumab 89 , placebo 31 ) . The clinical response was measured by changes in composite scores defined by the criteria of the European League Against Rheumatism ( EULAR ) and the American College of Rheumatology . RESULTS Single doses of adalimumab showed a rapid onset of clinical effect ( 24 hours to 1 week ) , with peak efficacy at 1 to 2 weeks that was sustained for at least 4 weeks and for as long as 3 months in some patients . EULAR response was seen at least once during the 4 week period after drug injection in 29 % of patients in the placebo group as well as in 41 % , 78 % , 72 % , 89 % , and 100 % in the 0.5 , 1 , 3 , 5 , and 10 mg/kg groups , respectively . No dose related increases in adverse events were observed in the adalimumab patients compared with the placebo group . Adalimumab systemic drug exposure ( AUC0- ( ) ) increased linearly with an increase in dose . The mean total serum clearance was 0.012 to 0.017 l/h , and the steady-state volume of distribution ranged from 4.7 to 5.5 l. The estimated mean terminal half-life ranged from 10.0 to 13.6 days for the 5 cohorts , with an overall mean half-life of 12 days . CONCLUSION Treatment with the fully human Mab adalimumab was safe and well tolerated when administered as a single intravenous injection at doses up to 10 mg/kg , and was associated with a clinical ly significant improvement in the signs and symptoms of active RA Abstract Objective : To use data from a phase II clinical trial to evaluate the effect of ustekinumab , a human immunoglobulin monoclonal antibody that binds with high affinity to the shared p40 subunit of human interleukins-12 and -23 , on physical disability and health-related quality of life ( HRQoL ) in patients with psoriatic arthritis ( PsA ) . Methods : In this multicenter , double-blind , placebo-controlled , crossover study of ustekinumab , patients with active PsA were r and omized ( 1:1 ratio ) to receive either ustekinumab at weeks 0 , 1 , 2 , and 3 and placebo at weeks 12 and 16 ( n = 76 ) or placebo at weeks 0 , 1 , 2 , and 3 and ustekinumab at weeks 12 and 16 ( n = 70 ) . Physical function was assessed using the disability index from the Health Assessment Question naire-Disability Index ( HAQ-DI ) in all r and omized patients . HRQoL was evaluated using the Dermatology Life Quality Index ( DLQI ) in a subset of patients ( 84.9 % ) with at least 3 % body surface area ( BSA ) psoriasis involvement at baseline . Results : At baseline , overall mean HAQ-DI and DLQI scores were 0.9 and 11.5 , respectively , indicating impaired physical function and moderate effect on HRQoL. At week 12 , ustekinumab patients had significantly more improvement ( decrease ) in the mean HAQ-DI ( −0.31 ) and DLQI ( −8.6 ) scores versus placebo ( −0.04 and −0.8 , respectively ; p < 0.001 for both comparisons ) . At week 12 , 58.7 % ( 37/63 ) of ustekinumab-treated patients had a DLQI score of 0 or 1 ( no negative effect of disease or treatment on HRQoL ) versus 5.5 % ( 3/55 ) for placebo ( p < 0.001 ) . The results also indicated a positive but weak correlation between improvement in physical function and HRQoL , pain , and skin response as well as between improvement in joint and skin responses in patients receiving ustekinumab or placebo . Potential limitations of the study include the short duration of the placebo-controlled period and the relatively small patient population . Conclusion : Ustekinumab significantly improved physical function and HRQoL in patients with PsA and psoriasis involving at least 3 % BSA OBJECTIVE To evaluate the safety and pharmacokinetics of multiple infusions of a humanized anti-interleukin-6 ( IL-6 ) receptor antibody , MRA , in patients with rheumatoid arthritis ( RA ) . METHODS In an open label trial , 15 patients with active RA were intravenously administered 3 doses ( 2 , 4 , or 8 mg/kg ) of MRA biweekly for 6 weeks , and pharmacokinetics were assessed . Patients continued on MRA treatment for 24 weeks , and were then assessed for safety and efficacy . RESULTS The treatment was well tolerated at all doses with no severe adverse event . Increased total serum cholesterol was detected as an MRA related reaction in 10/15 ( 66 % ) patients . There was no statistically significant difference in the frequency of adverse events among the 3 dose groups . There were no new observations of antinuclear antibody or anti-DNA antibody , and no anti-MRA antibody was detected . The T1/2 increased with repeated doses and as the dose increased . T1/2 after the 3rd dose of 8 mg/kg reached 241.8 + /- 71.4 h. In 12/15 ( 80 % ) patients whose serum MRA was detectable during the treatment period , objective inflammatory indicators such as C-reactive protein , erythrocyte sedimentation rate , and serum amyloid A were completely normalized at 6 weeks , although there was no statistically significant difference in efficacy among the 3 dose groups . Nine of 15 patients achieved ACR 20 at 6 weeks . At 24 weeks , 13 patients achieved ACR 20 and 5 achieved ACR 50 . CONCLUSION Repetitive treatment with MRA was safe and normalized acute phase response in patients with RA . Optimal dosing schedule was not defined in this small study , but maintenance of serum MRA concentration seemed important to achieve efficacy OBJECTIVES To evaluate the safety , immunogenicity , and biologic effects of chimeric monoclonal anti-CD4 ( cM-T412 ) in patients with refractory rheumatoid arthritis ( RA ) , and to obtain preliminary data on the clinical response to this treatment . METHODS Twenty-five patients with active refractory RA were treated with incremental doses ( 10 to 700 mg ) of cM-T412 in an open-label , escalating-dose phase I trial . RESULTS Infusion with cM-T412 was followed by an immediate , rapid decline in CD4 + T cells . The level of circulating CD4 + T cells remained depressed in most patients even at 6 months posttreatment . Following antibody infusion , proliferative responses of peripheral blood lymphocytes to mitogens and antigens were determined ; mitogen and antigen responses were decreased compared with pretreatment responses . Mitogen responses tended to return to baseline values more rapidly than did responses to antigen . Adverse events included fever ( 19 patients ) , which was associated with myalgias , malaise , and asymptomatic hypotension ; these symptoms were self-limited and appeared to correlate with transient elevations in interleukin-6 . No significant human antibody response to the cM-T412 variable region was detected ; only 2 patients developed transiently low levels of antibodies reactive with cM-T412 . Significant clinical improvement , defined as > or = 50 % decrease in tender joint counts compared with baseline , was noted in 43 % of patients at 5 weeks and 33 % at 6 months following cM-T412 infusion . CONCLUSIONS Treatment of refractory RA with cM-T412 appears to be safe and is associated with sustained decreases in circulating CD4 + T cell counts and depressed in vitro T cell responses . No significant human antichimeric antibody response was detected . Nonblinded assessment of clinical end points suggests that treatment with cM-T412 may have beneficial effects in these patients with refractory RA . A double-blind clinical trial is warranted to determine its clinical efficacy in treating RA OBJECTIVE To determine the clinical efficacy , safety , and immunogenicity of abatacept ( CTLA-4Ig ) , a selective costimulation modulator , in patients with rheumatoid arthritis ( RA ) that has remained active despite methotrexate ( MTX ) therapy . METHODS This was a 12-month , multicenter , r and omized , double-blind , placebo-controlled study . A total of 339 patients with active RA despite MTX therapy were r and omly assigned to receive 10 mg/kg abatacept ( n = 115 ) , 2 mg/kg abatacept ( n = 105 ) , or placebo ( n = 119 ) . This report focuses on the results observed at month 12 of a phase IIb trial . RESULTS A significantly greater percentage of patients treated with 10 mg/kg abatacept met the American College of Rheumatology 20 % improvement criteria ( achieved an ACR20 response ) at 1 year compared with patients who received placebo ( 62.6 % versus 36.1 % ; P < 0.001 ) . Greater percentages of patients treated with 10 mg/kg abatacept also achieved ACR50 responses ( 41.7 % versus 20.2 % ; P < 0.001 ) and ACR70 responses ( 20.9 % versus 7.6 % ; P = 0.003 ) compared with patients who received placebo . For patients treated with 10 mg/kg abatacept , there were also statistically significant and clinical ly important improvements in modified Health Assessment Question naire scores compared with patients who received placebo ( 49.6 % versus 27.7 % ; P < 0.001 ) . Abatacept at a dosage of 10 mg/kg elicited an increase in rates of remission ( Disease Activity Score in 28 joints of < 2.6 ) compared with placebo at 1 year ( 34.8 % versus 10.1 % ; P < 0.001 ) . The incidence of adverse events was comparable between the groups , and no significant formation of neutralizing antibodies was noted . CONCLUSION Abatacept was associated with significant reductions in disease activity and improvements in physical function that were maintained over the course of 12 months in patients with RA that had remained active despite MTX treatment . Abatacept was found to be well tolerated and safe over the course of 1 year . Abatacept in combination with MTX has the potential to play an important role in future RA therapy Background Autoantigen-specific immunotherapy by mucosal tolerance induction via the intranasal route is an attractive therapeutic option for the treatment of autoimmune diseases , including rheumatoid arthritis ( RA ) . Human cartilage glycoprotein-39 ( HC gp-39 ) has been identified as a potential key autoantigen in RA . Based on animal studies , intranasal administration of the autoantigen is hypothesised to induce immunological tolerance in patients with RA and to ameliorate disease activity . In a phase I/IIA clinical trial in patients with RA , intranasal application of HC gp-39 was safe and well tolerated . Objective To investigate the efficacy of intranasally administered fully human , recombinant HC gp-39 ( Org 39141 ) by a large clinical study . Methods In a 13-week multicentre , double-blind , r and omised , placebo-controlled , parallel-group , dose-finding , proof-of-concept trial , patients with RA ( disease-modifying antirheumatic drug ( DMARD ) naive or after washout of DMARD treatment ) were r and omised to receive either intranasal applications of placebo or HC gp-39 in doses of 30 , 150 , 300 or 600 µg , once a week . The primary efficacy variable was the 28 joint count Disease Activity Score ( DAS28 ) . Results During the treatment period the DAS28 decreased similarly for all treatment groups — including placebo — indicating lack of efficacy of intranasal HC gp-39 treatment in the current setting . Safety variables were similar for all study groups . Conclusion It was concluded that with the treatment protocol used ( dose levels and frequency of dosing ) , intranasal treatment with Org 39141 was safe but did not result in more clinical improvement than in placebo-treated patients |
13,772 | 30,911,373 | Mobilizations ( oscillatory technique ) probably produce an immediate and short-term , bilateral increase in skin sympathetic nerve activity ( reflected by an increase in skin conductance ) regardless of the area treated ( moderate-certainty evidence ) .
It is uncertain whether the sympathetic arousal also explains an increase in respiratory rate ( very low-certainty evidence ) .
Our evaluation of the literature suggests that spinal sustained apophyseal glides ( SNAGs ) mobilization and HVLA manipulation of the spine may have no acute effect on the studied markers of ANS activity ( very low- to low-certainty evidence ) .
ConclusionS ome types of mobilizations probably produce an immediate and short-term , statistically significant increase in skin sympathetic nerve activity when compared to a sham procedure , whereas spinal SNAGs and spinal HVLA techniques may have no acute effect on the studied markers of ANS activity .
No region-specific results were noted .
Il y a des preuves de certitude modérée que les mobilisations ( avec une technique d’oscillation ) produisent une augmentation bilatérale , immédiate et à court terme de l’activité sympathique cutanée , indépendamment de la région mobilisée .
Conclusion Certaines techniques de mobilisation articulaire produisent probablement une augmentation ( statistiquement significative ) immédiate et à court terme de l’activité sympathique cutanée comparées à une procédure placebo .
Les manipulations spinales ( HVLA ) pourraient ne pas avoir d’effet immédiat sur l’activité autonome étudiée .
Nous n’avons pas remarqué d’effet spécifique en fonction de la zone du traitement . | Background The autonomic nervous system ( ANS ) interests many chiropractors and manual therapists , because joint manipulative techniques ( JMT ) , e.g. high velocity low amplitude ( HVLA ) manipulations and mobilizations , appear to produce acute changes in ANS mediated physiology .
The complexity of this issue justifies a systematic critical literature review .
Objective To review the literature comparing the acute changes in markers of ANS activity between JMT applied on spinal or peripheral joints and a sham procedure in healthy or symptomatic subjects .
The literature suffers from several shortcomings , for which reason we strongly suggest further research .Résumé Introduction Le système nerveux autonome ( SNA ) intéresse de nombreux chiropracteurs et thérapeutes manuels car les techniques de manipulation articulaire , e.g. mobilisations ou manipulations de haute vélocité et faible amplitude ( HVLA ) semblent produire des changements immédiats de l’activité du SNA . | & NA ; • STUDY DESIGN : Controlled laboratory study . • BACKGROUND : Spinal manipulation ( SM ) can trigger a cascade of responses involving multiple systems , including the sympathetic nervous system and the endocrine system , specifically , the hypothalamic‐pituitary axis . However , no manual therapy study has investigated the neuroendocrine response to SM ( ie , sympathetic nervous system‐hypothalamic‐pituitary axis ) in the same trial . • OBJECTIVE : To determine short‐term changes in sympathetic nervous system activity , heart rate variability , and endocrine activity ( cortisol , testosterone , and testosterone‐cortisol [ T/C ] ratio ) following a thoracic SM . • METHODS : Twenty‐four healthy men aged between 18 and 45 years were r and omized into 2 groups : thoracic SM ( n = 12 ) and sham ( n = 12 ) . Outcome measures were salivary cortisol ( micrograms per deciliter ) , salivary testosterone ( picograms per milliliter ) , T/C ratio , heart rate variability , and changes in oxyhemoglobin concentration of the right calf muscle ( micromoles per liter ) . Measurements were done before and at 5 minutes , 30 minutes , and approximately 6 hours after intervention . • RESULTS : A statistically significant group‐by‐time interaction was noted for T/C ratio ( P<.05 ) and salivary cortisol ( P<.01 ) concentrations . Significant between‐group differences were noted for salivary cortisol concentration at 5 minutes ( mean difference , 0.35 ; 95 % confidence interval : 0.12 , 0.6 ; interaction : P<.01 ) and for T/C ratio at 6 hours postintervention ( mean difference , ‐0.09 ; 95 % confidence interval : ‐0.16 , ‐0.04 ; P = .02 ) . However , SM did not differentially alter oxyhemoglobin , testosterone , or heart rate variability relative to responses in the sham group . • CONCLUSION : Thoracic SM result ed in an immediate decrease in salivary cortisol concentration and reduced T/C ratio 6 hours after intervention . A pattern of immediate sympathetic excitation was also observed in the SM group . • KEY WORDS : autonomic nervous system , cortisol , spinal manipulation , sympathetic nervous system , BACKGROUND Some normotensive patients can have a spike in resting systolic blood pressure ( SBP ) in response to acute neck pain . Applying the typical dosage of mobilization may potentially result in a sympatho-excitatory response , further increasing resting SBP . Therefore , there is a need to explore other dosage regimens that could result in a decrease in SBP . OBJECTIVES To compare the blood pressure ( BP ) and heart rate ( HR ) response of pain-free , normotensive adults when receiving unilateral posterior-to-anterior mobilization ( PA ) applied to the neck versus its corresponding placebo ( PA-P ) . STUDY DESIGN Double-Blind , R and omized Clinical Trial . METHODS 44 ( 18 females ) healthy , pain-free participants ( mean age , 23.8 ± 3.04 years ) were r and omly allocated to 1 of 2 groups . Group 1 received a PA-P in which light touch was applied to the right 6th cervical vertebra . Group 2 received a PA to the same location . BP and HR were measured prior to , during , and after the application of PA or PA-P. A mixed-effect model of repeated measure analysis was used for statistical analysis . RESULTS During-intervention , the PA group had a significant reduction in SBP , while the placebo group had an increase in SBP . The change in SBP during-intervention was significantly different between the PA and the placebo group ( p-value = 0.003 ) . There were no significant between-group differences found for HR and diastolic BP ( DBP ) . The overall group-by-time interaction was statistically significant for SBP ( p-value = 0.01 ) . CONCLUSIONS When compared to placebo , the dosage of applied PA result ed in a small , short-lived drop in SBP not exceeding the minimal detectable change . Trial registered at Germanctr.de ( DRKS00005095 ) 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 Background This systematic review up date d and extended the " UK evidence report " by Bronfort et al. ( Chiropr Osteopath 18:3 , 2010 ) with respect to conditions/ interventions that received an ' inconclusive ’ or ' negative ’ evidence rating or were not covered in the report . Methods A literature search of more than 10 general medical and specialised data bases was conducted in August 2011 and up date d in March 2013 . Systematic review s , primary comparative studies and qualitative studies of patients with musculoskeletal or non-musculoskeletal conditions treated with manual therapy and reporting clinical outcomes were included . Study quality was assessed using st and ardised instruments , studies were summarised , and the results were compared against the evidence ratings of Bronfort . These were either confirmed , up date d , or new categories not assessed by Bronfort were added . Results 25,539 records were found ; 178 new and additional studies were identified , of which 72 were systematic review s , 96 were r and omised controlled trials , and 10 were non-r and omised primary studies . Most ' inconclusive ’ or ' moderate ’ evidence ratings of the UK evidence report were confirmed . Evidence ratings changed in a positive direction from inconclusive to moderate evidence ratings in only three cases ( manipulation/mobilisation [ with exercise ] for rotator cuff disorder ; spinal mobilisation for cervicogenic headache ; and mobilisation for miscellaneous headache ) . In addition , evidence was identified on a large number of non-musculoskeletal conditions not previously considered ; most of this evidence was rated as inconclusive . Conclusions Overall , there was limited high quality evidence for the effectiveness of manual therapy . Most review ed evidence was of low to moderate quality and inconsistent due to substantial method ological and clinical diversity . Areas requiring further research are highlighted Joint mobilisation to the T4 vertebra has been advocated as a treatment for T4 syndrome . To date no controlled studies have investigated the effects of thoracic spinal manual therapy ( SMT ) applied to T4 on sympathetic activity in the h and s. This study investigated whether a grade III postero-anterior rotatory joint mobilisation technique applied to the T4 vertebra at a frequency of 0.5 Hz had demonstrably greater effects than a vali date d placebo intervention on skin conductance ( SC ) in the h and s of healthy subjects . A power analysis calculation was performed and using a double blind , placebo-controlled , independent groups design , 36 healthy subjects ( 18 - 35 years ) were r and omly assigned to two groups ( placebo intervention or treatment intervention ) . A BioPac unit recorded continuous SC measures before , during and after each experimental intervention . An exit question naire was used to vali date the expectancy effects of the placebo intervention . Results demonstrated a significant difference between groups in SC in the right h and during the post-treatment rest period ( F = 4.888 , p = 0.034 ) ; with the treatment intervention being sympathoexcitatory in nature . A trend towards a significant difference between groups was also demonstrated in the left h and during the rest period ( F = 4.072 , p = 0.052 ) . This study provides preliminary evidence that joint mobilisation applied to the T4 vertebra at a frequency of 0.5 Hz can produce sympathoexcitatory effects in the h and . Further research is recommended in a patient population Blinding refers to the concealment of group allocation from one or more individuals involved in a clinical research study , most commonly a r and omized controlled trial ( RCT ) . Although r and omization minimizes differences between treatment groups at the outset of the trial , it does nothing to prevent differential treatment of the groups later in the trial or the differential assessment of outcomes , either of which may result in biased estimates of treatment effects . The optimal strategy to minimize the likelihood of differential treatment or assessment s of outcomes is to blind as many individuals as possible in a trial . R and omized controlled trials of surgical interventions are frequently more difficult to blind than RCTs of medications , which typically achieve blinding with placebos . However , imaginative techniques may make blinding more feasible in surgical trials than is commonly believed by many research ers . In this article we discuss the importance of blinding and provide practical suggestions to research ers who wish to incorporate blinding into their surgical studies Spinal manipulative therapy techniques are commonly employed by physiotherapists in the clinical setting for the management of neuromusculoskeletal pain and dysfunction , although their underlying mechanism is not fully understood . Mulligan 's sustained natural apophyseal glides ( SNAGs ) constitute one of these techniques . This preliminary investigation was undertaken to investigate the relationship between the application of cervical SNAGs to the C5/6 intervertebral joint ( with cervical right rotation ) and indirect measures of sympathetic nervous system ( SNS ) activity . Previous investigations have suggested that cervical manipulative therapy techniques , separate to cervical SNAGs , result in a sympatheoexcitatory effect and that this may be instrumental in producing an analgesic response . Sixteen asymptomatic subjects participated in a laboratory-based experiment . A single blind , r and omized , within subject , repeated measures study design which included control , placebo and treatment comparisons was used . Measures of skin conductance ( SC ) and skin temperature ( ST ) in the right and left upper limbs were used as indicators of SNS activity . The cervical SNAG technique produced a sympathoexcitatory response demonstrated by a significant increase in SC during application of the treatment intervention ( P<0.0005 ) and for a 2-min period after the intervention ( P=0.001 ) compared with control . There was also a significant increase in SC for the placebo condition , both during intervention ( P=0.015 ) and after intervention ( P=0.011 ) compared with control . There was a statistically significant difference in SC between placebo and treatment conditions for the 2-min period after the intervention had been applied ( P=0.01 ) . A trend did emerge for ST change , illustrating a decrease in ST for the treatment and placebo conditions compared with control , however this did not reach statistically significant levels . There were no apparent left/right upper limb differences for SC and ST for each condition . The results of this study suggest that cervical SNAG techniques , performed on naïve asymptomatic subjects , have a sympathoexcitatory effect as measured by changes in SC and ST . The importance of this sympathoexcitatory effect in relation to potential mechanisms for manipulation induced analgesia are discussed , and further areas of research proposed Background Neuromechanical responses to spinal manipulation therapy ( SMT ) have been shown to be modulated through the variation of SMT biomechanical parameters : peak force , time to peak force , and preload force . Although rate of force application was modulated by the variation of these parameters , the assumption that neuromuscular responses are modulated by the rate of force application remains to be confirmed . Therefore , the purpose of the present study was to evaluate the effect of a constant rate of force application in neuromechanical responses to SMT in healthy adults . Methods Four SMT force-time profiles presenting different time to peak force and peak force , but with a constant rate of force application were applied on 25 healthy participants ’ T7 transverse processes . Muscular responses were recorded through surface electromyography electrodes ( T6 and T8 levels ) , while vertebral displacements were assessed through pasted kinematic markers on T6 to T8 spinous processes . Effects of SMT force-time profiles on neuromechanical responses were assessed using repeated- measures ANOVAs . Results There was no main effect of SMT force-time profile modulation on muscular responses ( ps > .05 ) except for the left T8 ( F ( 3 , 72 ) = 3.23 , p = .03 ) and left T6 ( F ( 3 , 72 ) = 2.94 , p = .04 ) . Muscular responses were significantly lower for the lowest peak force condition than the highest ( for T8 ) or second highest ( for T6 ) . Analysis showed that increasing the SMT peak force ( and concomitantly time to peak force ) led to a significant vertebral displacement increase for the contacted vertebra ( FT7 ( 1 , 17 ) = 354.80 , p < .001 ) and both adjacent vertebras ( FT6(1 , 12 ) = 104.71 , p < .001 and FT8 ( 1 , 19 ) = 468.68 , p < .001 ) . Conclusion This study showed that peak force modulation using constant rate of force application leads to similar neuromuscular responses . Coupled with previous investigations of SMT peak force and duration effects , the results suggest that neuromuscular responses to SMT are mostly influenced by the rate of force application , while peak force modulation yields changes in the vertebral displacement . Rate of force application should therefore be defined in future studies . Clinical implication s of various SMT dosages in patients with spine related pain should also be investigated . Trial registration Clinical Trials.gov NCT02550132 . Registered 8 September OBJECTIVE The purpose of this study was to investigate the effects of a manual mobilization technique on indirect measures of sympathetic nervous system activity . METHODS Forty-five healthy volunteers participated in this r and omized , single-blinded , parallel-group 3-arm design ( experimental , sham [ placebo ] , and control group ) , comprising 15 subjects each . For the experimental group , lumbar mobilization involving an active movement , the Mulligan sustained natural apophyseal glide ( SNAG ) , was applied on L4 spinous process by an experienced manual therapist . Sustained natural apophyseal glides were performed in sitting with active flexion ( 6 times × 3 sets ) . The sham technique simulated the SNAG without applying any force . In the control group , participants were placed in a static sitting position throughout the experiment . Measures of skin conductance in the lower limbs ( L4 dermatome ) were recorded to reflect sympathetic nervous system activity in the preintervention , periintervention , and postintervention periods . Differences in percentage change of skin conductance were analyzed with analysis of variance and post hoc tests . RESULTS Lumbar SNAG produced sympathoexcitation compared with the control group in the intervention period ( P = .04 ) . No significant difference was found between SNAG and sham groups , and no statistically significant difference was found between groups in the final rest period . CONCLUSION The results of this study showed that , in asymptomatic participants , both lumbar SNAG and sham techniques performed on L4/5 intervertebral joint with active flexion induced a sympathoexcitatory response in lower limbs compared with the control group Background In r and omised trials , rather than comparing r and omised groups directly some research ers carry out a significance test comparing a baseline with a final measurement separately in each group . Methods We give several examples where this has been done . We use simulation to demonstrate that the procedure is invalid and also show this algebraically . Results This approach is biased and invalid , producing conclusions which are , potentially , highly misleading . The actual alpha level of this procedure can be as high as 0.50 for two groups and 0.75 for three . Conclusions R and omised groups should be compared directly by two- sample methods and separate tests against baseline are highly misleading BACKGROUND AND PURPOSE Mulligan has proposed the use of mobilization with movement for lateral epicondylalgia . In this study , mobilization with movement for the elbow was examined to determine whether this intervention was capable of inducing physiological effects similar to those reported for some forms of spinal manipulation . PARTICIPANTS Seven women and 17 men ( mean age=48.5 years , SD=7.2 ) with chronic lateral epicondylalgia participated in the study . METHODS A placebo , control , repeated- measures study was conducted to evaluate whether mobilization with movement at the elbow produced concurrent hypoalgesia and sympathoexcitation . RESULTS The treatment demonstrated an initial hypoalgesic effect and concurrent sympathoexcitation . Improvements in pain result ed in increased pain-free grip force and pressure pain thresholds . Sympathoexcitation was indicated by changes in heart rate , blood pressure , and cutaneous sudomotor and vasomotor function . DISCUSSION AND CONCLUSION This study showed that a mobilization with movement treatment technique exerted a physiological effect similar to that reported for some spinal manipulations The present study examined the effects of cervical spinal manipulation , a widely applied form of physical therapy , which involves innocuous mechanical stimulation , on heart rate and heart-rate variability , in a cohort of healthy young adults . Using a cross-over treatment design , with a one-week washout period and , in contrast to a sham procedure , the authentic manipulation produced significant alterations in both heart rate and measures of heart-rate variability calculated from power spectrum analysis . In particular , there was an increase in the ratio of low-frequency (LF)-to-high-frequency ( HF ) components of the power spectrum of heart-rate variability , which may reflect a shift in balance between sympathetic and parasympathetic output to the heart At present , no consensus exists among clinical and academic experts regarding an appropriate placebo for r and omized controlled trials ( RCTs ) of spinal manipulative therapy ( SMT ) . Therefore , we investigated whether it was possible to conduct a chiropractic manual-therapy RCT with placebo . Seventy migraineurs were r and omized to a single-blinded placebo-controlled clinical trial that consisted of 12 treatment sessions over 3 months . The participants were r and omized to chiropractic SMT or placebo ( sham manipulation ) . After each session , the participants were surveyed on whether they thought they had undergone active treatment ( “ yes ” or “ no ” ) and how strongly they believed that active treatment was received ( numeric rating scale 0–10 ) . The outcome measures included the rate of successful blinding and the certitude of the participants ’ beliefs in both treatment groups . At each treatment session , more than 80 % of the participants believed that they had undergone active treatment , regardless of group allocation . The odds ratio for believing that active treatment was received was > 10 for all treatment sessions in both groups ( all p < 0.001 ) . The blinding was maintained throughout the RCT . Our results strongly demonstrate that it is possible to conduct a single-blinded manual-therapy RCT with placebo and to maintain the blinding throughout 12 treatment sessions given over 3 months Physiotherapy management of lumbar disorders , based on Mulligan 's mobilization techniques , is a treatment of choice by many physiotherapists , however , there is only limited evidence of any neurophysiological effects and much of this has focused on the cervical spine and upper limbs . This study aims to extend the knowledge base underpinning the use of a modified Mulligan 's spinal mobilisation with leg movement technique ( SMWLM ) by exploring its effects on the peripheral sympathetic nervous system ( SNS ) of the lower limbs . Using a single blind , placebo controlled , independent groups study design , 45 normal naive healthy males were r and omly assigned to one of three experimental groups ( control , placebo or treatment ; SMWLM ) . SNS activity was determined by recording skin conductance ( SC ) obtained from lower limb electrodes connected to a BioPac unit . Validation of the placebo technique was performed by post- intervention question naire . Results indicated that there was a significant change in SC from baseline levels ( 30 % ) that was specific to the side treated for the treatment group during the intervention period ( compared to placebo and control conditions ) . This study provides preliminary evidence that a modified SMWLM technique results in side-specific peripheral SNS changes in the lower limbs Abstract Thoracic spine manipulation has been shown to be effective for the management of neck pain . The purpose of this study was to investigate the immediate effect of a T3–T4 spinal thrust manipulation on autonomic nervous system activity in subjects with chronic cervical pain . An additional aim was to determine if the manipulation result ed in an immediate pain relief in patients with chronic neck pain when compared to a placebo intervention . One hundred subjects with chronic neck pain were r and omly assigned to receive either a thoracic thrust manipulation or a placebo intervention . The Friedman 's test was used to evaluate the change in pupil diameter within both groups . The Wilcoxen signed-ranks test was used to explore pupil changes over time and to make paired comparisons of the pupil change between the groups . The Mann – Whitney U test was used to compare the change in pain perception for the chronic cervical pain group subjects receiving either the thrust manipulation or the placebo intervention . The results demonstrated that manipulation did not result in a change in sympathetic activity . Additionally , there was no significant difference in the subject 's pain perception ( P=0.961 ) when comparing the effects of the thrust manipulation to the placebo intervention within this group of subjects with chronic neck pain . The clinical impression of this study is that manipulation of the thoracic spine may not be effective in immediately reducing pain in patients with chronic neck pain Physiotherapeutic management of lumbar disorders often utilises specific segmental joint mobilisation techniques ; however , there is only limited evidence of any neurophysiological effects and much of this has focused on the cervical spine and upper limbs . This study aims to extend the knowledge base underpinning the use of a unilaterally applied lumbar spinal mobilisation technique by exploring its effects on the peripheral sympathetic nervous system ( SNS ) of the lower limbs . Using a double blind , placebo controlled , independent groups study design and based upon power calculations , 45 normal naïve healthy males were r and omly assigned to one of three experimental groups ( control , placebo or treatment ; a unilaterally applied postero-anterior mobilisation to the left L4/5 zygopophyseal joint ) . SNS activity was determined by recording skin conductance ( SC ) obtained from lower limb electrodes connected to a BioPac unit . Validation of the placebo technique was performed by post-intervention question naire . Results indicated that there was a significant change in SC from baseline levels ( 13.5 % ) that was specific to the side treated for the treatment group during the intervention period ( compared to placebo and control conditions ) . This study provides preliminary evidence that a unilaterally applied postero-anterior mobilisation technique performed , at a rate of 2 Hz , to the left L4/5 lumbar zygopophyseal joint results in side-specific peripheral SNS changes in the lower limbs Objectives : The aims were to investigate the effects of anterior-posterior upper cervical mobilization ( APUCM ) on pain modulation in craniofacial and cervical regions and its influence on the sympathetic nervous system . Methods : Thirty-two patients with cervico-craniofacial pain of myofascial origin were r and omly allocated into experimental or placebo groups . Each patient received 3 treatments . Outcome measures included bilateral pressure pain thresholds assessed at craniofacial and cervical points preintervention , after the second intervention and after the final treatment . Pain intensity and sympathetic nervous system variables ( skin conductance , breathing rate , heart rate , and skin temperature ) were assessed before and immediately after each intervention . Results : The pressure pain thresholds in the craniofacial and cervical regions significantly increased ( P<0.001 ) and pain intensity significantly decreased ( P<0.001 ) in the treatment group compared with placebo . APUCM also produced a sympathoexcitatory response demonstrated by a significant increase in skin conductance , breathing rate , and heart rate ( P<0.001 ) , but not in skin temperature ( P=0.071 ) , after application of the technique compared with placebo . Discussion : This study provided preliminary evidence of a short-term hypoalgesic effect of APUCM on craniofacial and cervical regions of patients with cervico-craniofacial pain of myofascial origin , suggesting that APUCM may cause an immediate nociceptive modulation in the trigeminocervical complex . We also observed a sympathoexcitatory response , which could be related to the hypoalgesic effect induced by the technique , but this aspect should be confirmed in future studies OBJECTIVE The aims of this study were ( 1 ) to determine if there were statistically significant immediate effects of anterior upper thoracic chiropractic manipulative therapy on cardiovascular response in normotensive individuals and ( 2 ) to quantify responses if any were found . METHODS Thirty-six chiropractic college students ( age , 26.8 ± 4.6 years ; height , 1.71 ± 0.12 m ; body mass , 75.6 ± 20.0 kg ; mean ± SD ) were equally r and omized into a single-blind , controlled trial involving 3 study groups : anterior thoracic manipulation of T1 - 4 , Activator-based placebo manipulation , or a " no T-spine contact " control . Outcome measures were electrocardiogram , bilateral pulse oximetry , and bilateral blood pressure measurement performed at baseline , post 1-minute intervention , post 10-minute intervention , and post 24-hour ( ±1 hour ) intervention . Between-group dependent variables were analyzed through 1-wsay analysis of variance at each of the 4 time points . Within-group dependent variables were analyzed through 2 paired- sample s t tests comparing baseline to post 10 minutes and again between baseline to post 24 hours ( ±1 hr ) . RESULTS No statistically significant difference was shown amongst any between-group or within-group cardiovascular dependent variables in this study . CONCLUSIONS The results of this study suggest cardiovascular physiologic responses are not affected in the short term by anterior upper thoracic spine chiropractic manipulative therapy in young normotensive individuals OBJECTIVE The aims of this study were to examine autonomic nervous system responses by using heart rate variability analysis ( HRV ) , hemodynamic parameters and numeric pain scale ( NPS ) when either upper ( C1 and C2 ) or lower ( C6 and C7 ) cervical segments were manipulated in volunteers , and whether such response would be altered in acute mechanical neck pain patients after spinal manipulative therapy ( SMT ) . METHODS A r and omized controlled , cross-over , preliminary study was conducted on 10 asymptomatic normotensive volunteers and 10 normotensive patients complaining of acute neck pain . HRV , blood pressure ( BP ) and heart rate ( HR ) , and NPS were recorded after upper cervical and lower cervical segments SMT in volunteer and patient groups . RESULTS The st and ard deviation of average normal to normal R-R intervals ( SDNN ) increased ( 83.54 ± 22 vs. 105.41 ± 20 ; P = .02 ) after upper cervical SMT . The normalized unit of high frequency ( nuHF ) , which shows parasympathetic activity , was predominant ( 40.18 ± 9 vs. 46.08 ± 14 ) after upper cervical SMT ( P = .03 ) with a significant decrease ( 109 ± 10 vs. 98 ± 5 ) in systolic BP ( P = .002 ) . Low frequency to high frequency ( LF/HF ) ratio , which shows predominance of sympathetic activity increased ( 1.05 ± 0.7 vs. 1.51 ± 0.5 ; P = .02 ) after lower cervical SMT in the healthy volunteers group . However , there was an increase in SDNN ( 70.48 ± 18 vs. 90.23 ± 20 ; P = .02 and 75.19 ± 16 vs 97.52 ± 22 ; P = .01 ) , a decrease in LF/HF ratio ( 1.33 ± 0.3 vs. 0.81 ± 0.2 ; P = .001 and 1.22 ± 0.4 vs. 0.86 ± 0.3 ; P = .02 ) , which was associated with decreased systolic BP ( 105 ± 10 vs. 95 ± 9 ; P = .01 and 102 ± 9 vs. 91 ± 10 ; P = .02 ) and NPS scores ( 3 ± 1 vs. 0 ; P = .01 and 3 ± 1 vs. 1 ± 1 ; P = .03 ) following both upper and lower cervical SMT in the patient 's group . The baseline HR was 67 ± 9 vs 64 ± 5 ( upper cervical ) and 65 ± 7 vs 69 ± 11 ( lower cervical ) in both the healthy volunteer ' and patient ' groups . CONCLUSION Upper cervical SMT enhances dominance of parasympathetic and lower cervical SMT enhances dominance of sympathetic activity in this young volunteer group . However , dominance of parasympathetic activity was found in patients with neck pain that received both upper and lower cervical SMT Recent findings that spinal manual therapy ( SMT ) produces concurrent hypoalgesic and sympathoexcitatory effects have led to the proposal that SMT may exert its initial effects by activating descending inhibitory pathways from the dorsal periaqueductal gray area of the midbrain ( dPAG ) . In addition to hypoalgesic and sympathoexcitatory effects , stimulation of the dPAG in animals has been shown to have a facilitatory effect on motor activity . This study sought to further investigate the proposal regarding SMT and the PAG by including a test of motor function in addition to the variables previously investigated . Using a condition r and omised , placebo-controlled , double blind , repeated measures design , 30 subjects with mid to lower cervical spine pain of insidious onset participated in the study . The results indicated that the cervical mobilisation technique produced a hypoalgesic effect as revealed by increased pressure pain thresholds on the side of treatment ( P=0.0001 ) and decreased resting visual analogue scale scores ( P=0.049 ) . The treatment technique also produced a sympathoexcitatory effect with an increase in skin conductance ( P<0.002 ) and a decrease in skin temperature ( P=<0.02 ) . There was a decrease in superficial neck flexor muscle activity ( P<0.0002 ) at the lower levels of a staged cranio-cervical flexion test . This could imply facilitation of the deep neck flexor muscles with a decreased need for co-activation of the superficial neck flexors . The combination of all findings would support the proposal that SMT may , at least initially , exert part of its influence via activation of the PAG OBJECTIVE To investigate a proposed model in which manipulative therapy produces a treatment-specific initial hypoalgesic and sympathoexcitatory effect by activating a descending pain inhibitory system . The a priori hypothesis tested was that manipulative therapy produces mechanical hypoalgesia and sympathoexcitation beyond that produced by placebo or control . Furthermore , these effects would be correlated , thus supporting the proposed model . DESIGN A r and omized , double-blind , placebo-controlled , repeated- measures study of the initial effect of treatment . SETTING Clinical neurophysiology laboratory . SUBJECTS Twenty-four subjects ( 13 women and 11 men ; mean age , 49 yr ) with chronic lateral epicondylalgia ( average duration , 6.2 months ) . INTERVENTION Cervical spine lateral glide oscillatory manipulation , placebo and control . OUTCOME MEASURES Pressure pain threshold , thermal pain threshold , pain-free grip strength test , upper limb tension test 2b , skin conductance , pileous and glabrous skin temperature and blood flux . RESULTS Treatment produced hypoalgesic and sympathoexcitatory changes significantly greater than those of placebo and control ( p < .03 ) . Confirmatory factor- analysis modeling , which was performed on the pain-related measures and the indicators of sympathetic nervous system function , demonstrated a significant correlation ( r = .82 ) between the latencies of manipulation-induced hypoalgesia and sympathoexcitation . The Lagrange Multiplier test and Wald test indicated that the two latent factors parsimoniously and appropriately represented their observed variables . CONCLUSION Manual therapy produces a treatment-specific initial hypoalgesic and sympathoexcitatory effect beyond that of placebo or control . The strong correlation between hypoalgesic and sympathoexcitatory effects suggests that a central control mechanism might be activated by manipulative therapy Background This study aim ed to quantify the effect of spinal manipulative treatment ( SMT ) from an analysis of baroreflex , systolic blood pressure and heart rate variability ( HRV ) on patients with acute back pain . It was hypothesized that SMT would increase the parasympathetic cardiovascular autonomic control . Methods Twenty-two patients with acute back pain were r and omly divided into two groups : one receiving sham treatment ( Sham ) and the other receiving SMT . Recordings were completed during the first day and the seventh day , immediately before and after treatment on both days . ECG and systolic blood pressure were continuously recorded to compute cardiovascular variability and baroreflex sensitivity components . The perceived level of pain was measured with the numeric pain scale ( NPS ) 48 h before , just before and just after each treatment . The NPS ranged from 0 to 100 % ( peak of pain before treatment ) . ECG and systolic blood pressure recordings were analyzed in time frequency domain using the Smoothed pseudo Wigner-Ville distribution . Results Root mean square of the successive differences , high frequency power of the heart rate variability , and high frequency baroreflex sensitivity differences between post and pre tests were higher in the SMT group than in the Sham group ( p < 0.01 ) , whereas no differences were observed with the other heart rate variability components . Also , no differences were observed with the systolic blood pressure components . Although the estimated pain scale values decreased over time , no difference was observed between the SMT and Sham groups . Conclusions This seems to be the first study to assess the effect of SMT on both heart rate variability and baroreflex sensitivity in patients with acute back pain . SMT can be seen to provoke an increase in parasympathetic control known to relate to a person ’s healthy state . Thus , cardiovascular variability analysis may be a useful tool for clinicians to quantify and objectify the beneficial effects of spinal manipulation treatment OBJECTIVE To compare the effects of two different mobilization techniques and a placebo intervention applied to the thoracic spine on heart rate variability ( HRV ) and pressure pain threshold ( PPT ) in asymptomatic individuals . METHODS Sixty healthy asymptomatic subjects aged between 18 and 40 years old were r and omized to a single session of one of the three interventions : posterior-to-anterior ( PA ) rotatory thoracic passive accessory intervertebral mobilization ( PAIVM ) ( PA group ) , unilateral thoracic PA in slump position ( SLUMP group ) or placebo intervention ( Placebo group ) . HRV and PPT at C7 and T4 spinous process , first dorsal interossei muscles bilaterally , and muscle belly of tibialis anterior bilaterally were measured before and immediately after the intervention . A univariate analysis of covariance ( ANCOVA ) adjusted for baseline values assessed the effect of " Group " . Pairwise comparisons with Bonferroni adjustment for multiple comparisons were performed . RESULTS There were no significant between-group differences for HRV . A significant between-group difference for PPT in the ipsilateral tibia was found favoring the SLUMP group in comparison with the PA group . There were no significant between-group differences for PPT in the other l and marks . CONCLUSION A single treatment of thoracic PAIVM in prone lying and slump position did not alter PPT and HRV compared to placebo in asymptomatic subjects OBJECTIVE The purpose of this study was to investigate the short-term effects of spinal manipulation applied to a hypomobile segment of the upper thoracic spine ( T1-T6 ) , on plasma concentrations of norepinephrine ( NE ) and epinephrine ( E ) in asymptomatic subjects , under strictly controlled conditions . METHODS Fifty-six asymptomatic subjects were r and omly assigned to receive either a chiropractic manipulative intervention or a sham intervention in the upper thoracic spine . A 20-gauge catheter fitted with a saline lock was used to sample blood before , immediately after , and 15 minutes after intervention . Plasma NE and E concentrations were determined using an enzyme-linked immunosorbent assay . Changes in plasma catecholamine concentrations were analyzed within and between groups using 1- and 2- sample t tests , respectively . RESULTS The plasma sample s of 36 subjects ( 18 treatment , 18 control ) were used in the analysis . Mean plasma concentrations of NE and E did not significantly differ between the 2 groups at any time point and did not change significantly after either the manipulative or sham intervention . CONCLUSIONS The results of this study indicate that a manipulative thrust directed to a hypomobile segment in the upper thoracic spine of asymptomatic subjects does not have a measurable effect on the plasma concentrations of NE or E. These results provide a baseline measure of the sympathetic response to spinal manipulation BACKGROUND Oscillatory Maitl and mobilisations are commonly used in the management of lower back pain with research suggesting that mobilisations at 2 Hz may excite the sympathetic nervous system ( SNS ) more than sustained pressure glides or 0.5 Hz oscillatory mobilisations . OBJECTIVES Investigate the effects of increasing the oscillation frequency greater than 2 Hz . DESIGN A double-blind , placebo-controlled , independent group experimental design . METHOD Sixty healthy male volunteers were r and omly allocated to one of four groups ; a control group ( no contact ) , placebo group ( sustained static pressure to L4 vertebra ) , and two intervention groups receiving a central ly applied postero-anterior mobilisation applied at either 2 Hz or 3 Hz for three 1-min periods . SNS activity was recorded by a blinded data collector by continuous skin conductance ( SC ) activity levels in the feet using a Biopac MP35 electrodermal amplifier . Participants were blinded to their group allocation which was further vali date d by a post-experiment question naire ( p > 0.05 ) . RESULTS The magnitude of sympathoexcitatory response was greatest for the 3 Hz mobilisation ( 20 % ) compared with the 2 Hz mobilisation ( 12 % ) , placebo ( -1 % ) and control conditions ( 3 % ) . Only the 3 Hz group demonstrated statistical significance when compared to placebo intervention ( p = 0.002 ) , and the control group ( p = 0.02 ) . CONCLUSION SC changes reflect those of previous studies using lumbar mobilisations at 2 Hz , however the 3 Hz group was found to have a greater magnitude of effect worthy of consideration within research and clinical setting s. These findings provide preliminary evidence to support the use of 3 Hz oscillatory mobilisations to affect a greater magnitude of SNS activity than those previously reported ( 0.5 , 1.5 and 2 Hz ) |
13,773 | 28,940,725 | Both treatments show an almost equally low complication rate , but there is a low level of reporting of hard and soft tissue conditions and PROM .
It is concluded that implant-supported 3-unit FDPs seem to be a reliable treatment with survival rates not significantly different from the results of teeth-supported 3-unit FDPs | The purpose of the systematic review and meta- analysis was to compare the performance of 3-unit bridges on teeth with 3-unit bridges on implants , evaluating survival of the bridges , survival of the teeth or implants , condition of the hard and soft tissues surrounding the supports , complications and patient-reported outcome measures ( PROM ) after a mean observation period of at least 1 year . | PURPOSE The objective of this research was to test the hypothesis that 3-unit fixed partial dentures ( FPDs ) made from a moderately high-strength core ceramic will adequately resist fracture in posterior regions if fabricated with a minimal connector size of 4 mm . MATERIAL S AND METHODS Thirty ceramic FPD core frameworks were prepared using a hot-pressing technique and a lithia disilicate-based core ceramic . The maximum occlusal force was measured for each patient prior to tooth preparation . Connector heights and widths were measured for each FPD . Patients were recalled annually after cementation for 4 years and evaluated using 11 clinical criteria . All FPDs were examined by 2 independent clinicians , and rankings for each criterion were made from 1 to 4 ( 4 = excellent ; 1 = unacceptable ) . RESULTS The fracture rate was approximately 3 % per year , and the proportion of good overall ratings in the nonfractured FPDs was reduced by more than 6 % per year , where a good overall rating was defined to be a rank of 3 or 4 in all 11 criteria . There was little evidence that the use of either resin-reinforced glass-ionomer cement ( Protec CEM ) or dual-cure resin cement ( Variolink II ) made any difference in terms of fracture rate or overall rating ( P= .30 , .63 , .97 , and .71 for the 4 years , respectively ) . From a fracture resistance perspective , 4 of the 30 ceramic FPDs fractured within the 4-year evaluation period , representing an 86.7 % success rate . Another FPD was replaced because of a caries lesion on 1 abutment tooth away from the margin . One FPD fracture was associated with the subject having the greatest occlusal force ( 1,031 N ) . The other 2 fractures were associated with FPDs that exhibited connector heights of less than 3 mm . All criteria were ranked good to excellent during the 4-year period for the remaining FPDs . CONCLUSION Fractured FPDs were associated with a connector height of less than 4 mm ; thus , the hypothesis was accepted PURPOSE The aim of this prospect i ve study was to evaluate the clinical efficacy and long-term survival rate of three-unit fixed partial dentures ( FPDs ) made from lithium disilicate-based core ceramic . MATERIAL S AND METHODS Twenty-one three-unit FPDs were placed in 19 patients to replace single lost teeth in the esthetic area , following a study protocol that took clinical , esthetic , and radiologic aspects into consideration . Each case was review ed at 1 week following placement , at 6 months , and then annually for 10 years . Statistical analysis was performed using Kaplan-Meier survival analysis . RESULTS Out of the 19 patients , 14.3 % presented reversible postoperative sensitivity . Recession was observed in 24 % of dental posts , and 7.1 % presented marginal discoloration . Treatment did not increase either Bleeding or Plaque Index scores at prepared teeth ; secondary caries did not appear either . The restorations ' survival rate at the 10-year follow-up was 71.4 % ; six FPDs had fractured and one debonded . CONCLUSIONS Fracture failure rate was 28.6 % after 10 years ; a high percentage corresponded to connector fractures and occurred during the first 5 years . Lithium disilicate glass-ceramic FPDs present a higher risk of fracture than st and ard therapies ( metal-ceramic ) or other more recently developed ceramic material s. The prognosis for survival improves for Class I occlusion and nonparafunctional patients This clinical study evaluated posterior three-unit fixed dental prostheses ( FDPs ) made of zirconia substructures veneered with pressable glass – ceramic . Nineteen patients received 21 FDPs replacing either the second premolar , first molar , or second molar . The FDPs were cemented with glass ionomer . Recall examinations were performed every 12 months . The mean service time of the FDP was 40 months . At 30 months , one maxillary FDP exhibited zirconia framework fracture at a thinned occlusal area of the abutment . Loss of retention led to the removal of one FDP after 38 months . The Kaplan – Meier survival probability was 90.5 % after 40 months for all types of failures and 95.2 % concerning framework fractures . The overpressing technique appears to be reliable in terms of the veneering material . However , one framework fracture was observed in this study PURPOSE This study prospect ively evaluated the clinical performance of posterior zirconium-oxide-based all-ceramic fixed partial dentures ( FPDs ) . METHODS Forty-two abutments of 21 Cercon FPDs were fitted in 20 patients at the Tsurumi University Dental Hospital from August 2005 to August 2006 . The performance of these FPDs was evaluated using the California Dental Association ( CDA ) quality assessment system at baseline and at all follow-up examinations . RESULTS All FPDs were examined after a mean observation period of 28.1 ( + /-3.4 ) months . During the observation period , no fracturing of FPDs was seen . All of the FPDs examined were rated as satisfactory with regard to all factors at the follow-up examinations based on the CDA quality assessment criteria . CONCLUSION Within the limitations of this short-term clinical study , no core framework fractures were seen . According to the CDA criteria , 100 % of the FPDs were rated as satisfactory during this observation period The clinical question at issue , whether it is possible to combine implants and natural teeth via fixed bridges , is of current interest . The treatment of the subjects of this prospect i ve study was performed between June 1984 and December 1986 . This article presents the 5-year results of the study . The consecutive patient material comprised 23 patients with Applegate Kennedy Class I residual dentition in the m and ible and a complete maxillary denture . All 23 patients were provided with implants ad modum Brånemark in each m and ibular quadrant . One side was r and omized to rehabilitation with fixed bridge between the distal tooth of the residual dentition and an implant ; the other side received a free-st and ang bridge on 2 implants . The fixture survival rate was 88 % . No difference was found between the two sides . Bridge stability was 89 % for the implant bridges and 91 % for the combination bridges . The change in marginal bone level at the implants was small during the 5-year follow up period ( on average 0.1 - 0.3 mm ) and with no difference between the two sides . In conclusion , it was not possible to demonstrate any higher risk of implant or prosthetic failure for tooth-implant fixed bridges compared with implant-supported bridges OBJECTIVE To evaluate the clinical performance of zirconia-based cantilever fixed dental prostheses ( FDPs ) . METHOD AND MATERIAL S Twenty-one cantilever FDPs with three or four units were design ed to replace one premolar or incisor ( no canines ) . The FDPs were divided into 11 zirconia cantilever FDPs ( test group ) and 10 metal-ceramic cantilever FDPs ( control group ) and r and omly assigned to patients . The results documented included failures , complications , plaque accumulation , and esthetic performance . Statistical analysis was performed using the Mann-Whitney U and chi-square tests . RESULTS During the 2-year observation period , a total of five clinical ly relevant complications in four patients occurred : three endodontic problems ( two in the test group and one in the control group ) and two veneer chippings ( both in the test group ) . Plaque accumulation on the abutment teeth was not significantly different among groups . The esthetic performance of all FDPs was acceptable . CONCLUSION Stability and esthetic performance were acceptable for all-ceramic cantilever FDPs fabricated with zirconia . A longer observation period and larger sample size are necessary to make valid predictions about the longevity of these restorations This study aim ed to evaluate three- and four-unit posterior fixed partial dentures ( FPDs ) with zirconia frameworks after 5 years of function . Of the initial 30 subjects , 25 patients with 25 FPDs were examined after a mean follow-up period of 62.1 months . Five patients were not available for recall visits . Two FPDs failed before the 60-month evaluation because of framework fracture or delamination of the veneering ceramic after endodontic treatment . The 5-year survival rate was 92 % . Based on these results , it can be suggested that zirconia frameworks have sufficient mechanical requirements for use in the stress-bearing posterior region . Major fracture of the ceramic veneer could be related to inadequate framework design or bruxism The aim of this r and omized controlled trial was to evaluate the clinical performance of lithium disilicate fixed partial dentures ( FPDs ) . Eighteen patients received lithium disilicate FPDs ( study group ) , and 19 patients received porcelain-fused-to-metal FPDs ( control ) . After 6 years , the survival probabilities were found to be 63 % in the study group and 95 % in the control group ( log-rank test , P = .028 ) . The data suggest that strict conditions should be considered before the use of lithium disilicate glass-ceramic for FPDs OBJECTIVES The purpose of this prospect i ve study was to evaluate the clinical outcome of crown-retained fixed dental prostheses ( FDPs ) made from a lithium-disilicate glass-ceramic ( IPS e.max Press , Ivoclar-Vivadent ) . METHODS Thirty-six three-unit FDPs were placed in 28 patients . The FDPs replaced teeth in the anterior ( 16 % ) and posterior ( 84 % ) regions . All teeth were prepared following a st and ardized protocol . The size of the proximal connector of the FDPs was 12 mm2 ( anterior ) or 16 mm2 ( posterior ) . FDPs were cemented either with glass-ionomer cement ( n=19 ) or composite resin ( n=17 ) . The following parameters were evaluated at baseline , 6 months after cementation and then annually ( at abutment and contralateral teeth ) : probing pocket depth , plaque index , bleeding on probing , and tooth vitality . RESULTS Three FDPs were defined as drop-out . The mean observation period of the remaining 33 FDPs was 86 months ( range : 67 - 98 months ) : two FDPs in two patients had to be replaced ( 6 % ) because of fractures . The 8-year survival rate according to Kaplan-Meier was 93 % . In addition , chipping of the veneering material was found in two FDPs ( 6 % ) . Two abutments ( 3 % ) of two restorations had to be treated endodontically ; and two FDPs ( 6 % ) lost retention and had to be recemented . These complications did not affect the function of the involved restorations clinical ly . There were no significant differences between the periodontal parameters of the test and control teeth . SIGNIFICANCE Short-span crown-retained three-unit FDPs made from lithium-disilicate glass-ceramic can be used clinical ly irrespective of an adhesive or conventional cementation STATEMENT OF PROBLEM A new method for fabrication of crowns and fixed partial dentures ( Procera system ) that involves electric discharge machining and copy milling has been developed . The metal used is unalloyed titanium , which can be processed as a single coping or multiple units joined to a pontic by laser welding . PURPOSE The single-unit coping or the fixed partial denture ( FPD ) substructure is then veneered with a low-fusing porcelain . MATERIAL AND METHODS In this article the clinical application of this technique was evaluated by six major universities in the United States . A total of 114 patients participated in this study , which involved 126 restorations ( 55 maxillary and 71 m and ibular prostheses ) . There were 179 abutments , of which 73 were crowns and 53 were three-unit FPDs . Surface and color , anatomic form , and margin integrity were assessed 1 month after cementation and at 1 year with the California Dental Association ( CDA ) quality assessment evaluation system . RESULTS No statistically significant differences in CDA scores between the 1 month evaluations and the 1 year assessment s were found for surface and color ( p = 0.68 ) , anatomic form ( p > 0.99 ) , or margin integrity ( p = 0.57 ) . By use of the lowest ranking in the three categories as the overall quality of the restoration , only 3.3 % ( two crowns and two FPDs ) were not acceptable at the 1-month visit and 4.5 % ( two crowns and three FPDs ) were not acceptable at the 1-year evaluation . At-the 1-month visit 96.6 % ( 114 ) of the restorations were considered to be satisfactory , whereas 95.5 % ( 107 restorations ) were evaluated similarly at the 1-year evaluation . CONCLUSIONS The Procera system demonstrated , by use of the CDA criteria , its capability to produce quality prostheses that were rated satisfactory more than 95 % of the time after insertion and maintained this high rating at least for 1 year OBJECTIVES To report the results at year three of an evaluation of fixed-fixed all-ceramic bridges , constructed in a yttria oxide stabilized tetragonal zirconium oxide polycrystal ( Y-TZP ) substructure , placed in adult patients in UK general dental practice s and luted using a self-adhesive resin-based cement . METHODS Ethical approval was obtained . Four UK general dental practitioners were asked to recruit patients in accordance with the trial protocol . After obtaining informed written consent , appropriate vitality and radiographic assessment s were completed and the pre-operative status of the gingival tissues noted . The teeth were prepared and bridges constructed in accordance with the manufacturer 's instructions . Each bridge was review ed annually within 3 months of the anniversary of its placement by a calibrated examiner , together with the clinician who had placed the restoration . The examiners evaluated the integrity of the restoration , its anatomic form , marginal adaptation , surface quality , sensitivity , the condition of the adjacent gingivae , and the presence or absence of secondary caries . RESULTS A total of 34 bridges were examined at the three-year review . All Y-TZP frameworks were intact and no bridge retainers had debonded . Two veneering ceramic chips , in total , were detected over the three-year period of observation : the patients in whom this had occurred were unconcerned . A further abutment tooth had been successfully endodontically treated , through an occlusal access cavity , in addition to the two already reported at year one . SIGNIFICANCE At year three , the 34 Lava Y-TZP fixed-fixed bridges , placed in patients attending UK general dental practice s , were found to be performing satisfactorily OBJECTIVES The purpose of this prospect i ve long-term study was to evaluate the incidence of the most common technical problems , namely screw loosening , screw fracture , fracturing of veneering porcelain and framework fracture in implant-supported fixed partial dentures ( FPDs ) , and assess the survival and success rate ( event-free survival ) after 5 years of function . MATERIAL S AND METHODS In 76 partially edentulous patients , a total of 205 3i-implants ( machined surface ) were placed and restored with 112 implant-supported FPDs ( 46 single crowns , 81 splinted crowns , seven FPD bridges and 23 FPDs with cantilevers ) . The survival rate of FPDs supported by implants was 94.5 % ( CI-95 : 90.1 - 98.8 ) after an average observation period of 5 years . The success rate ( event-free survival ) of the FPDs was 80 % ( CI-95 : 87.3 - 72.7 ) . After an observation period of 5 years the cumulative incidence of screw loosening was 6.7 % ( CI-95 : 1.8 - 11.5 ) , the cumulative incidence for screw fracture was 3.9 % ( CI-95 : 0.1 - 7.7 ) . Fracture of the veneering porcelain occurred in 5.7 % ( CI-95 : 1.2 - 10.2 ) of all FPDs . Fracturing of the suprastructure framework was rare ( 1 % ; CI-95 : 0 - 2.9 ) . The overall complication incidence after 5 years was highest in the group of FPDs with cantilever , which showed the lowest success rate 68.6 % ( CI-95 : 50 - 87.3 ) , followed by single crowns ( 77.6 % ; CI-95 : 53.3 - 100 ) and splinted crowns ( 86.1 % ; CI-95 : 59.5 - 100 ) . No complication occurred in FPD bridges . CONCLUSION Fixed partial dentures supported by 3i-implants showed low technical complications rates , the most common being loosening of the abutment screw . Managing these complications can cause extra amount of chair-side time and patient dissatisfaction The aim of this study was to compare the prosthetic outcomes of implant/tooth-supported three-unit fixed partial dentures ( FPDs ) with those of freest and ing implant-supported FPDs after 2 years of function . Twenty-nine partially edentulous patients presenting with unilateral or bilateral distal-extension edentulous areas received FPDs and were followed for a minimum of 24 months . In all , 49 FPDs were fabricated . In 34 FPDs , implants were connected to teeth and thus the FPDs were categorized as mixed ( m-FPDs ) , whereas 15 FPDs were supported by freest and ing terminal implants ( fs-FPDs ) . Evaluation of prosthetic parameters including mechanical complications was performed . Changes in marginal bone level ( DeltaMBL ) around implants in both treatment groups were measured on digitalized periapical radiographs . Neither loss of osseointegration of an implant nor intrusion of abutment teeth was recorded . All FPDs were functioning after 24 months . Mean DeltaMBLs of posterior implants supporting m-FPDs and fs-FPDs at 24 months were 0.189 mm and -0.285 mm , respectively , representing a significant difference ( P < .05 ) . Mean DeltaMBLs at the mesial and distal surfaces of anterior and posterior implants supporting fs-FPDs were similar ( P > .05 ) . In the treatment of short-span distal-extension edentulous areas , similar clinical outcomes may be obtained for implant- and tooth/implant-supported three-unit FPDs in the early stages of function OBJECTIVE The aim of this prospect i ve clinical study was to evaluate the survival rates of IPS Empress 2 ( Ivoclar Vivadent ) all-ceramic crowns and fixed partial dentures ( FPDs ) after an observation period of up to 5 years . METHOD AND MATERIAL S Forty-three patients ( 19 women and 24 men ) were included in this study . The patients were treated with a total of 58 adhesive bonded IPS Empress 2 restorations . A total of 27 single crowns were placed on molars and premolars , and 31 three-unit FPDs were placed in the anterior and premolar regions . Clinical follow-up examinations took place at 6 , 12 , 24 , 36 , 48 , and 60 months after insertion . Statistical analysis of the data was calculated using the Kaplan-Meier method . RESULTS Results of the 50-month analysis ( interquartile range , 33 to 61 months ) showed that the survival rate was 100 % for crowns and 70 % for FPDs . Six failures that occurred exclusively in the three-unit FPDs were observed . Framework fractures were recorded in three FPD units where the connector dimensions did not meet the manufacturer specifications . Only one FPD exhibited an irreparable partial veneer fracture , and 2 FPDs showed evidence of biologic failures . The accuracy of fit and esthetic parameters were clinical ly satisfactory for crowns and FPDs . CONCLUSION The results of this 5-year clinical evaluation suggest that IPS Empress 2 ceramic is an appropriate material for the fabrication of single crowns . Because of the reduced survival rates , strict conditions should be considered before the use of IPS Empress 2 material for the fabrication of three-unit FPDs OBJECTIVE To examine the clinical performance of veneered ceria-stabilized tetragonal zirconia/alumina-nanocomposite ( Ce-TZP/A-nanocomposite ) frameworks for three-unit fixed dental prostheses ( FDPs ) . METHOD AND MATERIAL S Eight patients in need of one FDP replacing one premolar or molar were included in this case series . Eight Ce-TZP/A-nanocomposite FDP frameworks were fabricated with a CAD/CAM system ( Hint-Els ) and veneered with a zirconia veneering ceramic ( Vintage ZR , Shofu ) . The FDPs were cemented with resin cement ( baseline ) and were evaluated at baseline ; 2 weeks ; and 3 , 6 , and 12 months after cementation . For the technical evaluation , the USPHS criteria were used . The biologic outcome was judged by comparing the plaque control record ( PCR ) , bleeding on probing ( BOP ) , and probing pocket depth ( PPD ) of the abutment teeth ( test ) and untreated contralateral teeth ( control ) . Radiographs were made at baseline and at 6 and 12 months of follow-up . The data were descriptively analyzed . RESULTS The mean observation period of the eight examined FDPs was 12.8 + /- 1.1 months . The survival rate of the FDPs was 100 % . Furthermore , no technical or biologic complications were found . No differences of the mean ( m ) PCR ( test : 0.1 + /- 0.1 , control : 0.2 + /- 0.2 ) , mBOP ( test : 0.2 + /- 0.2 , control : 0.1 + /- 0.1 ) , and mPPD ( test : 2.6 + /- 0.8 , control : 2.6 + /- 0.6 ) were found between test and control teeth . CONCLUSIONS Ce-TZP/A nanocomposite was found to be a reliable framework material at 1 year of function . Longer observation periods and r and omized controlled clinical trials including more patients are needed to vali date these findings PURPOSE In this prospect i ve clinical study , the performance of three- and four-unit fixed partial dentures ( FPDs ) with frameworks fabricated of yttria partially stabilized zirconia was determined after a mean observation period of 50 months . The study focused on the survival of the restoration ( in situ criterion ) and the success of the ceramic veneers ( no defect ) . MATERIAL S AND METHODS Seventy-five patients with a maximum of two missing teeth and an antagonistic dentition were treated at the Department of Prosthodontics , University of Goettigen , with 99 posterior FPDs . Fifty-one specimens ( experimental group ) were veneered with an experimental ceramic suitable for titanium and zirconia frameworks ( thermal expansion coefficient [ TEC ] : 8.5 microm/m*K ) ; 48 restorations ( Ceram-S group ) were veneered with a commercially available low-fusing ceramic optimized for zirconia frameworks ( TEC : 9.5 microm/m*K ) . All restorations were luted with zinc-phosphate cement . Statistical analysis was performed according to the Kaplan-Meier method ; time-dependent success rates of the different types of ceramic veneers were analyzed using the log-rank test . RESULTS Seven restorations were lost : 4 due to technical complications and 3 due to biologic complications . The overall survival rate after 48 months was 94 % ( Kaplan-Meier analysis ) . Twenty-three events required clinical intervention for restoration maintenance : 13 ceramic veneer chippings ( polishing ) , 6 losses of retention ( recementation ) , 3 caries lesions ( filling therapy ) , and 1 loss of vitality ( endodontic treatment ) . Between the two groups of veneering material s , no significant difference in the probability for success was determined ( log-rank test , P=.81 ) . CONCLUSIONS Within a mean observation period of 4 years , sufficient survival rates for zirconia-based posterior FPDs could be verified . The main complications included fracture of the ceramic veneering material and decementation , which occurred mainly in the m and ible The aim of this prospect i ve study was to evaluate the clinical outcomes of three and four-unit posterior fixed dental prostheses ( FDPs ) made of In-Ceram Zirconia . Twenty FDPs were inserted in 15 patients . Over a mean observation period of 74.6 months , the survival rate was 85 % . Sixty-five percent of cases did not allow for connector dimensions that met the manufacturer 's recommendations without the use of surgical procedures ( eg , crown lengthening ) . Posterior all-ceramic FDPs made of In-Ceram Zirconia appear to be a viable prosthetic treatment option to replace a missing tooth OBJECTIVES The aim of the present pilot study was to test whether or not posterior zirconia-ceramic fixed dental prostheses ( FDPs ) with pressed veneering ceramic exhibit less chipping than FDPs with layered veneering ceramics . METHODS Forty patients ( 13 female , 27 male ; mean age 54 years ( range 26.1 - 80.7 years ) in need of one maxillary or m and ibular three-unit FDP in the second premolar or molar region were recruited and treated at two separate centers at the University of Zurich according to the same study protocol . The frameworks were made out of zirconia using a CAD/CAM system ( Cerec Sirona , Bensheim , Germany ) . The patients were r and omly assigned to either the test group ( zirconia frameworks veneered with pressed ceramic ; IPS e.max ZirPress , Ivoclar Vivadent AG , Schaan , Liechtenstein ; n=20 ) or the control group ( layered veneering ceramic ; IPS e.max Ceram , Ivoclar Vivadent AG , Schaan , Liechtenstein ; n=20 ) . All FDPs were adhesively cemented and evaluated at baseline ( i.e. , cementation ) , at 6 months and at 1 and 3 years of clinical service . The survival of the reconstruction was recorded . The technical outcome was assessed using modified United States Public Health Services ( USPHS ) criteria . The biologic parameters analyzed at abutment teeth and analogous non-restored teeth included probing pocket depth ( PPD ) , plaque control record ( PCR ) , bleeding on probing ( BOP ) , and tooth vitality ( CO2 ) . Data was descriptively analyzed and survival was calculated using Kaplan-Meier statistics . RESULTS 36 patients ( 25 female , 11 male ; mean age 52.3 years ) with 18 test and 18 control FDPs were examined after a mean follow-up of 36 months ( 95 % CI : 32.6 - 39.1 months ) . Comparison of groups was done by Crosstabulation showing even distribution of the respective restored teeth amidst the groups . Survival rate was 100 % for both test and control FDPs . Chipping of the veneering ceramic tended to occur more frequently in test ( n=8 ; 40 % ) than in control ( n=4 ; 20 % ) FDPs , albeit not significantly ( p=0.3 ) . No further differences of the technical outcomes of test and control FDPs occurred . In both test and control group healthy conditions and no difference of the biologic parameters at the abutment and un-restored teeth was found . CONCLUSION Zirconia FDPs with pressed and layered veneering ceramics exhibited similar outcomes at 3 years . A trend to more chipping of the pressed veneering ceramic , however , was observed . CLINICAL SIGNIFICANCE Posterior restorations with zirconia frameworks are a viable treatment method . When restoring posterior teeth with all-ceramic restorations , care providers should be aware of the higher rate of chipping compared to the published data on conventional metal-ceramic restorations This prospect i ve study evaluated the clinical outcome of three-unit posterior fixed dental prostheses ( FDPs ) made of In-Ceram Zirconia . All 65 FDPs were inserted at the Department of Prosthodontics , School of Dentistry , Kiel , Germany , and cemented with glass-ionomer cement . Follow-ups were performed annually . During a mean observation time of 54.4 months , two FDPs failed ( one technical and one biologic failure ) . Two FDPs debonded and the veneering ceramic fractured in four cases . Three abutment teeth needed endodontic treatment and two additional abutment teeth exhibited secondary caries . Results suggest that posterior three-unit all-ceramic FDPs made from In-Ceram Zirconia may be a viable prosthetic treatment option with an outcome comparable to metal-ceramic FDPs AIMS Aim of this r and omized , long-term clinical trial was to compare clinical - and patient-based outcomes following periodontal regeneration or extraction and replacement of hopeless teeth with chronic perio-endo lesions and /or attachment loss to or beyond the apex . METHODS Fifty patients presenting with generalized severe periodontitis and at least one hopeless tooth to be extracted for periodontal reasons were entered in this study . The test treatment consisted in the application of a regenerative strategy to 25 hopeless teeth . The control treatment consisted in the extraction of the 25 hopeless teeth and their replacement with conventional or implant-supported fixed partial dentures . RESULTS In the control group , 14 teeth were replaced with implant-supported restorations , eight with tooth-supported bridges , two with Maryl and bridges , while one was not replaced . All fixed partial dentures survived the 5-year follow-up period and 83 % were free from biological complications . In the test group , 23 of the 25 regenerated teeth showed important clinical improvements : the two teeth with unsatisfactory outcomes were extracted at 1 year . The 23 successfully regenerated teeth ( 92 % ) were in good health and function at 5-year examination visit and 84 % did not develop biological complications during the recall period . All patients consistently reported comfort in function at the experimental test and control units . In the test group , average clinical attachment level gains were 7.7±2.8 mm , radiographic bone gain 8.5±3.1 mm , probing pocket depth ( PPD ) reduction 8.8±3 mm . Residual PPDs were 4±1.7 mm . Most of the regenerated teeth showed a decrease in tooth mobility . CONCLUSIONS Regenerative therapy can be applied at hopeless teeth and has the potential to change their prognosis ; it is a suitable alternative to extraction of severely compromised teeth with intra-bony defects to or beyond the root apex The purpose of this prospect i ve study was to evaluate the clinical outcome of three- to four-unit posterior all-ceramic fixed dental prostheses ( FDPs ) made of yttria-stabilized tetragonal zirconia-polycrystal ceramic frameworks ( CerconBase ; Degudent ) . Fifty-eight restorations were placed in 48 patients . Twenty-four FDPs had an end abutment design ( EAD ) replacing 3 premolars and 21 molars . Thirty-four FDPs had a cantilever design ( CD ) replacing 11 premolars and 23 molars . The frameworks had a minimum proximal connector dimension of 3 x 3 mm . The fixed dental prostheses were cemented with glass-ionomer cement after air-abrading the inner crown surfaces . Three FDPs were defined as drop-outs . The mean observation period was 48 + /- 7 months for the EAD ( 21 patients /24 FDPs ) and 50 + /- 14 months for the CD ( 25 patients /31 FDPs ) . The 4-yr survival rate , according to the Kaplan-Meier analyses , was 96 % for the EAD and 92 % for the CD . The technical complication rate was 13 % for the EAD and 12 % for the CD , and the biological complication rate was 21 % for the EAD and 15 % for the CD . For none of the analyses were significant differences found between both groups . After 4 yr the clinical outcome of three- to four-unit posterior FDPs with EAD and CD was promising STATEMENT OF PROBLEM In the posterior maxilla , tooth loss is usually associated with alveolar bone resorption and sinus pneumatization , limiting the placement of implants without grafting procedures . PURPOSE The purpose of this study was to evaluate a minimally invasive treatment of the atrophic posterior maxilla , with axial and tilted implants and immediate loading . The research hypothesis was that the combination of a guided , minimally invasive approach and the biomimetic features of computer-aided design and computer-aided manufacturing ( CAD/CAM ) abutments would be an effective alternative to maxillary sinus floor augmentation procedures with reduced bone resorption around implants . MATERIAL AND METHODS Twenty-seven consecutive participants ( female=12 , male=15 ) ( mean age 54.18 years ) with severe atrophy of the posterior maxilla were treated by using guided surgery with immediately loaded axial ( 39 ) and tilted ( 42 ) implants supporting CAD/CAM zirconia ( 39 ) and titanium ( 42 ) abutments ( 81 total ) and partial fixed prostheses . Each participant underwent a computed tomography scan , after which 2 or 3 implants were positioned with a flapless or miniflap approach . The drilling protocol was adapted to the bone density of each implant site to obtain an insertion torque ranging between 40 and 50 Ncm . CAD/CAM customized abutments composed of zirconia or titanium were fixed to the implants with prosthetic screws tightened with a torque of 35 Ncm . An acrylic resin interim restoration reinforced with metal was placed immediately . Five to 6 months after initial loading , a zirconia framework was manufactured , and a definitive prosthesis was placed . Clinical and radiological controls were performed at baseline and after 1 and 3 years to assess implant and prosthesis survival and success rate and compare marginal bone remodeling of axial and tilted implants . Inferential statistics for radiological data were acquired by using the Mann-Whitney U-test . All statistical comparisons were conducted at the .05 significance level . RESULTS The mean follow-up period was 43.3 months ( ranging from 36 months to 54 months ) . The cumulative implant survival rate was 96.3 % at 3 years . All prosthetic restorations were stable and in good function , result ing in a cumulative prosthetic survival rate of 100 % . Three restorations had chipping of the veneer material ; thereafter , the cumulative prosthetic success rate was 91.9 % . CONCLUSIONS Treatment of the posterior partially edentulous atrophic maxilla with guided surgery and immediate loading of tilted and straight implants supporting short-span partial fixed dental prostheses is effective BACKGROUND The authors conducted a prospect i ve study to evaluate the long-term outcome of crown-retained fixed dental prostheses ( FDPs ) made from monolithic lithium disilicate ceramic ( IPS e.max Press , Ivoclar Vivadent , Schaan , Liechtenstein ) . METHODS Faculty dentists at the Department of Prosthodontics , Propaedeutics and Dental Material s , School of Dentistry , Christian-Albrechts University at Kiel , Germany , placed 36 three-unit FDPs in 28 patients to replace six anterior and 30 posterior teeth . The proximal connector size ( height and width ) was 4 × 3 millimeters for anterior FDPs and 4 × 4 mm for posterior FDPs . FDPs were cemented either conventionally with glass ionomer cement ( n = 19 ) or adhesively with resin-based composite ( n = 17 ) . Patients made annual recall visits . RESULTS The mean ( st and ard deviation ) observation period was 121 ( 12.8 ) months . FDPs ' survival rate ( survival being defined as remaining in place either with or without complications ) was 100 percent after five years and 87.9 percent after 10 years , and their success rate ( success being defined as remaining unchanged and free of complications ) was 91.1 percent after five years and 69.8 percent after 10 years . The cementation method did not affect the outcome . CONCLUSION Three-unit FDPs made from monolithic lithium disilicate ceramic showed five- and 10-year survival and success rates that were similar to those of conventional metal-ceramic FDPs . CLINICAL IMPLICATION S If the manufacturer 's recommendations are followed , three-unit FDPs made from monolithic lithium disilicate ceramic may be a safe alternative to metal-ceramic FDPs regardless of the cementation method used This prospect i ve clinical trial aim ed at evaluating the clinical performance of three-unit posterior zirconia fixed dental prostheses ( FDPs ) after 5 years of clinical function . Thirty-seven patients received 48 three-unit zirconia-based FDPs . The restorations replaced either a premolar or a molar . Specific inclusion criteria were needed . Tooth preparation was st and ardized . Computer-aided design /computer-assisted manufacturing frameworks with a 9-mm2 cross section of the connector and a 0.6-mm minimum thickness of the retainer were made . The restorations were luted with resin cement . The patients were recalled after 1 , 6 , 12 , 24 , 36 , 48 , and 60 months . The survival and success of the ceramics and zirconia were evaluated . The technical and aesthetic outcomes were examined using the United States Public Health Service criteria . The biologic outcomes were analyzed at abutment and contralateral teeth . Descriptive statistics were performed . All FDPs completed the study , result ing in 100 % cumulative survival rate and 91.9 % and 95.4 % cumulative success rates for patients wearing one and two FDPs , respectively . No losses of retention were recorded . Forty-two restorations were rated alpha in all measured parameters . A minor chipping of the ceramics was detected in three restorations . No significant differences between the periodontal parameters of the test and control teeth were observed . Five-year clinical results proved that three-unit posterior zirconia-based FDPs were successful in the medium term for both function and aesthetic . Zirconia can be considered a promising substitute of metal frameworks for the fabrication of short-span posterior prostheses PURPOSE The aim of the present clinical trial was to evaluate the 12-month success rate of titanium dental implants placed in the posterior m and ible and immediately loaded with 3-unit fixed partial dentures . MATERIAL S AND METHODS Patients with missing m and ibular premolars and molars were enrolled in this study . To be included in the study , the implants had to show good primary stability . Implant stability was measured with resonance frequency analysis using the Osstell device ( Integration Diagnostics ) . Implants were included in the study when the stability quotient ( ISQ ) exceeded 62 . Clinical measurements , such as width of keratinized tissue , ISQ , and radiographic assessment of peri-implant bone crest levels , were performed at baseline and at the 12-month follow-up . The comparison between the baseline and the 12-month visits was performed with the Student t test for paired data ( statistically significant at a level of alpha = 0.05 ) . RESULTS Forty implants with a s and blasted , large grit , acid-etched ( SLA ) surface ( Straumann ) were placed in 20 patients . At 12 months , only 1 implant had been lost because of an acute infection . The remaining 39 implants were successful , result ing in a 1-year success rate of 97.5 % . Neither peri-implant bone levels , measured radiographically , nor implant stability changed significantly from baseline to the 12-month follow-up ( P > .05 ) . DISCUSSION The immediate functional loading of implants placed in this case series study result ed in a satisfactory success rate . CONCLUSION The findings from this clinical study showed that the placement of SLA transmucosal implants in the m and ibular area and their immediate loading with 3-unit fixed partial dentures may be a safe and successful procedure PURPOSE The aim of this prospect i ve study was to evaluate the clinical performance of fully sintered hot isostatic pressed yttria-partially-stabilized zirconia ( Denzir ) 3-unit fixed partial dentures ( FPDs ) . MATERIAL S AND METHODS Nineteen 3-unit FPDs were placed in 18 patients . Ten FPDs were placed in the maxilla and 9 in the m and ible . Two calibrated examiners evaluated the FPDs independently 1 week ( baseline ) , 1 year , 3 years , and 5 years after placement using the California Dental Association quality evaluation system . RESULTS All FPDs were intact at the 5-year examination . One FPD lost retention after 12 months but remained intact ; it was recemented and is still in function after 5 years . All FPDs were rated satisfactory over 5 years . No changes were seen in terms of color and anatomic form . The number of slightly rough or pitted occlusal surfaces increased approximately 30 % over 5 years . Visible evidence of ditching along the margin increased over time , but only for those FPDs luted with zinc phosphate cement . CONCLUSION The 5-year results indicate that yttria-partially-stabilized zirconia 3-unit FPDs with anatomically design ed frameworks are promising prosthetic alternatives , even in the premolar and molar regions . However , for all-ceramic FPDs with more units in function , further studies are necessary PURPOSE The aim of this clinical trial was to evaluate the influence of gingival tissue thickness on crestal bone loss around dental implants after a 1-year follow-up . MATERIAL S AND METHODS Forty-six implants ( 23 test and 23 control ) were placed in 19 patients . The test implants were placed about 2 mm supracrestally , whereas the control implants were positioned at the bone level . Before implant placement , the tissue thickness at implant sites was measured with a periodontal probe . After healing , metal-ceramic cement-retained prostheses were constructed . According to tissue thickness , the test implants were divided into A ( thin ) and B ( thick ) groups . Intraoral radiographs were performed and crestal bone changes were measured at implant placement and after 1 year . RESULTS Mean bone loss around the test implants in group A ( thin mucosa ) was 1.61 + /- 0.24 mm ( SE ; range , 0.9 to 3.3 mm ) on the mesial and 1.28 + /- 0.167 mm ( range , 0.8 to 2.1 mm ) on the distal . Mean bone loss in test group B ( thick mucosa ) implants was 0.26 + /- 0.08 mm ( range , 0.2 to 0.9 mm ) on the mesial aspect and 0.09 + /- 0.05 mm ( range , 0.2 to 0.6 mm ) on the distal aspect . Mean bone loss around control implants was 1.8 + /- 0.164 mm ( range , 0.6 to 4.0 mm ) and 1.87 + /- 0.166 mm ( range , 0.0 to 4.1 mm ) on the mesial and distal aspects , respectively . Analysis of variance revealed a significant difference in terms of bone loss between test A ( thin ) and B ( thick ) groups on both the mesial and the distal . CONCLUSION Initial gingival tissue thickness at the crest may be considered as a significant influence on marginal bone stability around implants . If the tissue thickness is 2.0 mm or less , crestal bone loss up to 1.45 mm may occur , despite a supracrestal position of the implant-abutment interface OBJECTIVES The aim of this prospect i ve clinical study was to assess the long-term clinical survival rate and the technical and biological complication rates of zirconia-based posterior FDPs . MATERIAL S AND METHODS Forty-five patients in need of one or more posterior FDPs received 57 three- to five-unit zirconia-based FDPs . The frameworks were fabricated by means of a prototype computer-aided manufacturing ( CAM ) system ( direct ceramic machining , DCM ) , first processing zirconia in the white stage . The frameworks were veneered with a prototype veneering ceramic . The FDPs were adhesively placed . At baseline , 6 months , and 1,2 , 3 , 5 , 8 and 10 years of function , the FDPs were examined for technical and /or biological complications . Furthermore , the periodontal health of the abutment teeth ( test ) and untreated control teeth was analyzed . Statistical analysis was performed applying descriptive statistics , Kaplan-Meier survival and multiple mixed effects regression tests . RESULTS Twenty-one patients with 26 FDPs were examined at a mean observation time of 10.7 + /- 1.3 years . A total of 16 FDPs were lost to follow-up . Fifteen FDPs had to be replaced due to technical/biological complications ; hence , the 10-year survival rate of the FDPs was 67 % . Three framework fractures occurred , result ing in a 10-year survival rate for the zirconia frameworks of 91.5 % . Chipping/fracture of the veneering ceramic was detected in 16 FDPs over 10 years ( complication rate 32 % ) . A significant correlation of the span of the FDPs and the incidence of chipping was observed : 4- and 5-unit FDPs had a 4.9 times higher probability for chipping than 3-unit FDPs . Marginal discrepancy/degradation was found in 90.7 % of the FDPs over 10 years . At 11 of the FDPs ( complication rate 27 % ) , secondary caries occurred . No difference of the periodontal health was found around test and control teeth . CONCLUSION The zirconia frameworks exhibited very good long-term stability . However , the zirconia-based FDPs frequently exhibited problems such as marginal deficiency or chipping of the veneering ceramic . Both problems may be associated with the prototype status of the system In-Ceram is a sintered , high-alumina-content , glass-infiltrated ceramic core material reported to have sufficient strength for all-ceramic fixed partial dentures . While Vita/Vident recommends that In-Ceram should be used only for anterior FPDs , the purpose of this study was to push the sintered alumina material to its limits by testing posterior FPDs with premolar and molar pontics . This prospect i ve clinical trial tested the longevity of 61 three-unit In-Ceram alumina FPDs . The failed specimens were analyzed to determine factors contributing to failure . The abutment teeth were prepared for full crown retainers with shoulder margins and 1.3 mm of axial reduction . All FPDs were cemented with an encapsulated glass ionomer . None of the patients reported postcementation sensitivity . During the three-year period , seven FPDs fractured through the connector area . By location of the pontic , failure rates were 0 percent for anteriors , 11 percent for premolars and 24 percent for molars . Based on the results of this clinical study at the three-year point , In-Ceram alumina can be reliably utilized for anterior FPDs as indicated by a 100 percent success rate . The findings do not support the use of In-Ceram alumina for posterior FPDs as was advised by the porcelain manufacturer . Glass ionomer cement can be predictably used to cement In-Ceram FPDs with few clinical side effects . Because of a technological malfunction , this article could not be presented with the others on ceramic restorations that appeared in the February issue OBJECTIVES The aim of this study was to evaluate the clinical performance of crowns and fixed partial dentures ( FPDs ) made with the Empress 2 system over a 2-year period . METHODS Twenty anterior or posterior all-ceramic ( Empress 2 ) crowns and 20 anterior or posterior , three-unit fixed partial dentures were fabricated for 15 patients . Evaluations of the restorations were performed at baseline and once a year during the 2-year follow-up period . U.S. Public Health Service criteria were used to examine the marginal adaptation , color match , secondary caries and visible fractures in the restorations . Survival rate of the restorations were determined using Kaplan-Meier statistical analysis . RESULTS U.S. Public Health Service criteria showed 100 % Alpha scores concerning recurrent caries for both crowns and FPDs . No crown fractures were observed during the 2-year follow-up , however , 10 ( 50 % ) catastrophic failures of FPDs occurred . Five ( 25 % ) failures occurred within the 1-year clinical period and the others ( 25 % ) within the second year . SIGNIFICANCE Single unit Empress 2 all-ceramic crowns exhibited a satisfactory clinical performance over 2-year period . Furthermore , the high fracture rate of Empress 2 FPDs limits the usage of Empress 2 for the fabrication of all-ceramic FPD BACKGROUND Comparatively few studies with at least 5 years of follow-up are available that describe the use of implants in prosthetic rehabilitation of partially edentulous patients . R and omized , controlled clinical studies that evaluated the effect of different surface design s of screw-shaped implants on the outcome of treatment are also sparse . OBJECTIVE To determine , in a prospect i ve r and omized , controlled clinical trial , the outcome of restorative therapy in periodontitis-susceptible patients who , following basic periodontal therapy , had been restored with implants with either a machined- or a rough-surface topography . MATERIAL AND METHODS Fifty-one subjects ( mean age , 59.5 years ) , 20 males and 31 females who , following treatment of moderate-to-advanced chronic periodontitis , required implant therapy for prosthetic rehabilitation were recruited . Seventeen of the patients were current smokers . Following the active treatment , all subjects were included in an individually design ed maintenance program . A total of 56 fixed partial dentures ( FPDs ) and a total of 149 screw-shaped , and self-tapping implants ( Astra Tech implants ) -- 83 in the maxilla and 66 in the m and ible -- were installed in a two-stage procedure . Each patient received a minimum of two implants and by r and omization every second implant that was installed had been design ed with a machined surface and the remaining with a roughened Tioblast surface . Abutment connection was performed 3 - 6 months after implant installation . Clinical and radiographical examinations were performed following FPD connection and once a year during a 5-year follow-up period . The analysis of peri-implant bone-level alterations was performed on subject , FPD and implant levels . RESULTS Four patients and four FPDs were lost to the 5 years of monitoring . One implant ( machined surface ) did not properly integrate ( early failure ) , and was removed at the time of abutment connection . Three implants were lost during function and a further eight implants could not be accounted for at the 5-year follow-up examination . The overall failure rate at 5 years was 5.9 % ( subject level ) , 5.3 % ( FPD level ) and 2.7 % ( implant level ) . Radiographic signs of loss of osseointegration were not found at any of the implants during the 5-year observation period . During the first year in function there was on average 0.33 ( SD , 0.61 ) mm loss of peri-implant marginal bone on the subject and FPD levels and 0.31 ( 0.81 ) mm on the implant level . During the subsequent 4 years , the peri-implant bone-level alterations were small . The calculated annual change in peri-implant bone level was -0.02 ( 0.15 ) on subject and FPD levels and -0.03 ( 0.20 ) on the implant level . Thus , the mean total bone-level change over the 5-year interval amounted to 0.41 mm on all three levels of analysis . In the interval between baseline and 5 years , the machined and the Tioblast implants lost on average 0.33 and 0.48 mm , respectively ( p>0.05 ) . CONCLUSION The present r and omized , controlled clinical trial that included partially edentulous periodontitis-susceptible subjects demonstrated that bone loss ( i ) during the first year of function as well as annually thereafter was small and ( ii ) did not vary between implants with machined- or rough-surface design OBJECTIVES The aim of this study was to test whether or not customized zirconia abutments exhibit the same survival rates in canine and posterior regions as titanium abutments , and to compare the esthetic result of the two abutment types . MATERIAL AND METHODS Twenty-two patients with 40 implants in posterior regions were included and the implant sites were r and omly assigned to 20 customized zirconia and 20 customized titanium abutments . All-ceramic ( AC ) and metal-ceramic ( MC ) crowns were fabricated . In all except two cases , the crowns were cemented on the abutments using resin or glass-ionomer cements . Two zirconia reconstructions were screw retained . At baseline , 6 and 12 months , the reconstructions were examined for technical and biological problems . Probing pocket depth ( PPD ) , plaque ( Pl ) and bleeding on probing ( BOP ) were assessed and compared with natural control teeth . Furthermore , the difference of color ( DeltaE ) of the peri-implant mucosa and the gingiva of control teeth was evaluated by means of a spectrophotometer ( Spectroshade ) . The data were analyzed with Student 's unpaired t-test , ANOVA and regression analyses . RESULTS Twenty patients with 19 zirconia and 12 titanium abutments were examined at a mean follow-up of 12.6+/-2.7 months . The survival rate for reconstructions and abutments was 100 % . No technical or biological problems were found at the test and control sites . Two chippings ( 16.7 % ) occurred at crowns supported by titanium abutments . No difference was found regarding PPD ( meanPPD(ZrO2 ) 3.4+/-0.7 mm , mPPD(Ti ) 3.3+/-0.6 mm ) , Pl ( mPl(ZrO2 ) 0.2+/-0.3 , mPl(Ti ) 0.1+/-1.8 ) and BOP ( mBOP(ZrO2 ) 60+/-30 % , mBOP(Ti ) 30+/-40 % ) between the two groups . Both crowns on zirconia and titanium abutments induced a similar amount of discoloration of the soft tissue compared with the gingiva at natural teeth ( DeltaE(ZrO2 ) 8.1+/-3.9 , DeltaE(Ti ) 7.8+/-4.3 ) . CONCLUSIONS At 1 year , zirconia abutments exhibited the same survival and a similar esthetic outcome as titanium abutments OBJECTIVES This article is part of a r and omized clinical trial on different treatments in the shortened dental arch ( SDA ) . It focused on the abutment tooth prognosis with cantilevered fixed dental prostheses ( CFDPs ) . METHODS Sixty-two patients with a bilaterally SDA up to the first or second premolar in the m and ible or maxilla were evaluated . In 57 of 124 quadrants , second premolars were replaced by a CFDP ( cantilever group ) . In the remaining 67 quadrants , a natural second premolar was present and thus no need for a CFDP was given ( non-cantilever group ) . Patients were recalled annually up to 5 years . RESULTS The mean observation period was 56.3 months ( min . 3.0 , max . 76.2 , SD 16.1 ) . Kaplan-Meier survival rates concerning tooth loss and tooth fracture were 93.9%/94.0 % in the cantilever group and 91.9%/92.8 % in the non-cantilever group . Differences between both groups were not significant . The survival rate concerning loss of retention of CFDP retainers was 92.1 % in the cantilever group . CONCLUSION After 5 years of clinical service , CFDPs for the replacement of the second premolar showed no negative impact on the abutment tooth prognosis . CLINICAL SIGNIFICANCE Cantilevered fixed dental prostheses present a viable treatment option in the shortened dental arch without compromising the medium-term abutment tooth prognosis PURPOSE The purpose of the present study was to compare the crestal bone loss around implants placed according to either a 1-stage or 2-stage implant installation procedure using a digital subtraction radiography technique . MATERIAL S AND METHODS In the present r and omized clinical trial , screw-shaped tapered implants were inserted in the posterior m and ible of patients needing fixed partial dentures . In each edentulous area , according to the r and omization table , 1 implant was inserted using a 1-stage procedure ( group 1 ) and 1 was placed using a 2-stage approach ( group 2 ) . The implants were temporized with the relined denture after 2 weeks . All implants were functionally loaded with fixed partial dentures after 3 months . Crestal bone loss ( primary outcome variable ) was measured using a digital subtraction radiography technique . St and ardized radiovisiographs were taken after implant insertion , after fixed partial denture installation ( 3 months after surgery ) , and after 6 and 12 months of functional loading . The data were analyzed using the Wilcoxon signed ranks test ( α = 0.05 ) . RESULTS Eleven patients ( mean age 46.9 years , 3 women and 8 men ) were included in the study . A total of 34 implants were inserted , 17 using a 1-stage protocol and 17 using a 2-stage protocol . Three months after implant placement , the 2-stage implants showed significantly more crestal bone loss ( 0.65 ± 0.71 mm ) than the 1-stage implants ( 0.41 ± 0.53 mm ; P = .02 ) . However , after 6 and 12 months of functional loading , both groups showed comparable changes in bone level ( P > .05 ) . CONCLUSIONS No differences were found between 1-stage and 2-stage implant placement in crestal bone loss after 1 year of functional loading |
13,774 | 22,002,504 | Short-term use of AF ( 72 h or less ) associated with medical prevention of ischemic deficit seems to yield better results on functional outcome than long-term use of AF , especially if not associated with a medical prevention of ischemic deficit .
The risk of cerebral infa rct ion is not increased by the short-term use of AF and the risk of rebleeding is decreased independently of the length of AF use .
Conclusions The use of AF should be reconsidered in the setting of modern-era treatment strategies , as the short-term use associated with medical prevention of ischemic deficit decreases the rate of rebleeding and does not increase the risk of cerebral infa rct ion , thus potentially yielding better protection against poor functional outcome | Background To reassess the use of antifibrinolytics ( AF ) in the management of aneurysmal subarachnoid hemorrhage ( SAH ) in the setting of present-day treatment strategies . | Background and Purpose Population -based patient material s have not been used earlier in assessing the effects of neurosurgical treatment on survival and functional outcome of subarachnoid hemorrhage . Moreover , the proportion of all subarachnoid hemorrhage patients who might be c and i date s for neurosurgical treatment has not been estimated . Methods We compared the survival and functional outcome of two population -based patient material s from Central Finl and in 1976 through 1978 ( n=146 ) and 1980 through 1987 ( n=351 ) . The most important basic characteristics of both material s were similar . In the 1970s , only patients aged < 60 years with carotid territory aneurysms were operated on after an interval of 2 weeks from the bleeding . In the 1980s , early surgery was attempted , and the other exclusion criteria were ab and oned . Allocation to medical or surgical treatment was not r and omized . Results During the 1970s , only 14 % of the patients had surgical treatment , with a median delay of 15 days after the bleeding ; in the 1980s , the corresponding figures were 46 % and 4 days . Despite these fundamental changes in the treatment policy , the survival up to 3 years in the 1980s was only marginally improved compared with the 1970s . Conversely , the functional outcome at 4 years after the bleeding was significantly better in the 1980s than the 1970s , with 82 % and 64 % of the survivors , respectively , being independent in the activities of daily living ( P=.002 ) . We estimated that 60 % of all patients with subarachnoid hemorrhage might be c and i date s for neurosurgical treatment , provided that there are no delays in admission or evaluation . Conclusions An active treatment policy of subarachnoid hemorrhage including early surgery only marginally improves survival , but the quality of life of the survivors is significantly better . Only 60 % of all patients in the population with subarachnoid hemorrhage can , at least theoretically , benefit from surgical treatment . ( Stroke . 1993;24:1649 - 1654 . A controlled clinical trial of epsilon-aminocaproic acid ( E.A.C.A. ) , 36 g/day , was undertaken to assess its effectiveness in reducing immediate recurrence in patients with spontaneous subarachnoid haemorrhage ( S.A.H. ) proved by lumbar puncture . Of 83 patients treated with E.A.C.A. , 3 ( 4 % ) had recurrent haemorrhage , and 1 ( 33 % ) of these died . Of 82 control patients who were not given any antifibrinolytic drug , 22 ( 26 % ) had recurrent haemorrhage , and 10 ( 45 % ) of these patients died . E.A.C.A. produced a striking reduction in the early recurrence of S.A.H. No serious side-effect result ed Summary Tranexamic acid as an antifibrinolytic agent has been investigated in a controlled study in patients with recent subarachnoid haemorrhage . It is concluded that tranexamic acid improves neither rebleeding rates , nor mortality . Predominantly thrombotic complications have been noted as a more serious side effect of tranexamic acid OBJECTIVE --To audit the outcome in patients with subarachnoid haemorrhage ( SAH ) after a change in management strategy . METHODS --A retrospective analysis of patients with aneurysmal subarachnoid haemorrhage over a 20 month period ( phase 1 ) was followed by a prospect i ve analysis of patients presenting during the next 20 months ( phase 2 ) in which a protocol driven management regime of immediate intravenous fluid resuscitation and earlier surgery was pursued . Patients in this phase were grouped into those receiving early ( within four days of subarachnoid haemorrhage ) and late ( after four days of subarachnoid haemorrhage ) surgery . In phase 1 , 75 out of a total of 92 patients underwent surgery on ( median ) day 12 . From phase 2 , 109 patients out of a total of 129 underwent surgery on ( median ) day 4 , 58 of which had their surgery within 4 days of the subarachnoid haemorrhage . Patients in each phase/group were well matched for demographic features , site of aneurysm , and severity of subarachnoid haemorrhage . RESULTS --The surgical morbidity and mortality were no different in the two phases ( P < 0.92 ; chi2 test ) . The management outcomes in the two phases of the study were also no different ( P < 0.52 ) . However , there was a significant reduction in the rebleed rate in patients undergoing surgery within four days of the subarachnoid haemorrhage in phase 2 ( P < 0.0001 ) with an associated trend towards reduced incidence of postoperative ischaemia ( P = 0.06 ) and mortality ( P = 0.11 ) . Operating earlier in phase 2 of the trial result ed in a lower total hospital inpatient stay of 15.8 ( 95 % CI 13.1 - 18.5 ) days for survivors compared with 25.7 ( 95 % CI 21.6 - 29.8 ) days in the late group ( P < 0.00001 ; t test ) . CONCLUSIONS --surgical morbidity and mortality seemed independent of the timing of aneurysm surgery . Early surgery within four days was associated with a highly significant reduction in rebleed rate , and in the duration of total hospital inpatient stay The outcome of treatment with an antifibrinolytic agent ( tranexamic acid ) for six weeks after rupture of an intracranial aneurysm was assessed in a r and omised controlled trial . Twenty-two out of 25 ( 88 % ) treated patients survived at follow-up of three to 33 months compared with 14 out of 25 ( 56 % ) control patients . Among the patients who did not undergo operation the survival rate was 81 % ( 13 out of 16 ) in treated patients and 42 % ( 8 out of 19 ) in controls . Antifibrinolytic treatment has so far been assumed merely to postpone rebleeding and has been used to enable surgery to be deferred . These findings suggest that tranexamic acid may actually prevent rebleeding without operation . Prolonged antifibrinolysis may therefore prove useful in those patients in good condition whose aneurysms do not lend themselves to surgical obliteration Objective : To investigate whether antifibrinolytics in combination with treatment to prevent cerebral ischemia improve outcome in patients with subarachnoid hemorrhage ( SAH ) in whom occlusion of the aneurysm is delayed . Background : Antifibrinolytic treatment reduces rebleeding , but outcome does not improve because of a concurrent increase in the occurrence of cerebral ischemia . Because treatment of ischemia has improved , antifibrinolytics might now have a beneficial effect . Methods : A prospect i ve , double-blind , placebo-controlled multicenter clinical trial was performed . R and omized were 462 patients ( 229 received tranexamic acid , 233 placebo ) admitted within 96 hours after onset of SAH , in whom treatment of the aneurysm was delayed beyond 48 hours after SAH . All patients were treated with calcium antagonists and hypervolemia . At 3 months , outcome was assessed with the Glasgow Outcome Scale . The occurrence of cerebral ischemia and other complications were recorded , and the effects of treatment were related to the clinical condition on admission . Results : Antifibrinolytic treatment had no beneficial effect on outcome ( relative risk [ RR ] , 1.10 ; 95 % confidence limits [ CL ] , 0.91–1.34 ) . Antifibrinolytics significantly reduced the occurrence of rebleeding ( RR , 0.58 ; 95 % CL , 0.42–0.80 ) ; the occurrence of ischemic and other complications was the same in the two groups . Conclusion : Antifibrinolytic treatment combined with treatment to prevent cerebral ischemia does not improve outcome A prospect i ve , observational clinical trial was conducted by the International Cooperative Study on the Timing of Aneurysm Surgery to determine the best time in relation to the hemorrhage for surgical treatment of ruptured intracranial aneurysms . Sixty-eight centers contributed 3521 patients in a 2 1/2-year period beginning in December , 1980 . Analysis by a prespecified " planned " surgery interval demonstrated that there was no difference in early ( 0 to 3 days after the bleed ) or late surgery ( 11 to 14 days ) . Outcome was worse if surgery was performed in the 7 to 10-day post-bleed interval . Surgical results were better for patients operated on after 10 days . Patients alert on admission fared best ; however , alert patients had a mortality rate of 10 % to 12 % when undergoing surgery prior to Day 11 compared with 3 % to 5 % when surgery was performed after Day 10 . Patients drowsy on admission had a 21 % to 25 % mortality rate when operated on up to Day 11 and 7 % to 10 % with surgery thereafter . Overall , early surgery was neither more hazardous nor beneficial than delayed surgery . The postoperative risk following early surgery is equivalent to the risk of rebleeding and vasospasm in patients waiting for delayed surgery Summary One hundred patients with a verified subarachnoid haemorrhage were studied in a double blind , placebo-controlled trial at a single centre to determine the value and relative risks of tranexamic acid ( TXA ) in the management of ruptured intracranial aneurysms . The incidence of recurrent haemorrhage between active and placebo groups was identical ( 12 % ) and the mortality from recurrent haemorrhage was 7 % and 5 % , respectively . The overall incidence of cerebral infa rct ion before surgery , at discharge and at 6 months follow-up was greater in the TXA group ( 27 % ) than in the control group ( 11 % ) . Post-operative cerebral ischaemia was significantly more frequent in the active , 18 of 29 as compared to 6 of 32 patients , in the placebo group . In a fifth of the patients in whom cerebral blood flow was estimated there was a significant reduction of cerebral blood flow ( CBF ) on the side of the ruptured aneurysm in the TXA treated group . It is suggested that this may be the cause of the increased incidence of cerebral ischaemia in this group . There was no significant difference in the incidence of cerebral vasospasm , hydrocephalus , visual disturbances and gastrointestinal disturbances . More fatalities were encountered from ischaemia and recurrent haemorrhage in the TXA group but these differences did not reach statistical significance at the 5 % level . Given that disability was due to either vasospasm or recurrent haemorrhage then a patient under TXA treatment was significantly more likely to have disability due to vasospasm ( p<0.04 ) ; the reverse was true for the placebo patient ( p<0.05 ) In a series of 176 prospect ively studied patients who survived for at least 24 hours after aneurysmal subarachnoid hemorrhage , 39 had at least one computerized tomography (CT)-proven rebleed within 4 weeks after the first rupture . There were peaks in the incidence of rebleeding at the end of the 2nd and 3rd weeks . Sudden loss of consciousness occurred in 35 patients , preceded in one-third of them by headache . A sudden increase in headache was a symptom of rebleeding in only one patient . Loss of brain-stem reflexes was recorded in 13 patients , respiratory arrest in six , and both symptoms in eight patients . Apnea was temporary in 11 patients . Rebleeding occurred as gross intraventricular hemorrhage in 20 patients , as a space-occupying hematoma in four , as both types of hemorrhage in three , and as a purely subarachnoid hemorrhage in 12 . The location of the rebleed could not be inferred from the clinical features . Rebleeding was fatal in 51 % of cases ( two of 12 patients with a purely subarachnoid hemorrhage , and 18 of the other 27 patients ( p less than 0.005 ) ) . The risk of rebleeding could not be predicted from the patients ' clinical condition on admission or from the amount of subarachnoid blood identified on the initial CT scan . The risk of further rebleeding was significantly increased in survivors of a first rebleed ( 47 % : p less than 0.01 ) . Only seven ( 18 % ) of the 39 patients with rebleeding had survived at 3 months after the initial hemorrhage A r and omized controlled clinical trial was carried out to study the effect of tranexamic acid ( AMCA , Cyklokapron ; AB Kabi , Stockholm , Sweden ) in the prevention of early rebleeding after the rupture of an intracranial aneurysm . The incidence of vasospasm , hydrocephalus , cerebral ischemic and thromboembolic complications , morbidity , and mortality was also evaluated . The series comprises 59 patients , 30 treated with tranexamic acid and 29 controls . The treatment was stopped if there was rebleeding , operation , or discharge from the hospital . There were 6 recurrent hemorrhages in 6 patients in the tranexamic acid-treated group and 11 recurrences in 7 patients in the control group . Recurrent hemorrhages occurred later in tranexamic acid-treated patients than in controls . Five patients in each group died from rebleeding . Five additional treated patients and 2 controls died from cerebral ischemic dysfunction . The results suggest that tranexamic acid may protect patients with ruptured aneurysms from rebleeding for 1 or 2 weeks , but that it also may produce cerebral ischemic complications Background and Purpose — ϵ-Aminocaproic acid ( EACA ) is an antifibrinolytic agent used to prevent rebleeding in aneurysmal subarachnoid hemorrhage . Although studies have found that a decrease in rebleeding with long-term antifibrinolytic therapy is offset by an increase in ischemic deficits , more recent studies have indicated that early , short-term therapy may be beneficial . Methods — We instituted a protocol for acute EACA administration starting at diagnosis and continued for a maximum duration of 72 hours after subarachnoid hemorrhage onset . We compared 73 patients treated with EACA with 175 non-EACA-treated patients . We sought to identify differences in the occurrence of rebleeding , side effects , and outcome . Results — Baseline characteristics were similar in the 2 groups . There was a significant decrease in rebleeding in EACA-treated patients ( 2.7 % ) versus non-EACA patients ( 11.4 % ) . There was no difference in ischemic complications between cohorts . There was a significant 8-fold increase in deep venous thrombosis in the EACA group but no increase in pulmonary embolism . There was a nonsignificant 76 % reduction in mortality attributable to rebleeding , a 13.3 % increase in favorable outcome in good- grade EACA-treated patients , and a 6.8 % increase in poor- grade patients . Conclusions — When used acutely , short-term EACA treatment result ed in decreased rebleeding without an increase in serious side effects in our selected group of patients . R and omized placebo-controlled trials are needed to determine whether acute antifibrinolytic therapy should be accepted as the st and ard of care in all patients A double‐blind clinical trial of tranexamic acid was carried out on 39 patients with fresh subarachnoid hemorrhage from a ruptured aneurysm . Twenty patients received tranexamic acid , 6 gm daily for 14 to 21 days , while 19 patients received conventional therapy of bedrest and dexamethasone when cerebral edema developed , plus isotonic saline . Rebleeding and mortality were reduced by one‐fourth and one‐fifth , respectively ( p < 0.001 ) . No side‐effects were observed . Tranexamic acid is valuable in the treatment of subarachnoid hemorrhage caused by ruptured intracranial aneurysms In a double‐blind controlled clinical trial on 51 patients with subarachnoid hemorrhage , tranexamic acid , 4 gm per day for ten consecutive days , did not favorably affect the outcome . Neither mortality nor rebleeding rates were improved after a follow‐up of three months OBJECT By pursuing a policy of very early aneurysm treatment in neurosurgical centers , in-hospital rebleeds can be virtually eliminated . Nonetheless , as many as 15 % of patients with aneurysm rupture suffer ultraearly rebleeding with high mortality rates , and these individuals are beyond the reach of even the most ambitious protocol for diagnosis and referral . Only drugs given immediately after the diagnosis of subarachnoid hemorrhage ( SAH ) has been established at the local hospital level can , in theory , contribute to the minimization of such ultraearly rebleeding . The object of this r and omized , prospect i ve , multicenter study was to assess the efficacy of short-term antifibrinolytic treatment with tranexamic acid in preventing rebleeding . METHODS Only patients suffering SAH verified on computerized tomography ( CT ) scans within 48 hours prior to the first hospital admission were included . A 1-g dose of tranexamic acid was given intravenously as soon as diagnosis of SAH had been verified in the local hospitals ( before the patients were transported ) , followed by doses of 1 g every 6 hours until the aneurysm was occluded ; this treatment did not exceed 72 hours . In this study , 254 patients received tranexamic acid and 251 patients were r and omized as controls . Age , sex , Hunt and Hess and Fisher grade distributions , as well as aneurysm locations , were congruent between the groups . Outcome was assessed at 6 months post-SAH by using the Glasgow Outcome Scale ( GOS ) . Vasospasm and delayed ischemic neurological deficits were classified according to clinical findings as well as by transcranial Doppler ( TCD ) studies . All events classified as rebleeding were verified on CT scans or during surgery . CONCLUSIONS More than 90 % of patients reached the neurosurgical center within 12 hours of their first hospital admission after SAH ; 70 % of all aneurysms were clipped or coils were inserted within 24 hours of the first hospital admission . Given the protocol , only one rebleed occurred later than 24 hours after the first hospital admission . Despite this strong emphasis on early intervention , however , a cluster of 27 very early rebleeds still occurred in the control group within hours of r and omization into the study , and 13 of these patients died . In the tranexamic acid group , six patients rebled and two died . A reduction in the rebleeding rate from 10.8 to 2.4 % and an 80 % reduction in the mortality rate from early rebleeding with tranexamic acid treatment can therefore be inferred . Favorable outcome according to the GOS increased from 70.5 to 74.8 % . According to TCD measurements and clinical findings , there were no indications of increased risk of either ischemic clinical manifestations or vasospasm that could be linked to tranexamic acid treatment . Neurosurgical guidelines for aneurysm rupture should extend also into the preneurosurgical phase to guarantee protection from ultraearly rebleeds . Currently available antifibrinolytic drugs can provide such protection , and at low cost . The number of potentially saved lives exceeds those lost to vasospasm We enrolled 479 patients with subarachnoid hemorrhage in a multicenter , r and omized , double-blind , placebo-controlled trial to determine whether treatment with the antifibrinolytic agent tranexamic acid improves outcome by preventing rebleeding . At three months there was no statistical difference between the outcomes in the tranexamic acid group and the control group . Of the 173 patients who died , 84 had received tranexamic acid and 89 placebo ( 95 per cent confidence interval for the difference in mortality rate , -6 to 11 per cent ) . Similarly , when analysis was restricted to patients with an angiographically demonstrated aneurysm , there was no significant difference between the groups . This absence of effect was not due to a lack of antifibrinolytic action , since the rate of rebleeding was reduced from 24 per cent in the control group to 9 per cent in the tranexamic acid-treated group ( chi-square = 18.07 , P less than 0.001 ) , but result ed from a concurrent increase in the incidence of ischemic complications ( 15 per cent in the control group and 24 per cent in the tranexamic acid group ; chi-square = 8.07 , P less than 0.01 ) . We conclude that until some method can be found to minimize ischemic complications , tranexamic acid is of no benefit in patients with subarachnoid hemorrhage A r and omized , controlled clinical trial was carried out to study the effect of tranexamic acid ( AMCA , trans-AMCHA ) in prevention of early rebleeding after proven rupture of an intracranial aneurysm . The series comprises 46 patients admitted to the hospital within three days after the first bleeding . Twenty-three were treated with tranexamic acid and 23 were controls . Nine patients in the control group and one in the group treated with tranexamic acid had confirmed rebleeding . The incidence of vasospasm , cerebral ischemia and hydrocephalus as well as mortality and morbidity is discussed The effects of intravenous tranexamic acid were compared with placebo in 64 patients with subarachnoid hemorrhage . A double-blind procedure was used . One gram of tranexamic acid was given intravenously every 4 hours up to the time of operation on an intracranial arterial aneurysm or for up to 21 days after the first bleeding if operative treatment was not feasible . There were no differences in re-bleeds , morbidity or mortality between the tranexamic and placebo-treated groups . No thromboemboiic complications were noted in either group . Our results do not support the use of tranexamic acid in subarachnoid hemorrhage in daily doses of 6 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 |
13,775 | 28,780,577 | There was no effect seen with ACE inhibitors , aldosterone receptor blockers , mineralocorticoid receptor antagonists and other drug classes , compared with placebo .
Similar results were observed for cardiovascular mortality .
No single drug class reduced heart failure hospitalisation compared with placebo .
Conclusion The efficacy of treatments in patients with heart failure and an LV ejection fraction≥40 % differ depending on the type of therapy , with beta-blockers demonstrating reductions in all-cause and cardiovascular mortality . | Background Clinical drug trials in patients with heart failure and preserved ejection fraction have failed to demonstrate improvements in mortality . | BACKGROUND The effect of treatment with β-blockers on the prognosis of patients newly diagnosed with heart failure with preserved ejection fraction ( HFpEF ) is unknown . OBJECTIVE To analyze the relationship of commencing treatment with the β-blockers bisoprolol or carvedilol ( CT-βB ) with the prognosis of newly diagnosed HFpEF . METHODS Prospect i ve study over 10years on 2704 patients with HFpEF . Main outcomes were mortality ( all-cause and cardiovascular ) , hospitalizations for HF worsening , and visits . The independent relationship between CT-βB and the prognosis , stratifying patients for cardiovascular co-morbidity after propensity score-matching ( 985 patients CT-βB vs. another 985 patients non-CT-βB ) , was analyzed . RESULTS During a median follow-up of 1877.4days ( interquartile range , 1 - 3651.2 ) 1600 died ( 81.2 % ) , and 1702 were hospitalized ( 86.4 % ) . CT-βB was associated with a lower risk of mortality ( all-cause : HR [ CI 95 % ] 0.78 [ 0.71 to 0.85 ] , and cardiovascular : 0.75 [ 0.69 to 0.82 ] ) , a lower hospitalization rate ( per 100 persons-year ) , 15.8 vs. 19.2 , and a lower 30-day readmission rate ( per 100 persons-year ) , 4.0 vs. 5.8 , ( P<0.001 in all cases ) , even after adjustment for the propensity to take β-blockers or other medications , comorbidities , and other potential confounders . These effects of CT-βB were independent of gender , and were observed in both patients taking high dose βB ( over the median dose ) and lower dose βB ( under or equal to the median dose ) . CONCLUSIONS In this propensity matched study , commencing treatment with bisoprolol or carvedilol , both at high and at lower doses , is associated with an improved prognosis of patients newly diagnosed with HFpEF Fifteen elderly patients with normal left ventricular ( LV ) systolic function and New York Heart Association functional class II-III were studied . The effect of verapamil on LV diastolic function was assessed by congestive heart failure ( CHF ) score , treadmill exercise test , and Doppler echocardiography at baseline , and after each three-month treatment period ( placebo or verapamil 120 mg once daily ) , separated by a one-week washout period before crossover . Blood pressure , heart rate , LV ejection fraction , LV mass , and cardiac output were unaltered by placebo or verapamil . Verapamil treatment significantly improved CHF score at 3 months ( 3.5 + /- 0.5 , p<0.05 ) compared with baseline ( 5.6 + /- 0.5 ) or placebo ( 5.5 + /- 0.5 ) . The exercise time was similar at baseline ( 7.4 + /- 1.2 min ) and after placebo ( 7.4 + /- 1.3 min ) treatment but significantly ( p<0.05 ) increased after verapamil ( 8.3 + /- 1.2 min ) treatment . The ratio of mitral A wave duration /pulmonary venous atrial systolic reversal duration increased after verapamil ( 1.11 + /- 0.08 ) treatment compared with placebo ( 0.91 + /- 0.07 , p<0.05 ) and baseline ( 0.89 + /- 0.08 ) which had similar duration s. The isovolumic relaxation time was significantly ( p<0.05 ) decreased from 84 + /- 12 ms at baseline and 86 + /- 13 ms with placebo to 73 + /- 9 ms with verapamil . The results of this study suggest that in elderly patients with Doppler evidence of diastolic dysfunction as the cause of CHF , three months treatment with verapamil can improve CHF , increase exercise tolerance and improve LV diastolic function Background — Heart failure ( HF ) developing in hypertensive patients may occur with preserved or reduced left ventricular ejection fraction ( PEF [ ≥50 % ] or REF [ < 50 % ] ) . In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , 42 418 high-risk hypertensive patients were r and omized to chlorthalidone , amlodipine , lisinopril , or doxazosin , providing an opportunity to compare these treatments with regard to occurrence of hospitalized HFPEF or HFREF . Methods and Results — HF diagnostic criteria were prespecified in the ALLHAT protocol . EF estimated by contrast ventriculography , echocardiography , or radionuclide study was available in 910 of 1367 patients ( 66.6 % ) with hospitalized events meeting ALLHAT criteria . Cox regression models adjusted for baseline characteristics were used to examine treatment differences for HF ( overall and by PEF and REF ) . HF case fatality rates were examined . Of those with EF data , 44.4 % had HFPEF and 55.6 % had HFREF . Chlorthalidone reduced the risk of HFPEF compared with amlodipine , lisinopril , or doxazosin ; the hazard ratios were 0.69 ( 95 % confidence interval [ CI ] , 0.53 to 0.91 ; P=0.009 ) , 0.74 ( 95 % CI , 0.56 to 0.97 ; P=0.032 ) , and 0.53 ( 95 % CI , 0.38 to 0.73 ; P<0.001 ) , respectively . Chlorthalidone reduced the risk of HFREF compared with amlodipine or doxazosin ; the hazard ratios were 0.74 ( 95 % CI , 0.59 to 0.94 ; P=0.013 ) and 0.61 ( 95 % CI , 0.47 to 0.79 ; P<0.001 ) , respectively . Chlorthalidone was similar to lisinopril with regard to incidence of HFREF ( hazard ratio , 1.07 ; 95 % CI , 0.82 to 1.40 ; P=0.596 ) . After HF onset , death occurred in 29.2 % of participants ( chlorthalidone/amlodipine/lisinopril ) with new-onset HFPEF versus 41.9 % in those with HFREF ( P<0.001 ; median follow-up , 1.74 years ) ; and in the chlorthalidone/doxazosin comparison that was terminated early , 20.0 % of HFPEF and 26.0 % of HFREF patients died ( P=0.185 ; median follow-up , 1.55 years ) . Conclusions — In ALLHAT , with adjudicated outcomes , chlorthalidone significantly reduced the occurrence of new-onset hospitalized HFPEF and HFREF compared with amlodipine and doxazosin . Chlorthalidone also reduced the incidence of new-onset HFPEF compared with lisinopril . Among high-risk hypertensive men and women , HFPEF has a better prognosis than HFREF Background — Patients with heart failure are at increased risk of sudden death and death attributed to progressive pump failure . We assessed the effect of c and esartan on cause-specific mortality in patients enrolled in the C and esartan in Heart failure Assessment of Reduction in Mortality and morbidity ( CHARM ) program . Methods and Results —The CHARM program consisted of 3 component trials that enrolled patients with symptomatic heart failure : CHARM-Alternative ( n=2028 ; LVEF=40 % and ACE intolerant ) , CHARM-Added ( n=2548 ; LVEF=40 % , already on ACE inhibitors ) , and CHARM-Preserved ( n=3023 ; LVEF > 40 % ) . Patients were r and omized to c and esartan , titrated to 32 mg QD , or placebo and were followed up for a median of 37.7 months . All deaths were review ed by a blinded adjudication committee and categorized according to prespecified definitions on the basis of a narrative and source documentation . The number and rate of deaths by cause were calculated for each of the component trials and the overall program . Of all the patients , 8.5 % died suddenly , and 6.2 % died of progressive heart failure . C and esartan reduced both sudden death ( HR 0.85 [ 0.73 to 0.99 ] , P=0.036 ) and death from worsening heart failure ( HR 0.78 [ 0.65 to 0.94 ] , P=0.008 ) . These reductions were most apparent in the patients with LVEF=40 % . Conclusions —C and esartan reduced sudden death and death from worsening heart failure in patients with symptomatic heart failure , although this reduction was most apparent in patients with systolic dysfunction AIMS To determine the effects of digoxin on all-cause mortality and heart failure ( HF ) hospitalizations , regardless of ejection fraction , accounting for serum digoxin concentration ( SDC ) . METHODS AND RESULTS This comprehensive post-hoc analysis of the r and omized controlled Digitalis Investigation Group trial ( n=7788 ) focuses on 5548 patients : 1687 with SDC , drawn r and omly at 1 month , and 3861 placebo patients , alive at 1 month . Overall , 33 % died and 31 % had HF hospitalizations during a 40-month median follow-up . Compared with placebo , SDC 0.5 - 0.9 ng/mL was associated with lower mortality [ 29 vs. 33 % placebo ; adjusted hazard ratio ( AHR ) , 0.77 ; 95 % confidence interval ( CI ) , 0.67 - 0.89 ] , all-cause hospitalizations ( 64 vs. 67 % placebo ; AHR , 0.85 ; 95 % CI , 0.78 - 0.92 ) and HF hospitalizations ( 23 vs. 33 % placebo ; AHR , 0.62 ; 95 % CI , 0.54 - 0.72 ) . SDC > or = 1.0 ng/mL was associated with lower HF hospitalizations ( 29 vs. 33 % placebo ; AHR , 0.68 ; 95 % CI , 0.59 - 0.79 ) , without any effect on mortality . SDC 0.5 - 0.9 reduced mortality in a wide spectrum of HF patients and had no interaction with ejection fraction > 45 % ( P=0.834 ) or sex ( P=0.917 ) . CONCLUSIONS Digoxin at SDC 0.5 - 0.9 ng/mL reduces mortality and hospitalizations in all HF patients , including those with preserved systolic function . At higher SDC , digoxin reduces HF hospitalization but has no effect on mortality or all-cause hospitalizations Background —Exercise intolerance is the primary symptom in older patients with heart failure and preserved ejection fraction ( HFPEF ) ; however , little is known regarding its mechanisms and therapy . Methods and Results —Seventy-one stable elderly ( 70±1 years ) patients ( 80 % women ) with compensated HFPEF and controlled blood pressure were r and omized into a 12-month follow-up double-blind trial of enalapril 20 mg/d versus placebo . Assessment s were peak exercise oxygen consumption ; 6-minute walk test ; Minnesota Living with HF Question naire ; MRI ; Doppler echocardiography ; and vascular ultrasound . Compliance by pill count was excellent ( 94 % ) . Twenty-five patients in the enalapril group versus 34 in the placebo group completed the 12-month follow-up . During follow-up , there was no difference in the primary outcome of peak exercise oxygen consumption ( enalapril , 14.5±3.2 mL/kg/min ; placebo , 14.3±3.4 mL/kg/min ; P=0.99 ) , or in 6-minute walk distance , aortic distensibility ( the primary mechanistic outcome ) , left ventricle mass , or neurohormonal profile . The effect size of enalapril on peak exercise oxygen consumption was small ( 0.7 % ; 95 % CI , 4.2 % to 5.6 % ) . There was a trend toward improved Minnesota Living with HF Question naire total score ( P=0.07 ) , a modest reduction in systolic blood pressure at peak exercise ( P=0.02 ) , and a marginal improvement in carotid arterial distensibility ( P=0.04 ) . Conclusions —In stable , older patients with compensated HFPEF and controlled blood pressure , 12 months of enalapril did not improve exercise capacity or aortic distensibility . These data , combined with those from large clinical event trials , suggest that angiotensin inhibition does not substantially improve key long-term clinical outcomes in this group of patients . This finding contrasts sharply with observations in HF with reduced EF and highlights our incomplete underst and ing of this important and common disorder Background —The Minnesota Living with Heart Failure Question naire ( MLHFQ ) was used in a large , multinational , r and omized , placebo-controlled trial to measure adverse effects of heart failure with preserved ejection fraction ( HF-PEF ) on patients ' lives and the effects of irbesartan . Methods and Results — Patients with symptomatic HF-PEF were r and omly assigned to irbesartan ( up to 300 mg daily ) or placebo . The MLHFQ was administered at baseline ( n=3605 ) , month 6 ( n=3137 ) , month 14 ( n=2904 ) , and the end of study ( median , 56 months , n=2205 ) . Baseline MLHFQ scores of 43±21 indicated that HF-PEF had a substantial adverse effects . Estimated retest reliability was 0.80 . Baseline MLHFQ scores were associated with other measures of the severity of heart failure including symptoms , signs of congestion , cardiac structure , and time to hospitalizations or deaths attributed to heart failure . Slight improvement in shortness of breath or fatigue was associated with significant improvement in MLHFQ scores ( −5.9 and −5.0 , P<0.0001 ) . Compared with placebo , further improvement in MLHFQ scores was not observed with irbesartan after 6 months ( mean adjusted difference , 0.4 ; 95 % confidence interval , −0.8 to 1.7 ) , 14 months ( 0.5 ; 95 % confidence interval , −0.9 to 1.8 ) , or the end of study ( 2.0 ; 95 % confidence interval , −4.1 to 0.01 ) . Conclusions —The MLHFQ scores are a reliable , valid , and sensitive measure of the adverse impact of HF-PEF on patients ' lives . Irbesartan did not substantially improve MLHFQ scores during a long period of follow-up . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT00095238 IMPORTANCE Diastolic heart failure ( ie , heart failure with preserved ejection fraction ) is a common condition without established therapy , and aldosterone stimulation may contribute to its progression . OBJECTIVE To assess the efficacy and safety of long-term aldosterone receptor blockade in heart failure with preserved ejection fraction . The primary objective was to determine whether spironolactone is superior to placebo in improving diastolic function and maximal exercise capacity in patients with heart failure with preserved ejection fraction . DESIGN AND SETTING The Aldo-DHF trial , a multicenter , prospect i ve , r and omized , double-blind , placebo-controlled trial conducted between March 2007 and April 2012 at 10 sites in Germany and Austria that included 422 ambulatory patients ( mean age , 67 [ SD , 8 ] years ; 52 % female ) with chronic New York Heart Association class II or III heart failure , preserved left ventricular ejection fraction of 50 % or greater , and evidence of diastolic dysfunction . INTERVENTION Patients were r and omly assigned to receive 25 mg of spironolactone once daily ( n=213 ) or matching placebo ( n=209 ) with 12 months of follow-up . MAIN OUTCOME MEASURES The equally ranked co- primary end points were changes in diastolic function ( E/e ' ) on echocardiography and maximal exercise capacity ( peak VO2 ) on cardiopulmonary exercise testing , both measured at 12 months . RESULTS Diastolic function ( E/e ' ) decreased from 12.7 ( SD , 3.6 ) to 12.1 ( SD , 3.7 ) with spironolactone and increased from 12.8 ( SD , 4.4 ) to 13.6 ( SD , 4.3 ) with placebo ( adjusted mean difference , -1.5 ; 95 % CI , -2.0 to -0.9 ; P < .001 ) . Peak VO2 did not significantly change with spironolactone vs placebo ( from 16.3 [ SD , 3.6 ] mL/min/kg to 16.8 [ SD , 4.6 ] mL/min/kg and from 16.4 [ SD , 3.5 ] mL/min/kg to 16.9 [ SD , 4.4 ] mL/min/kg , respectively ; adjusted mean difference , + 0.1 mL/min/kg ; 95 % CI , -0.6 to + 0.8 mL/min/kg ; P = .81 ) . Spironolactone induced reverse remodeling ( left ventricular mass index declined ; difference , -6 g/m2 ; 95 % CI , -10 to-1 g/m2 ; P = .009 ) and improved neuroendocrine activation ( N-terminal pro-brain-type natriuretic peptide geometric mean ratio , 0.86 ; 95 % CI , 0.75 - 0.99 ; P = .03 ) but did not improve heart failure symptoms or quality of life and slightly reduced 6-minute walking distance ( -15 m ; 95 % CI , -27 to -2 m ; P = .03 ) . Spironolactone also modestly increased serum potassium levels ( + 0.2 mmol/L ; 95 % CI , + 0.1 to + 0.3 ; P < .001 ) and decreased estimated glomerular filtration rate ( -5 mL/min/1.73 m2 ; 95 % CI , -8 to -3 mL/min/1.73 m2 ; P < .001 ) without affecting hospitalizations . CONCLUSIONS AND RELEVANCE In this r and omized controlled trial , long-term aldosterone receptor blockade improved left ventricular diastolic function but did not affect maximal exercise capacity , patient symptoms , or quality of life in patients with heart failure with preserved ejection fraction . Whether the improved left ventricular function observed in the Aldo-DHF trial is of clinical significance requires further investigation in larger population s. TRIAL REGISTRATION clinical trials.gov Identifier : IS RCT N94726526 ; Eudra-CT No : 2006 - 002605 - 31 Background Heart failure with preserved ejection fraction ( HFpEF ) causes significant cardiovascular morbidity and mortality . Current consensus guidelines reflect the neutral results from r and omised controlled trials ( RCTs ) . Adequate trial reporting is a fundamental requirement before concluding on RCT intervention efficacy and is necessary for accurate meta- analysis and to provide insight into future trial design . The Consoli date d St and ards of Reporting Trials ( CONSORT ) 2010 statement provides a framework for complete trial reporting . Reporting quality of HFpEF RCTs has not been previously assessed , and this represents an important validation of reporting qualities to date . Objectives The aim was to systematic ally identify RCTs investigating the efficacy of pharmacological therapies in HFpEF and to assess the quality of reporting using the CONSORT 2010 statement . Methods MEDLINE , EMBASE and CENTRAL data bases were search ed from January 1996 to November 2015 , with RCTs assessing pharmacological therapies on clinical outcomes in HFpEF patients included . The quality of reporting was assessed against the CONSORT 2010 checklist . Results A total of 33 RCTs were included . The mean CONSORT score was 55.4 % ( SD 17.2 % ) . The CONSORT score was strongly correlated with journal impact factor ( r=0.53 , p=0.003 ) and publication year ( r=0.50 , p=0.003 ) . Articles published after the introduction of CONSORT 2010 statement had a significantly higher mean score compared with those published before ( 64 % vs 50 % , p=0.02 ) . Conclusions Although the CONSORT score has increased with time , a significant proportion of HFpEF RCTs showed inadequate reporting st and ards . The level of adherence to CONSORT criteria could have an impact on the validity of trials and hence the interpretation of intervention efficacy . We recommend improving compliance with the CONSORT statement for future RCTs AIMS Many patients who receive a diagnosis of heart failure have neither a low left ventricular ( LV ) ejection fraction nor valve disease . Few substantial r and omized controlled trials have been conducted in this population , none has focussed on patients with evidence of diastolic dysfunction and none has shown clear benefit on symptoms , morbidity , or mortality . METHODS AND RESULTS This was a r and omized double-blind trial , comparing placebo with perindopril , 4 mg/day in patients aged > or = 70 years with a diagnosis of heart failure , treated with diuretics and an echocardiogram suggesting diastolic dysfunction and excluding substantial LV systolic dysfunction or valve disease . The primary endpoint was a composite of all-cause mortality and unplanned heart failure related hospitalization with a minimum follow-up of 1 year . A total of 850 patients were r and omized . Their mean age was 76 ( SD 5 ) years and 55 % were women . Median follow-up was 2.1 ( IQR 1.5 - 2.8 ) years . Enrollment and event rates were lower than anticipated , reducing the power of the study to show a difference in the primary endpoint to 35 % . Many patients withdrew from perindopril ( 28 % ) and placebo ( 26 % ) after 1 year and started taking open-label ACE-inhibitors . Overall , 107 patients assigned to placebo and 100 assigned to perindopril reached the primary endpoint ( HR 0.919 : 95 % CI 0.700 - 1.208 ; P = 0.545 ) . By 1 year , reductions in the primary outcome ( HR 0.692 : 95 % CI 0.474 - 1.010 ; P = 0.055 ) and hospitalization for heart failure ( HR 0.628 : 95 % CI 0.408 - 0.966 ; P = 0.033 ) were observed and functional class ( P < 0.030 ) and 6-min corridor walk distance ( P = 0.011 ) had improved in those assigned to perindopril . CONCLUSION Uncertainty remains about the effects of perindopril on long-term morbidity and mortality in this clinical setting since this study had insufficient power for its primary endpoint . However , improved symptoms and exercise capacity and fewer hospitalizations for heart failure in the first year were observed on perindopril , during which most patients were on assigned therapy , suggesting that it may be of benefit in this patient population Background : Although heart failure with a preserved or normal ejection fraction ( HFNEF or diastolic heart failure ) is common , treatment outcomes on quality of life and cardiac function are lacking . The effect of renin – angiotensin blockade by irbesartan or ramipril in combination with diuretics on quality of life ( QoL ) , regional and global systolic and diastolic function was assessed in HFNEF patients . Methods : 150 patients with HFNEF ( LVEF > 45 % ) were r and omised to ( 1 ) diuretics alone , ( 2 ) diuretics plus irbesartan , or ( 3 ) diuretics plus ramipril . QoL , 6-minute walk test ( 6MWT ) and Doppler echocardiography were performed at baseline , 12 , 24 and 52 weeks . Results : The QoL score improved similarly in all three groups by 52 weeks ( −46 % , 51 % , and 50 % respectively , all p<0.01 ) , although 6MWT increased only slightly ( average + 3–6 % ) . Recurrent hospitalisation rates were equal in all groups ( 10–12 % in 1 year ) . At 1 year , LV dimensions or LVEF had not changed in any group , though both systolic and diastolic blood pressures were lowered in all three groups from 4 weeks onwards . At baseline both mean peak systolic ( Sm ) and early diastolic ( Em ) mitral annulus velocities were reduced , and increased slightly in the diuretic plus irbesartan ( Sm 4.5 ( SEM 0.17 ) to 4.9 ( SEM 0.16 ) cm/sec ; Em 3.8 ( SEM 0.25 ) to 4.2 ( SEM 0.25 ) cm/sec ) and ramipril ( Sm 4.5 ( SEM 0.24 ) to 4.9 ( SEM 0.20 ) cm/sec ; Em 3.3 ( SEM 0.25 ) to 4.04 ( SEM 0.32 ) cm/sec ) groups ( both p<0.05 ) . NT-pro-BNP levels were raised at baseline ( 595 ( SD 905 ) pg/ml ; range 5–4748 ) and fell in the irbesartan ( −124 ( SD 302 ) pg/ml , p = 0.01 ) and ramipril ( −173 ( SD 415 ) pg/ml , p = 0.03 ) groups only . Conclusions : In this typically elderly group of HF patients with normal LVEF , diuretic therapy significantly improved symptoms and neither irbesartan nor ramipril had a significant additional effect . However , diuretics in combination with irbesartan or ramipril marginally improved LV systolic and diastolic longitudinal LV function , and lowered NT-proBNP over 1 year BACKGROUND Half of patients with chronic heart failure ( CHF ) have preserved left-ventricular ejection fraction ( LVEF ) , but few treatments have specifically been assessed in such patients . In previous studies of patients with CHF and low LVEF or vascular disease and preserved LVEF , inhibition of the renin-angiotensin system is beneficial . We investigated the effect of addition of an angiotensin-receptor blocker to current treatments . METHODS Between March , 1999 , and July , 2000 , we r and omly assigned 3023 patients c and esartan ( n=1514 , target dose 32 mg once daily ) or matching placebo ( n=1509 ) . Patients had New York Heart Association functional class II-IV CHF and LVEF higher than 40 % . The primary outcome was cardiovascular death or admission to hospital for CHF . Analysis was done by intention to treat . FINDINGS Median follow-up was 36.6 months . 333 ( 22 % ) patients in the c and esartan and 366 ( 24 % ) in the placebo group experienced the primary outcome ( unadjusted hazard ratio 0.89 [ 95 % CI 0.77 - 1.03 ] , p=0.118 ; covariate adjusted 0.86 [ 0.74 - 1.0 ] , p=0.051 ) . Cardiovascular death did not differ between groups ( 170 vs 170 ) , but fewer patients in the c and esartan group than in the placebo group were admitted to hospital for CHF once ( 230 vs 279 , p=0.017 ) or multiple times . Composite outcomes that included non-fatal myocardial infa rct ion and non-fatal stroke showed similar results to the primary composite ( 388 vs 429 ; unadjusted 0.88 [ 0.77 - 1.01 ] , p=0.078 ; covariate adjusted 0.86 [ 0.75 - 0.99 ] , p=0.037 ) . INTERPRETATION C and esartan has a moderate impact in preventing admissions for CHF among patients who have heart failure and LVEF higher than 40 % Abstract This double-blind , placebo-controlled study evaluated the effects of the ACE inhibitor , quinapril , on the functional status of elderly frail heart failure patients with preserved systolic function . Seventy-four elderly patients , mean ( SD ) age 78 ( 7 ) years , with symptomatic heart failure ( NYHA II – III ) and normal or only mildly impaired left ventricular systolic function ( ejection fraction ≥40 % ) were r and omly assigned to receive either quinapril or matched placebo ( titrated to 40 mg/day ) for 6 months . There were no significant differences at baseline in terms of age , cardiac function , aetiology , concomitant treatment , and echocardiographic values between active and placebo groups . Mean 6-minute walk distance increased at six months in the quinapril group [ 241.2 ( 132.0 ) v 267.3 ( 124.0 ) metres , p = 0.04 ] and in the placebo group [ 214.6 ( 114.5 ) v 267.6 ( 117.0 ) metres , p = 0.003 ] . The mean increases between the two groups were not significantly different . There were no significant changes in quality of life scores . The number of adverse drug events was similar in the two groups . Patients in the quinapril group were less likely to have worsening heart failure or to be admitted to hospital but these changes were not statistically significant . Conclusions . The present study confirmed the feasibility of single-centre drug trials in very elderly heart failure patients although recruitment and retention remain problematic . It did not show a beneficial effect of quinapril on exercise tolerance and quality of life in elderly heart failure patients with preserved systolic function Aims To determine whether valsartan improves treadmill exercise time , in patients with symptomatic heart failure with a preserved ejection fraction ( HFPEF ) , compared with placebo . Methods and results In this multicentred , double-blind , 14-week study , patients were r and omized to receive valsartan ( V ) 80 mg or placebo ( P ) once daily on top of background medications . The dose of valsartan was force-titrated up to 320 mg . A total of 152 patients were r and omized ( V = 70 , P = 82 ) . Most patients had well-controlled hypertension ( V = 91.2 % , P = 89.0 % ) ( mean baseline systolic BP ∼130 mmHg ) and > 50 % were receiving an angiotensin-converting enzyme inhibitor and /or beta-blocker ( V = 57.4 % , P = 54.9 % ) . The mean ejection fraction at baseline was 70.48 % in the placebo group ( n = 64 ) and 71.52 % in the valsartan group ( n = 79 ) . Valsartan had no significant effect on exercise time ( primary variable ) , gas exchange variables , 6 min walk test distance , exertion-related symptoms , brain natriuretic peptide levels , echocardiographic parameters , or quality -of-life scores . Valsartan significantly lowered peak exercise systolic BP ( −13.1 mmHg vs. placebo ; P < 0.001 ) and improved ratings of perceived exertion ( Borg score ) ( −0.69 vs. placebo ; P = 0.008 ) . Conclusion In this population , which predominantly included patients with well-controlled hypertension and symptomatic HFPEF , addition of valsartan did not increase exercise time within 14 weeks . However , valsartan 320 mg reduced blood pressure and improved symptoms of perceived exertion ( Borg score ) during exercise and was generally well-tolerated BACKGROUND Approximately 50 % of patients with heart failure have a left ventricular ejection fraction of at least 45 % , but no therapies have been shown to improve the outcome of these patients . Therefore , we studied the effects of irbesartan in patients with this syndrome . METHODS We enrolled 4128 patients who were at least 60 years of age and had New York Heart Association class II , III , or IV heart failure and an ejection fraction of at least 45 % and r and omly assigned them to receive 300 mg of irbesartan or placebo per day . The primary composite outcome was death from any cause or hospitalization for a cardiovascular cause ( heart failure , myocardial infa rct ion , unstable angina , arrhythmia , or stroke ) . Secondary outcomes included death from heart failure or hospitalization for heart failure , death from any cause and from cardiovascular causes , and quality of life . RESULTS During a mean follow-up of 49.5 months , the primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group . Primary event rates in the irbesartan and placebo groups were 100.4 and 105.4 per 1000 patient-years , respectively ( hazard ratio , 0.95 ; 95 % confidence interval [ CI ] , 0.86 to 1.05 ; P=0.35 ) . Overall rates of death were 52.6 and 52.3 per 1000 patient-years , respectively ( hazard ratio , 1.00 ; 95 % CI , 0.88 to 1.14 ; P=0.98 ) . Rates of hospitalization for cardiovascular causes that contributed to the primary outcome were 70.6 and 74.3 per 1000 patient-years , respectively ( hazard ratio , 0.95 ; 95 % CI , 0.85 to 1.08 ; P=0.44 ) . There were no significant differences in the other prespecified outcomes . CONCLUSIONS Irbesartan did not improve the outcomes of patients with heart failure and a preserved left ventricular ejection fraction . ( Clinical Trials.gov number , NCT00095238 . AIMS The therapeutic strategy for heart failure with preserved ejection fraction ( HFPEF ) has not been established . The Japanese Diastolic Heart Failure Study ( J-DHF ) is a multicentre , prospect i ve , r and omized , open , blinded-endpoint trial , design ed to assess the effects of carvedilol in HFPEF patients . METHODS AND RESULTS A total of 245 patients with heart failure and ejection fraction > 40 % were r and omly assigned into those treated with ( carvedilol group , n = 120 ) and without carvedilol ( control group , n = 125 ) . The primary outcome is a composite of cardiovascular death and unplanned hospitalization for heart failure . During a median follow-up of 3.2 years , the primary endpoint occurred in 29 patients in the carvedilol group and in 34 patients in the control group [ adjusted hazard ratio ( HR ) 0.902 , 95 % confidence interval ( CI ) 0.546 - 1.488 , P = 0.6854 ] . Another major composite endpoint , cardiovascular death and unplanned hospitalization for any cardiovascular causes , occurred in 38 patients of the carvedilol group and 52 patients of the control group ( HR 0.768 , 95 % CI 0.504 - 1.169 ; P = 0.2178 ) . The target dose of carvedilol was 20 mg/day , but the median prescribed dose was 7.5 mg/day . In the patients treated with st and ard doses ( carvedilol > 7.5 mg/day , n = 58 ) , this composite outcome was significantly less than in the controls ( HR 0.539 , 95 % CI 0.303 - 0.959 ; P = 0.0356 ) , whereas it was comparable with the controls in the patients treated with carvedilol ≤7.5 mg/day ( n = 62 , HR 1.070 , 95 % CI 0.650 - 1.763 ; P = 0.7893 ) . CONCLUSIONS Carvedilol did not improve prognosis of HFPEF patients overall ; however , the st and ard dose , not the low dose , prescription might be effective . This may facilitate further investigation . UMIN number : C000000318 BACKGROUND Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction . We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction . METHODS In this r and omized , double-blind trial , we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45 % or more to receive either spironolactone ( 15 to 45 mg daily ) or placebo . The primary outcome was a composite of death from cardiovascular causes , aborted cardiac arrest , or hospitalization for the management of heart failure . RESULTS With a mean follow-up of 3.3 years , the primary outcome occurred in 320 of 1722 patients in the spironolactone group ( 18.6 % ) and 351 of 1723 patients in the placebo group ( 20.4 % ) ( hazard ratio , 0.89 ; 95 % confidence interval [ CI ] , 0.77 to 1.04 ; P=0.14 ) . Of the components of the primary outcome , only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group ( 206 patients [ 12.0 % ] vs. 245 patients [ 14.2 % ] ; hazard ratio , 0.83 ; 95 % CI , 0.69 to 0.99 , P=0.04 ) . Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone . Treatment with spironolactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia ( 18.7 % , vs. 9.1 % in the placebo group ) but reduced hypokalemia . With frequent monitoring , there were no significant differences in the incidence of serious adverse events , a serum creatinine level of 3.0 mg per deciliter ( 265 μmol per liter ) or higher , or dialysis . CONCLUSIONS In patients with heart failure and a preserved ejection fraction , treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes , aborted cardiac arrest , or hospitalization for the management of heart failure . ( Funded by the National Heart , Lung , and Blood Institute ; TOPCAT Clinical Trials.gov number , NCT00094302 . ) OBJECTIVES The purpose of this study was to evaluate the efficacy and safety of the selective endothelin type A ( ETA ) receptor antagonist sitaxsentan in patients who have heart failure with preserved ejection fraction ( HFpEF ) . BACKGROUND Fifty percent of heart failure ( HF ) patients have a preserved ejection fraction . No treatment has been shown to improve their clinical outcomes . Previous studies have suggested that ETA receptor antagonists might improve diastolic function and exercise tolerance in some forms of HF . METHODS In all , 192 HFpEF patients ( EF ≥50 % ) were r and omly assigned 2:1 to sitaxsentan 100 mg/day ( n = 128 ) versus placebo ( n = 64 ) for 24 weeks . The primary endpoint was change in treadmill exercise time after 24 weeks of treatment . Secondary objectives included changes in left ventricular mass , transmitral inflow velocity to early diastolic mitral annulus velocity ratio , and Minnesota Living With Heart Failure question naire , and New York Heart Association functional class . Subjects were age 65 ± 11 years , 63 % female , 29 % non-Caucasian , and in functional class II ( 56.5 % ) or III ( 43.5 % ) . RESULTS Subjects treated with sitaxsentan had an increase in median treadmill time ( 90 s ) compared with placebo-treated subjects ( 37 s , p = 0.0302 ) . There was no significant treatment differences in transmitral inflow velocity to early diastolic mitral annulus velocity ratio , left ventricular mass , Minnesota Living With Heart Failure question naire , New York Heart Association functional class , deaths , or HF hospital stay . The incidence of adverse events was similar for sitaxsentan and placebo . CONCLUSIONS In HFpEF patients , treatment with a selective ETA receptor antagonist increased exercise tolerance but did not improve any of the secondary endpoints such as left ventricular mass or diastolic function . Further studies will be necessary to determine whether ETA receptor antagonists may be useful in the treatment of HFpEF . ( A Study of the Effectiveness of Sitaxsentan Sodium in Patients With Diastolic Heart Failure ; NCT00303498 ) Although the benefits of carvedilol in patients with heart failure and depressed ejection fraction ( EF ) have been eluci date d , those in patients with preserved EF are not understood . We enrolled 40 patients with mild or moderate heart failure and EF > /=45 % . They were r and omly assigned to carvedilol ( n = 19 ) or conventional therapy ( n = 21 ) . After 12 months of treatment , carvedilol significantly improved all end points ( plasma concentration of B-type natriuretic peptide [ BNP ] from 175 ( 35 to 209 ) to 106 ( 52 to 160 ) pg/ml , mean ( 95 % confidence interval ) p < 0.01 ; New York Heart Association functional class from 2.37 ( 2.13 to 2.61 ) to 1.56 ( 1.21 to 1.91 ) , p < 0.01 ; exercise capacity estimated with the Specific Activity Scale from 4.75 ( 4.50 to 5.00 ) to 5.68 ( 5.22 to 6.14 ) METs , p < 0.02 ) , whereas conventional therapy did not ( plasma BNP concentration from 150 ( 114 to 186 ) to 174 ( 100 to 248 ) pg/ml ; New York Heart Association functional class from 2.29 ( 2.08 to 2.50 ) to 2.11 ( 1.73 to 2.49 ) ; exercise capacity from 4.57 ( 4.34 to 4.80 ) to 4.72 ( 4.41 to 5.03 ) METs ) . Univariate regression analyses showed that only the use of carvedilol was correlated with the decrease in plasma BNP concentration ( p < 0.03 ) . Multivariate analyses demonstrated that an ischemic cause of heart failure ( p < 0.02 ) , high plasma concentration of BNP ( p < 0.02 ) , left ventricular dilation ( p < 0.03 ) , and use of carvedilol ( p < 0.04 ) at baseline were predictive of a decrease in plasma concentration of BNP . In conclusion , carvedilol potentially decreased neurohumoral activation , decreased symptoms , and increased exercise capacity in patients with heart failure and preserved EF IMPORTANCE Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction ( HFPEF ) . OBJECTIVE To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF . DESIGN Multicenter , double-blind , placebo-controlled , parallel-group , r and omized clinical trial of 216 stable out patients with HF , ejection fraction ≥50 % , elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures , and reduced exercise capacity . Participants were r and omized from October 2008 through February 2012 at 26 centers in North America . Follow-up was through August 30 , 2012 . INTERVENTIONS Sildenafil ( n = 113 ) or placebo ( n = 103 ) administered orally at 20 mg , 3 times daily for 12 weeks , followed by 60 mg , 3 times daily for 12 weeks . MAIN OUTCOME MEASURES Primary end point was change in peak oxygen consumption after 24 weeks of therapy . Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score ( range , 1-n , a higher value indicates better status ; expected value with no treatment effect , 95 ) based on time to death , time to cardiovascular or cardiorenal hospitalization , and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks . RESULTS Median age was 69 years , and 48 % of patients were women . At baseline , median peak oxygen consumption ( 11.7 mL/kg/min ) and 6-minute walk distance ( 308 m ) were reduced . The median E/e ' ( 16 ) , left atrial volume index ( 44 mL/m2 ) , and pulmonary artery systolic pressure ( 41 mm Hg ) were consistent with chronically elevated left ventricular filling pressures . At 24 weeks , median ( IQR ) changes in peak oxygen consumption ( mL/kg/min ) in patients who received placebo ( -0.20 [ IQR , -0.70 to 1.00 ] ) or sildenafil ( -0.20 [ IQR , -1.70 to 1.11 ] ) were not significantly different ( P = .90 ) in analyses in which patients with missing week-24 data were excluded , and in sensitivity analysis based on intention to treat with multiple imputation for missing values ( mean between-group difference , 0.01 mL/kg/min , [ 95 % CI , -0.60 to 0.61 ] ) . The mean clinical status rank score was not significantly different at 24 weeks between placebo ( 95.8 ) and sildenafil ( 94.2 ) ( P = .85 ) . Changes in 6-minute walk distance at 24 weeks in patients who received placebo ( 15.0 m [ IQR , -26.0 to 45.0 ] ) or sildenafil ( 5.0 m [ IQR , -37.0 to 55.0 ] ; P = .92 ) were also not significantly different . Adverse events occurred in 78 placebo patients ( 76 % ) and 90 sildenafil patients ( 80 % ) . Serious adverse events occurred in 16 placebo patients ( 16 % ) and 25 sildenafil patients ( 22 % ) . CONCLUSION AND RELEVANCE Among patients with HFPEF , phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks , compared with placebo , did not result in significant improvement in exercise capacity or clinical status . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00763867 BACKGROUND Patients with heart failure and preserved ejection fraction ( HFpEF ) have a poor prognosis , and no therapies have been proven to improve outcomes . It has been proposed that heart failure , including HFpEF , represents overlapping syndromes that may have different prognoses . We present an exploratory study of patients enrolled in the Irbesartan in Heart Failure with Preserved Ejection Fraction Study ( I-PRESERVE ) using latent class analysis ( LCA ) with validation using the C and esartan in Heart failure : Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved study to identify HFpEF subgroups . METHODS AND RESULTS In total , 4113 HFpEF patients r and omized to irbesartan or placebo were characterized according to 11 clinical features . The HFpEF subgroups were identified using LCA . Event-free survival and effect of irbesartan on the composite of all-cause mortality and cardiovascular hospitalization were determined for each subgroup . Subgroup definitions were applied to 3203 patients enrolled in CHARM-Preserved to vali date observations regarding prognosis and treatment response . Six subgroups were identified with significant differences in event-free survival ( P < 0.001 ) . Clinical profiles and prognoses of the six subgroups were similar in CHARM-Preserved . The two subgroups with the worst event-free survival in both studies were characterized by a high prevalence of obesity , hyperlipidaemia , diabetes mellitus , anaemia , and renal insufficiency ( Subgroup C ) and by female predominance , advanced age , lower body mass index , and high rates of atrial fibrillation , valvular disease , renal insufficiency , and anaemia ( Subgroup F ) . CONCLUSION Using a data -driven approach , we identified HFpEF subgroups with significantly different prognoses . Further development of this approach for characterizing HFpEF subgroups is warranted AIMS We hypothesized that nebivolol , a beta-blocker with nitric oxide-releasing properties , could favourably affect exercise capacity in patients with heart failure and preserved left ventricular ejection fraction ( HFPEF ) . METHODS AND RESULTS A total of 116 subjects with HFPEF , in New York Heart Association ( NYHA ) functional class II-III , with left ventricular ejection fraction ( LVEF ) > 45 % , and with echo-Doppler signs of LV diastolic dysfunction , were r and omized to 6 months treatment with nebivolol or placebo , following a double-blind , parallel group design . The primary endpoint of the study was the change in 6 min walk test distance ( 6MWTD ) after 6 months . Nebivolol did not improve 6MWTD ( from 420 ± 143 to 428 ± 141 m with nebivolol vs. from 412 ± 123 to 446 ± 119 m with placebo , P = 0.004 for interaction ) compared with placebo , and the peak oxygen uptake also remained unchanged ( peakVO(2 ) ; from 17.02 ± 4.79 to 16.32 ± 3.76 mL/kg/min with nebivolol vs. from 17.79 ± 5.96 to 18.59 ± 5.64 mL/kg/min with placebo , P = 0.63 for interaction ) . Resting and peak blood pressure and heart rate decreased with nebivolol . A significant correlation was found between the change in peak exercise heart rate and that in peakVO(2 ) ( r = 0.391 ; P = 0.003 ) for the nebivolol group . Quality of life , assessed using the Minnesota Living with Heart Failure Question naire , and NYHA classification improved to a similar extent in both groups , whereas N-terminal pro brain natriuretic peptide ( NT-pro BNP ) plasma levels remained unchanged . CONCLUSIONS Compared with placebo , 6 months treatment with nebivolol did not improve exercise capacity in patients with HFPEF . Its negative chronotropic effect may have contributed to this result OBJECTIVES We sought to evaluate the effects of angiotensin receptor blocker ( ARB ) on cardiac sympathetic nerve activity ( CSNA ) in patients with congestive heart failure ( CHF ) with a preserved left ventricular ejection fraction ( LVEF ) . BACKGROUND Approximately 50 % of patients with CHF have preserved LVEF . It is reported that ARB therapy improves CSNA in CHF patients and reduced LVEF . However , the effect of ARB therapy on CSNA evaluated by iodine-123 meta-iodobenzylguanidine ( (123)I-MIBG ) scintigraphy has not been determined in CHF patients with preserved LVEF . METHODS We selected 50 patients with nonischemic CHF and LVEF > 40 % who were treated with st and ard therapy . Twenty-five patients were r and omized to also receive c and esartan , whereas the remaining 25 patients received placebo . The delayed heart/mediastinum count ( H/M ) ratio , delayed total defect score ( TDS ) , and washout rate ( WR ) were determined by (123)I-MIBG scintigraphy before and six months after treatment . The LV end-diastolic volume and LVEF were determined by echocardiography , and the plasma brain natriuretic peptide ( BNP ) concentration was also measured . RESULTS In patients receiving c and esartan , (123)I-MIBG scintigraphic and echocardiographic parameters were significantly improved after treatment . In contrast , there were no significant changes in these parameters in patients receiving placebo . There was a significant correlation between the changes in (123)I-MIBG scintigraphic findings and the percent change in BNP from baseline to six months in patients receiving c and esartan ( TDS : r = 0.587 , p < 0.005 ; H/M ratio : r = -0.509 , p < 0.01 ; WR : r = 0.602 , p < 0.005 ) . CONCLUSIONS Adding c and esartan to st and ard therapy can improve CSNA and LV performance in CHF patients with preserved LVEF AIM The purpose of this study was to investigate the effects of carvedilol on diastolic function ( DF ) in heart failure patients with preserved left ventricular ( LV ) systolic function and abnormal DF . PATIENTS AND METHODS We r and omised 113 patients with diastolic heart failure ( DHF ) ( symptomatic , with normal systolic LV function and abnormal DF ) into a double blind multi-centre study . The patients received either carvedilol or matching placebo in addition to conventional treatment . After uptitration , treatment was continued for 6 months . Two-dimensional and Doppler echocardiography were used for quantification of LV function at baseline and at follow-up . Four different DF variables were evaluated by Doppler echocardiography : mitral flow E : A ratio , deceleration time ( DT ) , isovolumic relaxation time ( IVRT ) and the ratio of systolic/diastolic pulmonary venous flow velocity ( pv-S/D ) . Primary endpoint was change in the integrated quantitative assessment of all four variables during the study . RESULTS Ninety-seven patients completed the study . A mitral flow pattern reflecting a relaxation abnormality was recorded in 95 patients . There was no effect on the primary endpoint , although a trend towards a better effect in carvedilol treated patients was noticed in patients with heart rates above 71 beats per minute . At the end of the study , there was a statistically significant improvement in E : A ratio in patients treated with carvedilol ( 0.72 to 0.83 ) vs. placebo ( 0.71 to 0.76 ) , P<0.05 . CONCLUSIONS Treatment with carvedilol result ed in a significant improvement in E : A ratio in patients with heart failure due to a LV relaxation abnormality . E : A ratio was found to be the most useful variable to identify diastolic dysfunction in this patient population . This effect was observed particularly in patients with higher heart rates at baseline BACKGROUND Although spironolactone has been shown to decrease morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction , its role in patients with heart failure and preserved left ventricular ejection fraction ( HFpEF ) is not well defined . In this study we investigated the mechanisms involved when elderly women with HFpEF are treated with spironolactone . METHODS AND RESULTS Forty-eight women with HFpEF were enrolled in a r and omized placebo-controlled trial and were assigned to 25 mg spironolactone daily ( n = 24 ) or placebo ( n = 24 ) for 6 months . Six-minute walk distance , clinical composite score , Doppler echocardiography , and biomarkers were determined at baseline and after 3 and 6 months of therapy . Six months of spironolactone treatment stabilized clinical symptoms , as demonstrated by significant worsening of the clinical composite score in the placebo group ( P = .02 ) . In addition , spironolactone treatment improved diastolic function by significantly increasing early diastolic tissue Doppler velocity of the lateral mitral annulus ( lateral e ' ; P = .003 ) and significantly reducing the mitral peak E velocity to lateral e ' ratio ( lateral E/e ' ; P = .0001 ) . Finally , spironolactone favorably affected remodeling through a reduction in myocardial fibrosis measured by a reduction in type III procollagen levels ( P = .035 ) . Six-minute walk distance did not significantly improve with spironolactone treatment compared with placebo . CONCLUSIONS Spironolactone stabilizes functional capacity and symptoms and improves diastolic function , possibly through its ability to suppress type III procollagen synthesis At 32-month follow-up of older patients with prior myocardial infa rct ion , congestive heart failure , and a left ventricular ejection fraction > or = 40 % treated with diuretics plus angiotensin-converting enzyme inhibitors , and also with digoxin if atrial fibrillation was present , propranolol caused a 35 % significant reduction in total mortality and a 37 % significant decrease in total mortality plus nonfatal myocardial infa rct ion compared with no propranolol . At 1-year follow-up , propranolol caused a significantly greater increase in left ventricular ejection fraction ( 6 % ) and a significantly greater reduction in left ventricular mass ( 34 g ) than did no propranolol ( 2 % and 20 g , respectively ) IMPORTANCE Heart failure with preserved ejection fraction ( HFPEF ) may be as common and may have similar mortality as heart failure with reduced ejection fraction ( HFREF ) . β-Blockers reduce mortality in HFREF but are inadequately studied in HFPEF . OBJECTIVE To test the hypothesis that β-blockers are associated with reduced all-cause mortality in HFPEF . DESIGN Propensity score-matched cohort study using the Swedish Heart Failure Registry . Propensity scores for β-blocker use were derived from 52 baseline clinical and socioeconomic variables . SETTING Nationwide registry of 67 hospitals with inpatient and outpatient units and 95 outpatient primary care clinics in Sweden with patients entered into the registry between July 1 , 2005 , and December 30 , 2012 , and followed up until December 31 , 2012 . PARTICIPANTS From a consecutive sample of 41,976 patients , 19,083 patients with HFPEF ( mean [ SD ] age , 76 [ 12 ] years ; 46 % women ) . Of these , 8244 were matched 2:1 based on age and propensity score for β-blocker use , yielding 5496 treated and 2748 untreated patients with HFPEF . Also we conducted a positive-control consistency analysis involving 22,893 patients with HFREF , of whom 6081 were matched yielding 4054 treated and 2027 untreated patients . EXPOSURES β-Blockers prescribed at discharge from the hospital or during an outpatient visit , analyzed 2 ways : without consideration of crossover and per- protocol analysis with censoring at crossover , if applicable . MAIN OUTCOMES AND MEASURES The prespecified primary outcome was all-cause mortality and the secondary outcome was combined all-cause mortality or heart failure hospitalization . RESULTS Median follow-up in HFPEF was 755 days , overall ; 709 days in the matched cohort ; no patients were lost to follow-up . In the matched HFPEF cohort , 1-year survival was 80 % vs 79 % for treated vs untreated patients , and 5-year survival was 45 % vs 42 % , with 2279 ( 41 % ) vs 1244 ( 45 % ) total deaths and 177 vs 191 deaths per 1000 patient-years ( hazard ratio [ HR ] , 0.93 ; 95 % CI , 0.86 - 0.996 ; P = .04 ) . β-Blockers were not associated with reduced combined mortality or heart failure hospitalizations : 3368 ( 61 % ) vs 1753 ( 64 % ) total for first events , with 371 vs 378 first events per 1000 patient-years ( HR , 0.98 ; 95 % CI , 0.92 - 1.04 ; P = .46 ) . In the matched HFREF cohort , β-blockers were associated with reduced mortality ( HR , 0.89 ; 95 % CI , 0.82 - 0.97 , P=.005 ) and also with reduced combined mortality or heart failure hospitalization ( HR , 0.89 ; 95 % CI , 0.84 - 0.95 ; P = .001 ) . CONCLUSIONS AND RELEVANCE In patients with HFPEF , use of β-blockers was associated with lower all-cause mortality but not with combined all-cause mortality or heart failure hospitalization . β-Blockers in HFPEF should be examined in a large r and omized clinical trial BACKGROUND Cardiac fibrosis is a major determinant of myocardial stiffness , diastolic dysfunction , and heart failure ( HF ) . By reducing cardiac fibrosis , aldosterone antagonists have the potential to be beneficial in heart failure with preserved ejection fraction ( HFpEF ) . METHODS AND RESULTS In a r and omized , double-blind , placebo-controlled trial of 44 patients with HFpEF , we examined the effects of eplerenone , an aldosterone antagonist , on changes in 6-minute walk distance ( primary end point ) , diastolic function , and biomarkers of collagen turnover ( secondary end points ) . All patients had a history of hypertension , 61 % were diabetic , and 52 % had prior HF hospitalization . After 6 months of treatment , similar improvements in 6 minute walk distance were noted in the eplerenone and placebo groups ( P = .91 ) . However , compared with placebo , eplerenone was associated with a significant reduction in serum markers of collagen turnover ( procollagen type I aminoterminal peptide , P = .009 and carboxy-terminal telopeptide of collagen type I , P = .026 ) and improvement in echocardiographic measures of diastolic function ( E/E ' , P = .01 ) . CONCLUSIONS Although eplerenone was not associated with an improvement in exercise capacity compared to placebo , it was associated with significant reduction in markers of collagen turnover and improvement in diastolic function . Whether these favorable effects will translate into morbidity and mortality benefit in HFpEF remains to be determined A r and omized , double-blind study of 6 months of losartan 50 mg or hydrochlorothiazide ( HCTZ ) 12.5 mg was performed in 40 subjects with left ventricular diastolic dysfunction ( mitral flow velocity E/A ratio < 1 ) , exercise systolic blood pressure ( BP ) > 200 mm Hg , systolic BP at rest < 150 mm Hg , ejection fraction > 50 % , and no ischemia . Before treatment , exercise systolic BP was 213 + /- 13 mm Hg ( mean + /- SD ) in the 19 patients r and omized to losartan and 209 + /- 11 mm Hg in the 21 patients who received HCTZ . After 6 months , exercise systolic BP was similarly reduced in patients who received losartan ( 197 + /- 23 mm Hg , p < 0.01 ) and HCTZ ( 191 + /- 11 mm Hg , p < 0.01 ) . With losartan , treadmill exercise time increased from 894 + /- 216 to 951 + /- 225 seconds ( p = 0.011 ) , and quality of life improved from 15 + /- 12 to 7 + /- 10 ( p = 0.015 ) without a change in oxygen consumption ( 1,895 + /- 470 to 1,954 + /- 539 ml/min , p = 0.30 ) . With HCTZ , exercise time ( 842 + /- 225 to 872 + /- 239 seconds , p = 0.32 ) and quality of life ( 19 + /- 21 vs 19 + /- 24 , p = 0.43 ) did not change , whereas oxygen consumption decreased from 2,144 + /- 788 to 1,960 + /- 706 ml/min ( p = 0.022 ) . In conclusion , in patients with diastolic dysfunction and hypertensive responses to exercise , 6 months of losartan and HCTZ blunted systolic BP during exercise . Only losartan increased exercise tolerance and improved quality of life OBJECTIVES This study was design ed to evaluate the impact of eplerenone on collagen turnover in preserved systolic function heart failure ( HFPSF ) . BACKGROUND Despite growing interest in abnormal collagen metabolism as a feature of HFPSF with diastolic dysfunction , the natural history of markers of collagen turnover and the impact of selective aldosterone antagonism on this natural history remains unknown . METHODS We evaluated 44 patients with HFPSF , r and omly assigned to control ( n = 20 ) or eplerenone 25 mg daily ( n = 24 ) for 6 months , increased to 50 mg daily from 6 to 12 months . Serum markers of collagen turnover and inflammation were analyzed at baseline and at 6 and 12 months and included pro-collagen type-I and -III aminoterminal peptides , matrix metalloproteinase type-2 , interleukin-6 and -8 , and tumor necrosis factor-alpha . Doppler-echocardiographic assessment of diastolic filling indexes and tissue Doppler analyses were also obtained . RESULTS The mean age of the patients was 80 + /- 7.8 years ; 46 % were male ; 64 % were receiving an angiotensin-converting enzyme inhibitor , 34 % an angiotensin-II receptor blocker , and 68 % were receiving beta-blocker therapy . Pro-collagen type-III and -I aminoterminal peptides , matrix metalloproteinase type-2 , interleukin-6 and -8 , and tumor necrosis factor-alpha increased with time in the control group . Eplerenone treatment had no significant impact on any biomarker at 6 months but attenuated the increase in pro-collagen type-III aminoterminal peptide at 12 months ( p = 0.006 ) . Eplerenone therapy was associated with modest effects on diastolic function without any impact on clinical variables or brain natriuretic peptide . CONCLUSIONS This study demonstrates progressive increases in markers of collagen turnover and inflammation in HFPSF with diastolic dysfunction . Despite high background utilization of renin-angiotensin-aldosterone modulators , eplerenone therapy prevents a progressive increase in pro-collagen type-III aminoterminal peptide and may have a role in management of this disease . ( The Effect of Eplerenone and Atorvastatin on Markers of Collagen Turnover in Diastolic Heart Failure ; NCT00505336 ) AIMS The objectives of the present study were to describe epidemiology and outcomes in ambulatory heart failure ( HF ) patients stratified by left ventricular ejection fraction ( LVEF ) and to identify predictors for mortality at 1 year in each group . METHODS AND RESULTS The European Society of Cardiology Heart Failure Long-Term Registry is a prospect i ve , observational study collecting epidemiological information and 1-year follow-up data in 9134 HF patients . Patients were classified according to baseline LVEF into HF with reduced EF [ EF < 40 % ( HFrEF ) ] , mid-range EF [ EF 40 - 50 % ( HFmrEF ) ] and preserved EF [ EF > 50 % ( HFpEF ) ] . In comparison with HFpEF subjects , patients with HFrEF were younger ( 64 years vs. 69 years ) , more commonly male ( 78 % vs. 52 % ) , more likely to have an ischaemic aetiology ( 49 % vs. 24 % ) and left bundle branch block ( 24 % vs. 9 % ) , but less likely to have hypertension ( 56 % vs. 67 % ) or atrial fibrillation ( 18 % vs. 32 % ) . The HFmrEF group resembled the HFrEF group in some features , including age , gender and ischaemic aetiology , but had less left ventricular and atrial dilation . Mortality at 1 year differed significantly between HFrEF and HFpEF ( 8.8 % vs. 6.3 % ) ; HFmrEF patients experienced intermediate rates ( 7.6 % ) . Age , New York Heart Association ( NYHA ) class III/IV status and chronic kidney disease predicted mortality in all LVEF groups . Low systolic blood pressure and high heart rate were predictors for mortality in HFrEF and HFmrEF . A lower body mass index was independently associated with mortality in HFrEF and HFpEF patients . Atrial fibrillation predicted mortality in HFpEF patients . CONCLUSIONS Heart failure patients stratified according to different categories of LVEF represent diverse phenotypes of demography , clinical presentation , aetiology and outcomes at 1 year . Differences in predictors for mortality might improve risk stratification and management goals |
13,776 | 25,048,794 | There is limited evidence of the potential of these discrepancies to cause harm .
The studies reported conflicting findings regarding the impact of medication review on length of stays , readmissions , and mortality .
Conclusions : The evidence demonstrates that medication reconciliation has the potential to identify many medication discrepancies and reduce potential harm , but the impact on clinical outcomes is less clear .
Similarly , medication review can detect medication-related problems in many patients , but evidence of clinical impact is scant .
Overall , there is limited evidence that medication reconciliation and medication review processes , as currently performed , significantly improve clinical outcomes , such as reductions in hospital readmissions | Objective : To examine the evidence regarding the effectiveness of medication reconciliation and review and to improve clinical outcomes in hospitals , the community , and aged care facilities . | BACKGROUND Previous studies found that medication errors result from lack of sufficient information during the prescribing step . Therefore , it is proposed that having a pharmacist available when patients are evaluated during the rounding process may reduce the likelihood of preventable adverse drug events ( ADEs ) . The objectives of this study were to evaluate the impact of having a pharmacist participate with a physician rounding team on preventable ADEs in general medicine units and to document pharmacist interventions made during the rounding process . METHODS A single-blind , st and ard care-controlled study design was used to compare patients receiving care from a rounding team including a pharmacist with patients receiving st and ard care ( no pharmacist on rounding team ) . Patients admitted to and discharged from the same general medicine unit were included in the study . The main outcome measure of this study was preventable ADEs . Patient records were r and omly selected and evaluated by a blinded process involving independent senior pharmacist specialists and a senior staff physician . Interventions made by the pharmacists in the treatment group were documented . RESULTS The rate of preventable ADEs was reduced by 78 % , from 26.5 per 1000 hospital days to 5.7 per 1000 hospital days . There were 150 documented interventions recommended during the rounding process , 147 of which were accepted by the team . The most common interventions were ( 1 ) dosing-related changes and ( 2 ) recommendations to add a drug to therapy . CONCLUSION Pharmacist participation with the medical rounding team on a general medicine unit contributes to a significant reduction in preventable ADEs BACKGROUND There is evidence that pharmacist interventions improve clinical outcomes . The few studies that address economic outcomes ( a ) often report estimated instead of actual medical costs , ( b ) report only medication costs , or ( c ) have been conducted in setting s that are not typical of community-based primary care . OBJECTIVES To ( a ) determine whether a clinical pharmacist 's recommendations to physicians regarding optimizing medication therapy are related to medical costs in capitated patients in an internal medicine practice , and ( b ) compare what primary care physicians ( PCPs ) in a comparison group actually did proactively to optimize medication therapy versus what a clinical pharmacist would have recommended to them . METHODS This was a prospect i ve , controlled study comparing 2 internal medicine practice s. Study enrollment was performed using a screening process carried out every 1 - 2 weeks on a rolling basis for 1 year from July 2001 through June 2002 . Eligibility criteria for prospect i ve enrollment were ( a ) 1 or more risk factors : at least 1 chronic disease or an event ( e.g. , emergency room visit , adverse drug reaction , medication nonadherence ) or aged 50 years or older , ( b ) a scheduled visit to see a PCP within 2 weeks from the screening date or a diagnosis of diabetes without a PCP visit during the first 6 months of the study , ( c ) need for optimization of medication therapy as determined by a clinical pharmacist on the screening date , and ( d ) 12 months of continuous insurance eligibility before enrollment in the study . For inclusion in the final study analyses , patients were also required to have continuous insurance eligibility through 12 months from study enrollment . One clinical pharmacist made recommendations to optimize medication therapy in the intervention group . For the comparison group , the same pharmacist proposed recommendations that remained concealed from the physicians . The primary outcome measure was per patient per year ( PPPY ) medical cost , based on plan liability ( gross allowable costs minus patient costs ) , excluding prescription drug cost . Additional outcome measures included numbers of outpatient visits , hospital admissions , emergency room ( ER ) visits per 1,000 patients , and hospital days ; and percent of recommendations that were accepted by the PCPs . Changes in outcome measures from the pre-intervention to postintervention period were compared across study groups in a difference-indifference analysis , using the Student 's t-test for normally distributed data and the Mann-Whitney U-test ( nonparametric ) for skewed data . RESULTS There were 127 and 216 adult patients in the intervention and comparison groups , respectively . The primary outcome , change in mean PPPY medical ( excluding pharmacy ) cost , did not differ significantly between the groups ( P = 0.711 ) . The between-group difference in the change in ER visits per 1,000 patients approached statistical significance ( P = 0.054 ) . Intervention group patients were more likely than comparison group patients to have the following issues addressed : medication nonadherence ( 85.7 % vs. 40.0 % , respectively ; P = 0.032 ) , untreated indication ( 72.6 % vs. 11.5 % , P < 0.001 ) , suboptimal medication choice ( 60.0 % vs. 5.9 % , P < 0.001 ) and cost-ineffective drug therapies ( 72.1 % vs. 6.5 % , P < 0.001 ) . Of the estimated number of actionable opportunities identified for the comparison group ( but concealed from the physicians ) , 23.5 % were adopted by comparison group physicians without any assistance from a clinical pharmacist . CONCLUSION Compared with patients of PCPs who received no input from a clinical pharmacist , patients of PCPs who received clinical pharmacist recommendations were more likely to have several medication-related issues addressed , including medication nonadherence , untreated indications , suboptimal medication choices , and cost-ineffective drug therapies . However , total medical ( excluding pharmacy ) costs for the intervention and comparison groups were not significantly different Background : Hospital discharge is an interlace of care when patients are at a high risk of medication discrepancies as they transition from hospital to home . These discrepancies are important , as they may contribute to drug-related problems , medication errors , and adverse drug events . Objective : To Identify , characterize , and assess the clinical impact of unintentional medication discrepancies at hospital discharge . Methods : All consecutive general internal medicine patients admitted for at least 72 hours to a tertiary care teaching hospital were prospect ively assessed . Patients were excluded if they were discharged with verbal prescriptions ; died during hospitalization ; or transferred from or to a nursing home , another institution , or another unit within the same hospital . The primary endpoint was to determine the number of patients with at least one unintended medication discrepancy on hospital discharge . Medication discrepancies were assessed through comparison of a best possible medication discharge list with the actual discharge prescriptions . Secondary objectives were to characterize and assess the potential clinical impact of the unintentional discrepancies . Results : From March 14,2006 , to June 2,2006,430 patients were screened for eligibility ; 150 patients were included in the study . Overall , 106 ( 70.7 % ) patients had at least one actual or potential unintentional discrepancy . Sixty-two patients ( 41.3 % ) had at least one actual unintentional medication discrepancy al hospital discharge and 83 patients ( 55.3 % ) had at least one potential unintentional discrepancy . The most common unintentional discrepancies were an incomplete prescription requiring clarification , which could result in a patient delay in obtaining medications ( 49.5 % ) , and the omission of medications ( 22.9 % ) . Of the 105 unintentional discrepancies , 31 ( 29.5 % ) had the potential to cause possible or probable patient discomfort and /or clinical deterioration . Conclusions : Medication discrepancies occur commonly on hospital discharge . Underst and ing the type and frequency of discrepancies can help clinicians better underst and ways to prevent them . Structured medication reconciliation may help to prevent discharge medication discrepancies Background : Medication errors at the time of hospital admission and discharge are common and can lead to preventable adverse drug events . The objective of this study was to describe the potential impact of a medication reconciliation process to identify and rectify medication errors at the time of hospital admission and discharge . Methods : Sixty r and omly selected patients were prospect ively enrolled at the time of admission to a Canadian community hospital . At admission , patients ’ medication orders were compared with pre-admission medication use based on medication vials and interviews with patients , caregivers , and /or outpatient healthcare providers . At discharge , pre-admission and in-patient medications were compared with discharge orders and written instructions . All variances were discussed with the prescribing physician and classified as intended or unintended ; unintended variances were considered to be medication errors . An internist classified the clinical importance of each unintended variance . Results : Overall , 60 % ( 95 % CI 48 to 72 ) of patients had at least one unintended variance and 18 % ( 95 % CI 9 to 28 ) had at least one clinical ly important unintended variance . None of the variances had been detected by usual clinical practice before reconciliation was conducted . Of the 20 clinical ly important variances , 75 % ( 95 % CI 56 to 94 ) were intercepted by medication reconciliation before patients were harmed . Discussion : Unintended medication variances at the time of hospital admission and discharge are common and clinical ly important . The medication reconciliation process identified and addressed most of these unintended variances before harm occurred . In this small study , medication reconciliation was a useful method for identifying and rectifying medication errors at times of transition . Reconciliation warrants broader evaluation BACKGROUND Prior studies suggest that unintended medication discrepancies that represent errors are common at the time of hospital admission . These errors are particularly worthy of attention because they are not likely to be detected by computerized physician order entry systems . METHODS We prospect ively studied patients reporting the use of at least 4 regular prescription medications who were admitted to general internal medicine clinical teaching units . The primary outcome was unintended discrepancies ( errors ) between the physicians ' admission medication orders and a comprehensive medication history obtained through interview . We also evaluated the potential seriousness of these discrepancies . All discrepancies were review ed with the medical team to determine if they were intentional or unintentional . All unintended discrepancies were rated for their potential to cause patient harm . RESULTS After screening 523 admissions , 151 patients were enrolled based on the inclusion criteria . Eighty-one patients ( 53.6 % ; 95 % confidence interval , 45.7%-61.6 % ) had at least 1 unintended discrepancy . The most common error ( 46.4 % ) was omission of a regularly used medication . Most ( 61.4 % ) of the discrepancies were judged to have no potential to cause serious harm . However , 38.6 % of the discrepancies had the potential to cause moderate to severe discomfort or clinical deterioration . CONCLUSIONS Medication errors at the time of hospital admission are common , and some have the potential to cause harm . Better methods of ensuring an accurate medication history at the time of hospital admission are needed OBJECTIVES to investigate the effectiveness of a pharmacy discharge plan in elderly hospitalized patients . DESIGN r and omized controlled trial . SUBJECTS AND SETTING S we r and omized patients aged 75 years and older on four or more medicines who had been discharged from three acute general and one long-stay hospital to a pharmacy intervention or usual care . INTERVENTIONS the hospital pharmacist developed discharge plans which gave details of medication and support required by the patient . A copy was given to the patient and to all relevant professionals and carers . This was followed by a domiciliary assessment by a community pharmacist . In the control group , patients were discharged from hospital following st and ard procedures that included a discharge letter to the general practitioner listing current medications . OUTCOMES the primary outcome was re-admission to hospital within 6 months . Secondary outcomes included the number of deaths , attendance at hospital outpatient clinics and general practice and proportion of days in hospital over the follow-up period , together with patients ' general well-being , satisfaction with the service and knowledge of and adherence to prescribed medication . RESULTS we recruited 362 patients , of whom 181 were r and omized to each group . We collected hospital and general practice data on at least 91 and 72 % of patients respectively at each follow-up point and interviewed between 43 and 90 % of the study subjects . There were no significant differences between the groups in the proportion of patients re-admitted to hospital between baseline and 3 months or 3 and 6 months . There were no significant differences in any of the secondary outcomes . CONCLUSIONS we found no evidence to suggest that the co-ordinated hospital and community pharmacy care discharge plans in elderly patients in this study influence outcomes Introduction : Care home residents are at particular risk from medication errors , and our objective was to determine the prevalence and potential harm of prescribing , monitoring , dispensing and administration errors in UK care homes , and to identify their causes . Methods : A prospect i ve study of a r and om sample of residents within a purposive sample of homes in three areas . Errors were identified by patient interview , note review , observation of practice and examination of dispensed items . Causes were understood by observation and from theoretically framed interviews with home staff , doctors and pharmacists . Potential harm from errors was assessed by expert judgement . Results : The 256 residents recruited in 55 homes were taking a mean of 8.0 medicines . One hundred and seventy-eight ( 69.5 % ) of residents had one or more errors . The mean number per resident was 1.9 errors . The mean potential harm from prescribing , monitoring , administration and dispensing errors was 2.6 , 3.7 , 2.1 and 2.0 ( 0 = no harm , 10 = death ) , respectively . Contributing factors from the 89 interviews included doctors who were not accessible , did not know the residents and lacked information in homes when prescribing ; home staff ’s high workload , lack of medicines training and drug round interruptions ; lack of team work among home , practice and pharmacy ; inefficient ordering systems ; inaccurate medicine records and prevalence of verbal communication ; and difficult to fill ( and check ) medication administration systems . Conclusions : That two thirds of residents were exposed to one or more medication errors is of concern . The will to improve exists , but there is a lack of overall responsibility . Action is required from all concerned OBJECTIVES To evaluate the effect of pharmaceutical care provided in addition to acute Geriatric Evaluation and Management ( GEM ) care on the appropriateness of prescribing . DESIGN R and omized , controlled trial , with the patient as unit of r and omization . SETTING Acute GEM unit . PARTICIPANTS Two hundred three patients aged 70 and older . INTERVENTION Pharmaceutical care provided from admission to discharge by a specialist clinical pharmacist who had direct contacts with the GEM team and patients . MEASUREMENTS Appropriateness of prescribing on admission , at discharge , and 3 months after discharge , using the Medication Appropriateness Index ( MAI ) , Beers criteria , and Assessing Care of Vulnerable Elders ( ACOVE ) underuse criteria and mortality , readmission , and emergency visits up to 12 months after discharge . RESULTS Intervention patients were significantly more likely than control patients to have an improvement in the MAI and in the ACOVE underuse criteria from admission to discharge ( odds ratio (OR)=9.1 , 95 % confidence interval (CI)=4.2 - 21.6 and OR=6.1 , 95 % CI=2.2 - 17.0 , respectively ) . The control and intervention groups had comparable improvements in the Beers criteria . CONCLUSION Pharmaceutical care provided in the context of acute GEM care improved the appropriate use of medicines during the hospital stay and after discharge . This is an important finding , because only limited data exist on the effect of various strategies to improve medication use in elderly in patients . The present approach has the potential to minimize risk and improve patient outcomes BACKGROUND Hospitalization and subsequent discharge home often involve discontinuity of care , multiple changes in medication regimens , and inadequate patient education , which can lead to adverse drug events ( ADEs ) and avoidable health care utilization . Our objectives were to identify drug-related problems during and after hospitalization and to determine the effect of patient counseling and follow-up by pharmacists on preventable ADEs . METHODS We conducted a r and omized trial of 178 patients being discharged home from the general medicine service at a large teaching hospital . Patients in the intervention group received pharmacist counseling at discharge and a follow-up telephone call 3 to 5 days later . Interventions focused on clarifying medication regimens ; review ing indications , directions , and potential side effects of medications ; screening for barriers to adherence and early side effects ; and providing patient counseling and /or physician feedback when appropriate . The primary outcome was rate of preventable ADEs . RESULTS Pharmacists observed the following drug-related problems in the intervention group : unexplained discrepancies between patients ' preadmission medication regimens and discharge medication orders in 49 % of patients , unexplained discrepancies between discharge medication lists and postdischarge regimens in 29 % of patients , and medication nonadherence in 23 % . Comparing trial outcomes 30 days after discharge , preventable ADEs were detected in 11 % of patients in the control group and 1 % of patients in the intervention group ( P = .01 ) . No differences were found between groups in total ADEs or total health care utilization . CONCLUSIONS Pharmacist medication review , patient counseling , and telephone follow-up were associated with a lower rate of preventable ADEs 30 days after hospital discharge . Medication discrepancies before and after discharge were common targets of intervention Aim : To measure the outcomes of a harmonised , structured pharmaceutical care programme provided to elderly patients by community pharmacists . Method : A r and omised , controlled , longitudinal , clinical trial with repeated measures was performed over an 18‐month period , involving community pharmacies ( 5 intervention and 5 control ) in Northern Irel and . Elderly , ambulatory patients ( ≥ 65 years ) , taking 4 or more prescribed medications were eligible for participation . Patients attending an intervention pharmacy received education on medical conditions , implementation of compliance strategies , rationalising of drug regimens and appropriate monitoring ; patients attending control sites received normal services . A battery of clinical , humanistic and economic outcomes were assessed . Results : A significantly higher proportion of intervention patients were compliant at the end of the 18‐month study and experienced fewer problems with medication compared to control patients ( P < 0.05 ) . There was little impact on quality of life and health care utilisation . Conclusions : Pharmaceutical care provision to community‐dwelling patients result ed in an improvement in medication compliance and evidence of cost‐savings . Future pharmaceutical care studies may benefit from a more focussed selective approach to data collection and outcomes measurement OBJECTIVES to evaluate specialist geriatric input and medication review in patients in high-dependency continuing care . DESIGN prospect i ve , r and omised , controlled trial . SETTING two residential continuing care hospitals . PARTICIPANTS two hundred and twenty-five permanent patients . INTERVENTION patients were r and omised to either specialist geriatric input or regular input . The specialist group had a medical assessment by a geriatrician and medication review by a multidisciplinary expert panel . Regular input consisted of review as required by a medical officer attached to each ward . Re assessment occurred after 6 months . RESULTS one hundred and ten patients were r and omised to specialist input and 115 to regular input . These were comparable for age , gender , dependency levels and cognition . After 6 months , the total number of medications per patient per day fell from 11.64 to 11.09 in the specialist group ( P = 0.0364 ) and increased from 11.07 to 11.5 in the regular group ( P = 0.094 ) . There was no significant difference in mortality or frequency of acute hospital transfers ( 11 versus 6 in the specialist versus regular group , P = 0.213 ) . CONCLUSION specialist geriatric assessment and medication review in hospital continuing care result ed in a reduction in medication use , but at a significant cost . No benefits in hard clinical outcomes were demonstrated . However , qualitative benefits and lower costs may become evident over longer periods Purpose To examine the impact of systematic medication reconciliations upon hospital admission and of a medication review while in hospital on the number of inappropriate medications and unscheduled drug-related hospital revisits in elderly patients . Methods This was a prospect i ve , controlled study in 210 patients , aged 65 years or older , who were admitted to one of three internal medicine wards at a University Hospital in Sweden . Intervention patients received the complete Lund Integrated Medicines Management model ( medication reconciliation upon admission and discharge , and medication review and monitoring ) provided by a multi-professional team , including a clinical pharmacist . Control patients received st and ard care and medication reconciliation upon discharge . Blinded review ers evaluated the appropriateness of the prescribing ( using the Medication Appropriateness Index ) on admission and discharge , and assessed the probability that a drug-related problem was the reason for any patient readmitted to hospital or visiting the emergency department within 3 months of discharge ( using World Health Organisation causality criteria ) . Results There was a greater decrease in the number of inappropriate drugs in the intervention group than in the control group for both the intention-to-treat population { 51 % [ 95 % confidence interval ( CI ) 43–58 % ] vs. 39 % ( 95 % CI 30–48 % ) ; p = 0.0446 } and the per- protocol population [ 60 % ( 95 % CI 51–67 % ) vs. 44 % ( 95 % CI 34–52 % ) ; p = 0.0106 ) ] . There were six revisits to hospital in the intervention group which were judged as ‘ possibly , probably or certainly drug-related ’ , compared with 12 in the control group ( p = 0.0469 ) . Conclusions In this study , medication reconciliation and review provided by a clinical pharmacist in a multi-professional team significantly reduced the number of inappropriate drugs and unscheduled drug-related hospital revisits among elderly patients OBJECTIVE To quantify admission medication discrepancies in a tertiary-care , general pediatric population , to describe their clinical importance and associated factors , and to assess a screening approach to pharmacist involvement . METHODS A total of 272 patients were studied prospect ively at hospital admission . The study pharmacist performed a medication history and compared it to physicians ' admission medication orders . Discrepancies between the 2 were coded as intentional but undocumented or unintentional . Unintentional discrepancies were rated for potential to cause harm by 3 physicians . Additional data collected included patients ' reason for admission and presence of chronic conditions , whether physicians used a medication reconciliation form , the characteristics of patients ' home medication regimen , and the time required to perform a pharmacist history and reconciliation . Interrater reliability and associations between baseline characteristics and discrepancy rates were explored . RESULTS Eighty patients ( 30 % ) had at least one undocumented intentional discrepancy ( range , 0 - 7 ) . At least one unintentional discrepancy ( range , 0 - 9 ) was found in 59 patients ( 22 % ) . Of the unintentional discrepancies , 23 % had moderate and 6 % had severe potential to cause discomfort or deterioration . Ratings were similar among the 3 physicians . Characteristics associated with higher risk of clinical ly important discrepancies were : use of the medication reconciliation form , > or = 4 prescription medications , and antiepileptic drug use . Logistic regression revealed that only the variable > or = 4 medications was independently associated with clinical ly important discrepancies . CONCLUSIONS Admission medication errors are common in this tertiary-care , general pediatric population , and nearly a third represent potential adverse events . The use of a medication reconciliation form by physicians without pharmacist involvement does not appear to reduce errors . A cutoff of > or = 4 prescription medications is highly sensitive for identifying patients at risk of clinical ly important discrepancies Abstract Objective : To determine whether a pharmacist can effectively review repeat prescriptions through consultations with elderly patients in general practice . Design : R and omised controlled trial of clinical medication review by a pharmacist against normal general practice review . Setting : Four general practice s. Participants : 1188 patients aged 65 or over who were receiving at least one repeat prescription and living in the community . Intervention : Patients were invited to a consultation at which the pharmacist review ed their medical conditions and current treatment . Main outcome measures : Number of changes to repeat prescriptions over one year , drug costs , and use of healthcare services . Results : 590 ( 97 % ) patients in the intervention group were review ed compared with 233 ( 44 % ) in the control group . Patients seen by the pharmacist were more likely to have changes made to their repeat prescriptions ( mean number of changes per patient 2.2 v 1.9 ; difference=0.31 , 95 % confidence interval 0.06 to 0.57 ; P=0.02 ) . Monthly drug costs rose in both groups over the year , but the rise was less in the intervention group ( mean difference £ 4.72 per 28 days , −£7.04 to -£2.41 ) ; equivalent to £ 61 per patient a year . Intervention patients had a smaller rise in the number of drugs prescribed ( 0.2 v 0.4 ; mean difference −0.2 , −0.4 to −0.1 ) . There was no evidence that review of treatment by the pharmacist affected practice consultation rates , outpatient consultations , hospital admissions , or death rate . Conclusions : A clinical pharmacist can conduct effective consultations with elderly patients in general practice to review their drugs . Such review results in significant changes in patients ' drugs and saves more than the cost of the intervention without affecting the workload of general practitioners . What is already known on this topic Review of patients on long term drug treatment is important but is done inadequately Evidence from the United States shows that pharmacists can improve patient care by review ing drug treatment What this study adds Consultations with a clinical pharmacist are an effective method of review ing the drug treatment of older patients Review by a pharmacist results in more drug changes and lower prescribing costs than normal care plus a much higher review rate Use of healthcare services by patients is not Background —R and omized controlled trials have demonstrated that collaborative medication review s can improve outcomes for patients with heart failure . We aim ed to determine whether these results translated into Australian practice , where collaborative review s are nationally funded . Methods and Results —This retrospective cohort study using administrative cl aims data included veterans 65 years and older receiving bisoprolol , carvedilol , or metoprolol succinate for which prescribing physicians indicated treatment was for heart failure . We compared those exposed to a general practitioner – pharmacist collaborative home medication review with those who did not receive the service . The service includes physician referral , a home visit by an accredited pharmacist to identify medication-related problems , and a pharmacist report with follow-up undertaken by the physician . Kaplan-Meier analyses and Cox proportional hazards models were used to compare time until next hospitalization for heart failure between the exposed and unexposed groups . There were 273 veterans exposed to a home medicines review and 5444 unexposed patients . Average age in both groups was 81.6 years ( no significant difference ) . The median number of comorbidities was 8 in the exposed group and 7 in the unexposed ( P<0.0001 ) . Unadjusted results showed a 37 % reduction in rate of hospitalization for heart failure at any time ( hazard ratio , 0.63 ; 95 % CI , 0.44 to 0.89 ) . Adjusted results showed a 45 % reduction ( hazard ratio , 0.55 ; 95 % CI , 0.39 to 0.77 ) among those who had received a home medicines review compared with the unexposed patients . Conclusion —Medicines review in the practice setting is effective in delaying time to next hospitalization for heart failure in those treated with heart failure medicines OBJECTIVE To identify and resolve discrepancies in admission medication histories , utilizing community pharmacy dispensing data , in newly hospitalized patients and investigate the relationship between unresolved discrepancies and length of hospital stay . METHODS Eligible patients ( 2 or more chronic conditions , 3 or more chronic medications and aged over 50 years ) were r and omized to the intervention or control group . Within 24 h of admission , the patient 's nominated community pharmacy was contacted , a 6-month dispensing history obtained , patient was interviewed and a current medication list compiled . This was compared with the hospital drug chart . Discrepancies for the intervention group were discussed with the attending doctor . Subsequent resolution of discrepancies was assessed for all patients . RESULTS 487 patients were included ( 203 intervention , 284 control ) . Approximately 66 % of all patients had at least 1 discrepancy between their reconciled list of medications and their initial drug chart , with no significant difference between the groups . Significantly more intervention patients had at least 1 discrepancy resolved in the first 48 h than control patients ( intervention 78.1 % ; control 36.5 % ; p < 0.0001 ) . A weak correlation was found between the number of discrepancies not acted on and length of hospital stay ( Spearman Rho = 0.1 , n = 487 , p < 0.01 ) . CONCLUSION Errors in admission medication histories are common and potentially lead to an increased length of stay . The provision of a 6-month community pharmacy dispensing history at the time of hospital admission is an important addition to ensure an accurate medication chart is compiled BACKGROUND Clinical ly important medication errors are common after hospital discharge . They include preventable or ameliorable adverse drug events ( ADEs ) , as well as medication discrepancies or nonadherence with high potential for future harm ( potential ADEs ) . OBJECTIVE To determine the effect of a tailored intervention on the occurrence of clinical ly important medication errors after hospital discharge . DESIGN R and omized , controlled trial with concealed allocation and blinded outcome assessors . ( Clinical Trials.gov registration number : NCT00632021 ) SETTING Two tertiary care academic hospitals . PATIENTS Adults hospitalized with acute coronary syndromes or acute decompensated heart failure . INTERVENTION Pharmacist-assisted medication reconciliation , inpatient pharmacist counseling , low-literacy adherence aids , and individualized telephone follow-up after discharge . MEASUREMENTS The primary outcome was the number of clinical ly important medication errors per patient during the first 30 days after hospital discharge . Secondary outcomes included preventable or ameliorable ADEs , as well as potential ADEs . RESULTS Among 851 participants , 432 ( 50.8 % ) had 1 or more clinical ly important medication errors ; 22.9 % of such errors were judged to be serious and 1.8 % life-threatening . Adverse drug events occurred in 258 patients ( 30.3 % ) and potential ADEs in 253 patients ( 29.7 % ) . The intervention did not significantly alter the per-patient number of clinical ly important medication errors ( unadjusted incidence rate ratio , 0.92 [ 95 % CI , 0.77 to 1.10 ] ) or ADEs ( unadjusted incidence rate ratio , 1.09 [ CI , 0.86 to 1.39 ] ) . Patients in the intervention group tended to have fewer potential ADEs ( unadjusted incidence rate ratio , 0.80 [ CI , 0.61 to 1.04 ] ) . LIMITATION The characteristics of the study hospitals and participants may limit generalizability . CONCLUSION Clinical ly important medication errors were present among one half of patients after hospital discharge and were not significantly reduced by a health-literacy-sensitive , pharmacist-delivered intervention . PRIMARY FUNDING SOURCE National Heart , Lung , and Blood Institute Background : Internal hospital transfer is a vulnerable time during which patients are at high risk of medication discrepancies that can result in clinical ly significant harm , medication errors , and adverse drug events . Objective : To identify , characterize , and assess the clinical impact of unintentional medication discrepancies during internal hospital transfer and to investigate the influence of computerized prescriber order entry ( CPOE ) on medication discrepancies . Methods : All patients transferred between 10 inpatient units at 2 tertiary care hospitals were prospect ively assessed to identify discrepancies . Interfaces included transfers between ( 1 ) units that both used paper-based medication ordering systems ; ( 2 ) units that both used CPOE-based systems ; and ( 3 ) units that used both paper-based and CPOE-based systems ( hybrid transfer ) . The primary endpoint was the number of patients with at least 1 unintentional medication discrepancy during internal hospital transfer . Discrepancies were identified through assessment and comparison of a best possible medication transfer list with the actual transfer orders . A multidisciplinary team of clinicians assessed the potential clinical impact and severity of unintentional discrepancies . Results : Overall , 190 patients were screened and 129 patients were included . Eighty patients ( 62.0 % ) had at least 1 unintentional medication discrepancy at the time of transfer , and the most common discrepancy was medication omission ( 55.6 % ) . Factors that independently increased the risk of a patient experiencing at least 1 unintentional discrepancy included lack of best possible medication history , increasing number of home medications , and increasing number of transfer medications . Forty-seven patients ( 36.4 % ) had at least 1 unintentional discrepancy with the potential to cause discomfort and /or clinical deterioration . The risk of discrepancies was present regardless of the medication-ordering system ( paper , CPOE , or hybrid ) . Conclusions : Clinical ly significant medication discrepancies occur commonly during internal hospital transfer . A structured , collaborative , and clearly defined medication reconciliation process is needed to prevent internal transfer discrepancies and patient harm BACKGROUND Patients 80 years or older are underrepresented in scientific studies . The objective of this study was to investigate the effectiveness of interventions performed by ward-based pharmacists in reducing morbidity and use of hospital care among older patients . METHODS A r and omized controlled study of patients 80 years or older was conducted at the University Hospital of Uppsala , Uppsala , Sweden . Four hundred patients were recruited consecutively between October 1 , 2005 , and June 30 , 2006 , and were r and omized to control ( n = 201 ) and intervention ( n = 199 ) groups . The interventions were performed by ward-based pharmacists . The control group received st and ard care without direct involvement of pharmacists at the ward level . The primary outcome measure was the frequency of hospital visits ( emergency department and readmissions [ total and drug-related ] ) during the 12-month follow-up period . RESULTS Three hundred sixty-eight patients ( 182 in the intervention group and 186 in the control group ) were analyzed . For the intervention group , there was a 16 % reduction in all visits to the hospital ( quotient , 1.88 vs 2.24 ; estimate , 0.84 ; 95 % confidence interval [ CI ] , 0.72 - 0.99 ) and a 47 % reduction in visits to the emergency department ( quotient , 0.35 vs 0.66 ; estimate , 0.53 ; 95 % CI , 0.37 - 0.75 ) . Drug-related readmissions were reduced by 80 % ( quotient , 0.06 vs 0.32 ; estimate , 0.20 ; 95 % CI , 0.10 - 0.41 ) . After inclusion of the intervention costs , the total cost per patient in the intervention group was $ 230 lower than that in the control group . CONCLUSION If implemented on a population basis , the addition of pharmacists to health care teams would lead to major reductions in morbidity and health care costs Background Polypharmacy in the Swedish elderly population is currently a prioritised area of research with a focus on reducing the use of potentially inappropriate medications ( PIMs ) . Multi-professional interventions have previously been tested for their ability to improve drug therapy in frail elderly patients . Objective This study aim ed to assess a structured model for pharmacist-led medication review s in primary health care in southern Sweden and to measure its effects on numbers of patients with PIMs ( using the definition of the Swedish National Board of Health and Welfare ) using ≥10 drugs and using ≥3 psychotropics . Methods This study was a r and omised controlled clinical trial performed in a group of patients aged ≥75 years and living in nursing homes or the community and receiving municipal health care . Medication review s were performed by trained clinical pharmacists based on nurse-initiated symptom assessment s with team-based or distance feedback to the physician . Data were collected from the patients ’ electronic medication lists and medical records at baseline and 2 months after the medication review . Results A total of 369 patients were included : 182 in the intervention group and 187 in the control group . One-third of the patients in both groups had at least one PIM at baseline . Two months after the medication review s , the number of intervention group patients with at least one PIM and the number of intervention group patients using ten or more drugs had decreased ( p = 0.007 and p = 0.001 , respectively ) , while there were no statistically significant changes in the control patients . No changes were seen in the number of patients using three or more psychotropic drugs , although the dosages of these drugs tended to decrease . Drug-related problems ( DRPs ) were identified in 93 % of the 182 patients in the intervention group . In total , there were 431 DRPs in the intervention group ( a mean of 2.5 DRPs per patient , range 0–9 , SD 1.5 at 95 % CI ) and 16 % of the DRPs were related to PIMs . Conclusions Medication review s involving pharmacists in primary health care appear to be a feasible method to reduce the number of patients with PIMs , thus improving the quality of pharmacotherapy in elderly patients Background Intravenous medication administrations have a high incidence of error but there is limited evidence of associated factors or error severity . Objective To measure the frequency , type and severity of intravenous administration errors in hospitals and the associations between errors , procedural failures and nurse experience . Methods Prospect i ve observational study of 107 nurses preparing and administering 568 intravenous medications on six wards across two teaching hospitals . Procedural failures ( eg , checking patient identification ) and clinical intravenous errors ( eg , wrong intravenous administration rate ) were identified and categorised by severity . Results Of 568 intravenous administrations , 69.7 % ( n=396 ; 95 % CI 65.9 to 73.5 ) had at least one clinical error and 25.5 % ( 95 % CI 21.2 to 29.8 ) of these were serious . Four error types ( wrong intravenous rate , mixture , volume , and drug incompatibility ) accounted for 91.7 % of errors . Wrong rate was the most frequent and accounted for 95 of 101 serious errors . Error rates and severity decreased with clinical experience . Each year of experience , up to 6 years , reduced the risk of error by 10.9 % and serious error by 18.5 % . Administration by bolus was associated with a 312 % increased risk of error . Patient identification was only checked in 47.9 % of administrations but was associated with a 56 % reduction in intravenous error risk . Conclusions Intravenous administrations have a higher risk and severity of error than other medication administrations . A significant proportion of errors suggest skill and knowledge deficiencies , with errors and severity reducing as clinical experience increases . A proportion of errors are also associated with routine violations which are likely to be learnt workplace behaviours . Both areas suggest specific targets for intervention BACKGROUND regular medication review has been recommended for those over 75 and those on multiple drug therapy . Pharmacists are a potential source of assistance in review ing medication . Evidence of the benefits of this process is needed . OBJECTIVE to study the effect of medication review led by a pharmacist on resolution of pharmaceutical care issues , medicine costs , use of health and social services and health-related quality of life . DESIGN r and omized , controlled trial . SETTING general medical practice s in the Grampian region of Scotl and . SUBJECTS patients aged at least 65 years , with at least two chronic disease states who were taking at least four prescribed medicines regularly . METHODS pharmacists review ed the drug therapy of 332 patients , using information obtained from the practice computer , medical records and patient interviews . In 168 patients , a pharmaceutical care plan was then drawn up and implemented . The 164 control patients continued to receive normal care . All outcome measures were assessed at baseline and after 3 months . RESULTS all patients had at least two pharmaceutical care issues at baseline . Half of these were identified from the prescription record , the rest from notes and patient interview . Of all the issues , 21 % were resolved by information found in notes and 8.5 % by patient interview . General practitioners agreed with 96 % of all care issues documented on the care plans in the intervention group . At the time of follow-up , 70 % of the remaining care issues had been resolved in the intervention group , while only 14 % had been resolved in the control group . There were no changes in medicine costs or health-related quality of life in either group . There were small increases in contacts with health-care professionals and slightly fewer hospital admissions among the intervention group than the control group . CONCLUSIONS pharmacist-led medication review has the capacity to identify and resolve pharmaceutical care issues and may have some impact on the use of other health services Objective To describe the scenario and frequency of drug-related problems ( DRPs ) in in- patients and to determine whether a pharmacotherapeutic advisory intervention aim ing at reducing DRPs could affect rates of re-hospitalisation and /or death within 6 months . Methods This prospect i ve , r and omised , controlled advisory intervention study was carried out at the Clinic of Internal Medicine at Stockholm Söder Hospital . Three hundred patients from four wards took part in the study . Patients taking two drugs or more were included . In the intervention arm , potential drug interactions were found using a computer system . Medical symptoms were estimated by a nurse together with the patient . Creatinine clearance was calculated . Thereafter a clinical pharmacologist scrutinised the patient´s medical record for DRPs together with the nurse . DRPs judged to be clinical ly relevant result ed in written advice to the physician in charge of the patient . The control group received usual care . Results In the intervention group , a total of 299 DRPs were found among 71 % of the patients ( 106/150 ) . The number of written letters of advice to the physicians in charge was 106 . Of these , 63 % were accepted . After 6 months , the proportion of re-hospitalisations or death in the intervention group was 49 % ( 73/150 ) compared to 46 % ( 69/150 ) in the control group . The difference was not significant . Conclusions DRPs were common . Potential drug interactions and adverse drug reactions dominated . Hospital-based medication review by a clinical pharmacologist was not associated with reduced rates of re-hospitalisation and /or death . The clinical relevancy of DRPs might be overestimated as a risk for re-hospitalisation or death . It is of great importance to clarify if and how drug-related problems can be prevented . In design ing such studies , one should consider choosing inclusion criteria that accumulate risk BACKGROUND Pharmacists can improve patient outcomes in institutional and pharmacy setting s , but little is known about their effectiveness as consultants to primary care physicians . We examined whether an intervention by a specially trained pharmacist could reduce the number of daily medication units taken by elderly patients , as well as costs and health care use . METHODS We conducted a r and omized controlled trial in family practice s in 24 sites in Ontario . We r and omly allocated 48 r and omly selected family physicians ( 69.6 % participation rate ) to the intervention or the control arm , along with 889 ( 69.5 % participation rate ) of their r and omly selected community-dwelling , elderly patients who were taking 5 or more medications daily . In the intervention group , pharmacists conducted face-to-face medication review s with the patients and then gave written recommendations to the physicians to resolve any drug-related problems . Process outcomes included the number of drug-related problems identified among the senior citizens in the intervention arm and the proportion of recommendations implemented by the physicians . RESULTS After 5 months , seniors in the intervention and control groups were taking a mean of 12.4 and 12.2 medication units per day respectively ( p = 0.50 ) . There were no statistically significant differences in health care use or costs between groups . A mean of 2.5 drug-related problems per senior was identified in the intervention arm . Physicians implemented or attempted to implement 72.3 % ( 790/1093 ) of the recommendations . INTERPRETATION The intervention did not have a significant effect on patient outcomes . However , physicians were receptive to the recommendations to resolve drug-related problems , suggesting that collaboration between physicians and pharmacists is feasible OBJECTIVES To test the effect of an adapted U.S. model of pharmaceutical care on prescribing of inappropriate psychoactive ( anxiolytic , hypnotic , and antipsychotic ) medications and falls in nursing homes for older people in Northern Irel and ( NI ) . DESIGN Cluster r and omized controlled trial . SETTING Nursing homes r and omized to intervention ( receipt of the adapted model of care ; n=11 ) or control ( usual care continued ; n=11 ) . PARTICIPANTS Residents aged 65 and older who provided informed consent ( N=334 ; 173 intervention , 161 control ) . INTERVENTION Specially trained pharmacists visited intervention homes monthly for 12 months and review ed residents ' clinical and prescribing information , applied an algorithm that guided them in assessing the appropriateness of psychoactive medication , and worked with prescribers ( general practitioners ) to improve the prescribing of these drugs . The control homes received usual care . MEASUREMENTS The primary end point was the proportion of residents prescribed one or more inappropriate psychoactive medicine according to st and ardized protocol s ; falls were evaluated using routinely collected falls data m and ated by the regulatory body for nursing homes in NI . RESULTS The proportion of residents taking inappropriate psychoactive medications at 12 months in the intervention homes ( 25/128 , 19.5 % ) was much lower than in the control homes ( 62/124 , 50.0 % ) ( odds ratio=0.26 , 95 % confidence interval=0.14 - 0.49 ) after adjustment for clustering within homes . No differences were observed at 12 months in the falls rate between the intervention and control groups . CONCLUSION Marked reductions in inappropriate psychoactive medication prescribing in residents result ed from pharmacist review of targeted medications , but there was no effect on falls BACKGROUND Chronic heart failure ( CHF ) accounts for significant morbidity , mortality and health expenditure . Furthermore , patients with CHF are often on numerous pharmacological agents for their comorbidities . The objective of this study was to determine whether a pharmacist directed home medication review intervention had positive effects on CHF patient outcomes . METHODS A total of 120 patients hospitalised for CHF were r and omised to receive a pharmacist directed post-discharge home medication review ( n = 64 , 53.3 % ) or st and ard care ( n = 56 , 46.7 % ) . Participants were followed for 6 months . Primary outcomes were death , CHF hospitalisation and length of hospital stay . RESULTS There were no between group differences in mortality ( hazard ratio = 1.41 , 0.50 to 3.97 ; P = 0.514 ) or CHF hospitalizations ( incidence rate ratio [ IRR ] = 1.74 95 % CI : 0.85 - 3.60 P = 0.131 ) over the 6 month follow-up period . Days of hospital stay for CHF exacerbations in the 6 month follow-up were significantly greater in the intervention group ( IRR = 2.34 95 % CI : 1.80 - 3.05 P = 0.000 ) . CONCLUSIONS Post-discharge pharmacy directed home medication review appeared to have no effect on mortality and health care utilisation above that achieved with st and ard care . The post-acute management of CHF must be a collaborative multi-disciplinary effort by the health care team as it is the additive effect of interventions that are most effective Objective : To evaluate the impact of a hospital based community liaison pharmacy service on a range of outcomes in patients aged more than 55 years and taking more than 3 prescribed drugs , who had been admitted to the medical unit of a district general hospital in Northern Irel and . Methods : Having recruited 243 patients , a total of 162 patients completed the full protocol ( 81 r and omly assigned to intervention and 81 to control ; mean age of control patients 75 years ; mean age of intervention patients 73 years ) . The interventions by the community liaison pharmacist included : preparation of an accurate medication record following a full review of current medication use ; medication counselling ; provision of a medicines record sheet informing the patient how to take their drugs ; provision of a pharmaceutical discharge letter detailing changes made to drug therapy ( this was faxed to the patient 's GP and community pharmacist on the day of discharge ) ; provision of a Medicines Helpline . Results : The key findings were as follows : problems were identified in 80 % of the intervention patients ' prescription charts , 49 % of which related to drug omissions from the patients ' domiciliary prescriptions . The GP practice record was the most accurate ( mean error rate 12.6 % ) while the GP referral letter was the least accurate ( mean error rate 47.3 % ) source of medication information . Drugs patients brought to hospital were also an inaccurate source ( mean error rate 44.0 % ) . The intervention group patients , when compared with control patients , had a significant reduction ( P=0.005 ) in drug mismatch between drugs prescribed at discharge and taken at home , and had a greater knowledge of their drug regimen 10–14 days after discharge ( P |Ld 0.001 ) . The vast majority of patients ( 96 % ) felt that the provision of a medicine helpline was a useful service . Conclusions : The study indicated clear benefits from the involvement of a hospital based community liaison pharmacist in achieving seamless pharmaceutical care between the primary and secondary healthcare setting Background : Accurate medication histories at hospital admission are an important element of medication safety . Discrepancies may have clinical ly significant consequences , especially in the elderly population . Objective : To assess the clinical pharmacist 's performance in obtaining patients ' medication histories and in reconciling these data with the medical records and medication orders and whether the patients ' residential situation prior to hospitalization influences the number of drug discrepancies . Methods : A prospect i ve observational study was conducted at a 29-bed acute geriatric ward of a Belgian university hospital . Medication histories acquired by clinical pharmacists were compared with those documented in the medical records by the attending physicians . All discrepancies were identified and categorized by an independent pharmacist and were scored for their clinical relevance in consensus by a senior internist and a senior geriatrician . Results : Of the 215 screened geriatric ( aged ≥66 years ) patients admitted between October 27 , 2007 , and September 23 , 2008 , 197 were enrolled in the study . For patients living in the community , as well as those residing in a nursing home prior to hospitalization , clinical pharmacists identified significantly more preadmission drugs compared with physicians , with a median number of 8 correctly identified medications versus 6 , respectively ( p < 0.001 ) . Extra identified drugs consisted of over-the-counter as well as prescription medications . Furthermore , 117 other medication discrepancies were noted , mainly related to erroneous drug identification and incorrect drug dose . In all , the clinical pharmacists identified 379 ( 24.2 % ) medication discrepancies , of which 188 ( 49.6 % ) were judged clinical ly relevant . Conclusions : Pharmacist-acquired medication histories enhance the medication reconciliation process , both in patients residing at home and in a nursing home prior to hospitalization . A focus should be placed on seamless care procedures that facilitate the transfer of medication histories between primary and secondary care in both of these population Objective To evaluate the non-intentional prescription discrepancies between home medication and hospital medication for in- patients , their potential clinical impact and the impact of pharmaceutical communication between community pharmacists ( CP ) and hospital clinical pharmacists ( HCP ) to prevent them . Setting Prospect i ve study of 278 in-patient ’s files hospitalized in orthopaedic surgery + units . Methods After reconciliation by the HCP including patient interviews , GP prescription review s and CP drug delivery analyses , we analysed patient files ( prescription and patient chart ) and we compared the administered drugs ( home medication ) to those that the patient should have received . We tracked the pharmaceutical intervention , the physician acceptance and the identified and avoided errors . The clinical impact of each discrepancy was evaluated by a team composed of a physician and a clinical pharmacist . Main outcome measure Frequency of intentional and non-intentional discrepancy ( NID ) , evaluation of NID clinical impact and rate of NID identified and corrected by the reconciliation procedure . Results 278 consecutive patients were included in the study . 1,532 prescription lines were analysed and 471 discrepancies were observed [ IC95 % = ( 28.43 ; 33.00 ) ] . Nonintentional discrepancies ( NID ) affected 9.2 % of prescription lines [ IC95 % = ( 7.7 ; 10.6 ) ] and 34.2 % of patients [ IC95 % = ( 31.3 ; 37.1 ) ] . Fifty-one patients ( 18.3 % ) had at least one NID classified as potentially harmful . Sixty-nine percent of errors at admission were identified by the reconciliation procedure including data exchanges with CP . Conclusion This study demonstrates the importance of drug reconciliation at patient ’s admission by the HCP supported by communication with the CP RATIONALE , AIMS AND OBJECTIVES To determine whether an increased input by clinical pharmacists at each stage of the patient 's hospital journey , from admission through discharge , result ed in an enhanced level of patient care as measured by a number of clinical and economic outcomes . METHODS This project was design ed to address medicines management issues in patients deemed at risk of drug-related problems . During the project , these latter patients at the time of admission were r and omly assigned to an integrated medicines management ( IMM ) service group ( n = 371 ) or regular hospital care group ( n = 391 ) . The IMM service involved comprehensive pharmaceutical care provided by a pharmacy team throughout each of three stages : patient admission , inpatient monitoring and counselling , and patient discharge . RESULTS Patients who received the IMM service benefited from a reduced length of hospital stay [ by 2 days ( P = 0.003 ; independent sample s t-test log(e ) ) ] . IMM patients also had a decreased rate of readmission over a 12-month follow-up period ( 40.8 % vs. 49.3 % ; p = 0.027 ; Fisher 's exact test ) and an increased time to readmission [ 20 days longer ( P = 0.0356 ; log rank test ) ] . A numbers-needed-to-treat calculation indicated that for approximately every 12 patients receiving the IMM service , one readmission to hospital , within 12 months of discharge , would be prevented . The new service was welcomed by cognate health care professionals . CONCLUSION The IMM service proved very effective and can be used as a template to support the implementation of comprehensive pharmaceutical care as a routine service across Northern Irel and and beyond Purpose We have developed a model for integrated medicines management , including tools and activities for medication reconciliation and medication review . In this study , we focus on improving the quality of the discharge summary including the medication report to reduce medication errors in the transition from hospital to primary and community care . Methods This study is a longitudinal study with an intervention group and a control group . The intervention group comprised 52 patients , who were included from 1 March 2006 until 31 December 2006 , with a break during summer . Inclusion in the control group was performed in the same wards during the period 1 September 2005 until 20 December 2005 , and 63 patients were included in the control group . In order to improve the quality of the medication report , clinical pharmacists review ed and gave feedback to the physician on the discharge summary before patient discharge , using a structured checklist . Medication errors were then identified by comparing the medication list in the discharge summary with the first medication list used in the community health care after the patient had returned home . Results By improving the quality of the discharge summary , patients had on average 45 % fewer medication errors per patient ( P = 0.012 ) . The proportion of patients without medication errors was 63.5 % in the control group and 73.1 % in the intervention group . However , this increase was not significant ( P = 0.319 ) . Patients who used a specific medication dispensing system ( ApoDos ) had a 5.9-fold higher risk of suffering from medication errors than those without this medication dispensing system ( P < 0.001 ) . Conclusion Review and feedback on errors in the discharge summary , including the medication report and a correct medication list , reduced medication errors during the transfer of information from hospital to primary and community care AIMS To evaluate whether a year long clinical pharmacy program involving development of professional relationships , nurse education on medication issues , and individualized medication review s could change drug use , mortality and morbidity in nursing home residents . METHODS A cluster r and omised controlled trial , where an intervention home was matched to three control homes , was used to examine the effect of the clinical pharmacy intervention on resident outcomes . The study involved 905 residents in 13 intervention nursing homes and 2325 residents in 39 control nursing homes in south-east Queensl and and north-east New South Wales , Australia . The outcome measures were : continuous drug use data from government prescription subsidy cl aims , cross-sectional drug use data on prescribed and administered medications , deaths and morbidity indices ( hospitalization rates , adverse events and disability indices ) . RESULTS This intervention result ed in a reduction in drug use with no change in morbidity indices or survival . Differences in nursing home characteristics , as defined by cluster analysis with SUDAAN , negated intervention-related apparent significant improvements in survival . The use of benzodiazepines , nonsteroidal anti-inflammatory drugs , laxatives , histamine H2-receptor antagonists and antacids was significantly reduced in the intervention group , whereas the use of digoxin and diuretics remained similar to controls . Overall , drug use in the intervention group was reduced by 14.8 % relative to the controls , equivalent to an annual prescription saving of A64 dollars per resident ( approximately 25 pound sterling ) . CONCLUSIONS This intervention improved nursing home resident outcomes related to changes in drug use and drug-related expenditure . The continuing divergence in both drug use and survival at the end of the study suggests that the difference would have been more significant in a larger and longer study , and even more so using additional instruments specific for measuring outcomes related to changes in drug use BACKGROUND Aged Care Assessment Teams ( ACATs ) in Australia assess the care needs of frail older people . Despite being at high risk of medication-related problems ( MRPs ) , ACAT patients do not routinely receive a comprehensive medication review . OBJECTIVES The aims of the study were to compare three methods for facilitating a pharmacist-led comprehensive medication review for people referred to an ACAT , and compare MRPs identified via ACAT usual care with those identified via pharmacist-led medication review s. METHODS A prospect i ve , r and omized , comparative study involving 80 community-dwelling patients ( median age 84 years ) referred to an ACAT in Melbourne , Australia , was conducted . Following ACAT assessment ( usual care ) , a clinical pharmacist review ed all participating patients ' ACAT files to identify potential MRPs not identified by the ACAT ( medication review method 1 ) . Patients were then r and omized into two groups . Group A received information about the Australian government-funded , general practitioner (GP)-initiated Home Medicines Review ( HMR ) programme , and a letter was sent to their GP recommending an HMR ( GPHMR ; medication review method 2 ) . Group B patients were referred directly to a clinical pharmacist associated with the ACAT for an ACAT-initiated pharmacist home medicines review ( APHMR ; medication review method 3 ) ; the pharmacist arranged a home visit , obtained a thorough medication history and conducted a comprehensive medication review . The main outcome measures were the proportion of patients who received a pharmacist home visit within 28 days ; the number of MRPs identified by ACAT usual care , pharmacist review of ACAT files , and APHMR , and their clinical risk ( assessed by a geriatrician-pharmacist panel ) ; and patients ' , GPs ' and ACAT clinicians ' opinions about pharmacist medication review . RESULTS Three hundred patients were referred to the ACAT , and 80 were recruited into the study . Thirty-six of 40 APHMR patients ( 90.0 % ) received a pharmacist home visit within 28 days , compared with 7/40 GPHMR patients (17.5%).[p < 0.001 ] . Twenty-one MRPs were identified via ACAT usual care . Pharmacist review of ACAT files identified a further 164 potential MRPs ( median 2.0 per patient ; inter-quartile range [ IQR ] 1.0 - 3.0 ) ; however , in patients who received an APHMR , 35/82 potential MRPs ( 42.7 % ) turned out not to be actual problems , most commonly because of discrepancies between the patient 's ACAT medication list and the medications currently being used by the patient ( median 3.0 discrepancies per patient ; IQR 2.0 - 5.5 ) . APHMR identified a further 79 MRPs ( median 2.0 ; IQR 1.0 - 3.0 ) . One hundred and twenty-two MRPs were included in APHMR reports sent to patients ' GPs . Of these , 94 ( 77.0 % ) were assessed as being associated with a moderate , high or extreme risk of an adverse event . Sixty-four APHMR recommendations ( 52.5 % ) led to changes to patients ' medication regimens or medication management . Thirty-six of 39 GPs ( 92.3 % ) who provided feedback reported that pharmacist medication review s were useful . Patients ( or their carers ) also reported that pharmacist home visits were useful : median rating 4.25 out of 5 ( IQR 4.0 - 5.0 ) . Seven of 11 ACAT clinicians ( 77.8 % ) agreed that pharmacist-led medication review should be a st and ard component of ACAT assessment s. CONCLUSIONS ACAT assessment s without pharmacist involvement detected fewer MRPs than any of the evaluated pharmacist-led medication review methods . APHMR was more effective than pharmacist review of routinely collected ACAT data , and more reliable and timely than referral to the patients ' GP for a GPHMR Elderly patients are vulnerable to medication errors and adverse drug events due to increased morbidity , polypharmacy and inappropriate interactions . The objective of this study was to investigate whether systematic medication review and counselling performed by a clinical pharmacist and clinical pharmacologist would reduce length of in-hospital stay in elderly patients admitted to an acute ward of internal medicine . A r and omized , controlled study of 100 patients aged 70 years or older was conducted in an acute ward of internal medicine in Denmark . Intervention arm : a clinical pharmacist conducted systematic medication review s after an experienced medical physician had prescribed the patients ' medication . Information was collected from medical charts , interview with the patients and data base registration s of drug purchase . Subsequently , medication histories were conferred with a clinical pharmacologist and advisory notes recommending medication changes were completed . Physicians were not obliged to comply with the recommendations . Control arm : medication was review ed by usual routine in the ward . Primary end-point was length of in-hospital stay . In addition , readmissions , mortality , contact to primary healthcare and quality of life were measured at 3-month follow-up . In the intervention arm , the mean length of in-hospital stay was 239.9 hr ( 95 % CI : 190.2 - 289.6 ) and in the control arm : 238.6 hr ( 95 % CI : 137.6 - 339.6 ) , which was neither a statistical significant nor a clinical ly relevant difference . Moreover , no differences were observed for any of the secondary end-points . Systematic medication review and medication counselling did not show any effect on in-hospital length of stay in elderly patients when admitted to an acute ward of internal medicine OBJECTIVE to measure the impact of pharmacist-conducted clinical medication review with elderly care home residents . DESIGN r and omised controlled trial of clinical medication review by a pharmacist against usual care . SETTING sixty-five care homes for the elderly in Leeds , UK . PARTICIPANTS a total of 661 residents aged 65 + years on one or more medicines . INTERVENTION clinical medication review by a pharmacist with patient and clinical records . Recommendations to general practitioner for approval and implementation . Control patients received usual general practitioner care . MAIN OUTCOME MEASURES primary : number of changes in medication per participant . Secondary : number and cost of repeat medicines per participant ; medication review rate ; mortality , falls , hospital admissions , general practitioner consultations , Barthel index , St and ardised Mini-Mental State Examination ( SMMSE ) . RESULTS the pharmacist review ed 315/331 ( 95.2 % ) patients in 6 months . A total of 62/330 ( 18.8 % ) control patients were review ed by their general practitioner . The mean number of drug changes per patient were 3.1 for intervention and 2.4 for control group ( P < 0.0001 ) . There were respectively 0.8 and 1.3 falls per patient ( P < 0.0001 ) . There was no significant difference for GP consultations per patient ( means 2.9 and 2.8 in 6 months , P = 0.5 ) , hospitalisations ( means 0.2 and 0.3 , P = 0.11 ) , deaths ( 51/331 and 48/330 , P = 0.81 ) , Barthel score ( 9.8 and 9.3 , P = 0.06 ) , SMMSE score ( 13.9 and 13.8 , P = 0.62 ) , number and cost of drugs per patient ( 6.7 and 6.9 , P = 0.5 ) ( pounds sterling 42.24 and pounds sterling 42.94 per 28 days ) . A total of 75.6 % ( 565/747 ) of pharmacist recommendations were accepted by the general practitioner ; and 76.6 % ( 433/565 ) of accepted recommendations were implemented . CONCLUSIONS general practitioners do not review most care home patients ' medication . A clinical pharmacist can review them and make recommendations that are usually accepted . This leads to substantial change in patients ' medication regimens without change in drug costs . There is a reduction in the number of falls . There is no significant change in consultations , hospitalisation , mortality , SMMSE or Barthel scores BACKGROUND In the hospital setting , postoperative admission is a key vulnerable moment when patients are at increased risk of medication discrepancies . This study measures the reduction of medication discrepancies associated with a combined intervention of structured pharmacist medication history interviews with assessment s in a surgical preadmission clinic and a postoperative medication order form . METHODS In the Surgical Pharmacist in Preadmission Clinic Evaluation ( SPPACE ) study , patients who had a preadmission clinic appointment before undergoing surgical procedures were eligible for inclusion . Patients were excluded if they were scheduled for discharge the same day as their surgery . Eligible patients were r and omly assigned to the intervention arm ( structured pharmacist medication history interview with assessment and generation of a postoperative medication order form ) or to the st and ard care arm ( nurse-conducted medication histories and surgeon-generated medication orders ) . The primary end point was the number of patients with at least 1 postoperative medication discrepancy related to home medications . RESULTS Between April 19 , 2005 , and June 3 , 2005 , a total of 464 patients were enrolled in the study , of which 227 and 237 patients were r and omized to the intervention and st and ard care arms , respectively . In the intervention arm , 41 ( 20.3 % ) of 202 patients had at least 1 postoperative medication discrepancy related to home medications , compared with 86 ( 40.2 % ) of 214 patients in the st and ard care arm ( P<.001 ) . In the intervention arm , 26 ( 12.9 % ) of 202 patients had at least 1 postoperative medication discrepancy with the potential to cause possible or probable harm , compared with 64 ( 29.9 % ) of 214 patients in the st and ard care arm ( P<.001 ) . These were mostly omissions of reordering home medications . CONCLUSION A combined intervention of pharmacist medication assessment s and a postoperative medication order form can reduce postoperative medication discrepancies related to home medications BACKGROUND A systematic study into outpatient medication reconciliation was conducted to determine if a multifaceted intervention influencing providers and patients reduced discrepancies related to inadequate prescription medication reconciliation in an outpatient setting . METHODS A prospect i ve trial was conducted on 104 primary care patients at the Mayo Clinic . Patients in Phase I received st and ard care . Patients in Phase II received the intervention reconciliation process , which consisted of ( 1 ) mailed letters before appointments to remind patients to bring medication bottles or up date d medication lists to their visits , ( 2 ) verification , and ( 3 ) correction of the medication list in the electronic medical record by the patient , and academic detailing and weekly audit and feedback of performance . RESULTS Interventions result ed in a decrease in prescription medication errors from 88.9 % of the visits in Phase 1 to 66 % of the visits in Phase II ( p = .005 ) and from 98.2 % of the visits in Phase I to 84 % of the visits in Phase II ( p = .0134 ) when all medications were considered . The average number of discrepancies per patient decreased by more than 50 % from 5.24 in Phase I to 2.46 in Phase II . The majority of discrepancies were minor . DISCUSSION A multifaceted intervention including various members of the health care provider team ( and the patient ) is crucial to enhancing medication reconciliation Aim of study : This study sought to determine whether multidisciplinary case conference review s improved outcomes for nursing home residents , and the effects of this team approach to resident care on carers , including the h and s-on carers employed by the nursing home , and health professionals . Method : 245 residents of three Canberra nursing homes were enrolled in this non-r and omised controlled trial . The intervention consisted of sessions of three case conference review s held between 10/4sol;96 and 4sol;12sol;96 . These sessions were attended by the General Practitioners ( GPs ) of the residents discussed , the GP project officer from the ACT Division of General Practice , a clinical pharmacist , senior nursing staff , other health professionals eg physiotherapist , and occasionally the resident concerned or their representative . At each review , a case presentation by the resident 's GP was followed by a multidisciplinary discussion of all aspects , medical and non-medical , of the resident 's care . The review concluded with a management plan for the resident . In total 75 residents were review ed . Main outcome measures : Medication use and cost , and mortality . Results : One month after the review s were completed comparisons between those who were review ed and those who were not showed non-significant reductions in medication orders , medication cost , and mortality in the review ed group . Many of the 92 recommendations in the management plans that were carried out benefited the residents ( n=37 ) and /or carers ( n=24 ) . The responses of the GPs and the Directors of Nursing to the review s were overwhelmingly positive . Conclusion : Recommendations arising from multidisciplinary case conferences were carried out to the benefit of patients and carers . Given the support shown by key stakeholders , multidisciplinary conferences should be used more Purpose To evaluate if nurses after receiving training in clinical pharmacology can improve the quality of the drug therapy in elderly hospitalized patients . Methods Nurses were given a 1-day training in clinical pharmacology to identify drug-related problems ( DRPs ) . All patients admitted to the ward aged 65 or more were studied . Patients at the same ward before the intervention were considered as control group . Outcome variables were re-hospitalized 3 months from discharge , drug-related re-admissions , the proportion of inappropriate drug use ( IDU ) , and DRPs found by the nurses . Results Of 460 patients ( 250 intervention group and 210 in the control group ) 38 and 36 % , respectively , had at least one re-admission to hospital ( p = 0.86 ) and 24 % of the patients died . Eighteen and 17 % ( 43/37 ) , respectively , used one or more inappropriate drug ( p 0.90 ) . The nurses found 86 clinical ly significant DRPs not detected by the usual care . A substantial part of the DRPs detected by the nurses were revealed with assistance of Symptoms Assessment Form ( SYM ) . There were no statistical difference in the number of drug-related re-admissions between the groups , 14/16 , respectively , ( p = 0.40 ) . Conclusions Nurses are able to detect a high proportion of clinical ly relevant DRPs not detected by the usual care and thereby increase the quality of the drug treatment in elderly hospitalized patients . Our study showed no effect on re-hospitalization or IDU . By using a SYM nurses can find DRPs that computer-based decision support systems miss OBJECTIVES To determine the extent to which the use of a clinical informatics tool that implements prospect i ve monitoring plans reduces the incidence of potential delirium , falls , hospitalizations potentially due to adverse drug events , and mortality . DESIGN R and omized cluster trial . SETTING Twenty-five nursing homes serviced by two long-term care pharmacies . PARTICIPANTS Residents living in nursing homes during 2003 ( 1,711 in 12 intervention ; 1,491 in 13 usual care ) and 2004 ( 1,769 in 12 intervention ; 1,552 in 13 usual care ) . INTERVENTION The pharmacy automatically generated Geriatric Risk Assessment MedGuide ( GRAM ) reports and automated monitoring plans for falls and delirium within 24 hours of admission or as part of the normal time frame of federally m and ated drug regimen review . MEASUREMENTS Incidence of potential delirium , falls , hospitalizations potentially due to adverse drug events , and mortality . RESULTS GRAM triggered monitoring plans for 491 residents . Newly admitted residents in the intervention homes experienced a lower rate of potential delirium onset than those in usual care homes ( adjusted hazard ratio (HR)=0.42 , 95 % confidence interval (CI)=0.35 - 0.52 ) , overall hospitalization ( adjusted HR=0.89 , 95 % CI=0.72 - 1.09 ) , and mortality ( adjusted HR=0.88 , 95 % CI=0.66 - 1.16 ) . In longer stay residents , the effects of the intervention were attenuated , and all estimates included unity . CONCLUSION Using health information technology in long-term care pharmacies to identify residents who might benefit from the implementation of prospect i ve medication monitoring care plans when complex medication regimens carry potential risks for falls and delirium may reduce adverse effects associated with appropriate medication use PURPOSE To determine if inpatient or outpatient geriatric evaluation and management , as compared with usual care , reduces adverse drug reactions and suboptimal prescribing in frail elderly patients . METHODS The study employed a r and omized 2 x 2 factorial controlled design . Subjects were patients in 11 Veterans Affairs ( VA ) hospitals who were > or = 65 years old and met criteria for frailty ( n = 834 ) . Inpatient geriatric unit and outpatient geriatric clinic teams evaluated and managed patients according to published guidelines and VA st and ards . Patients were followed for 12 months . Blinded physician-pharmacist pairs rated adverse drug reactions for causality ( using Naranjo 's algorithm ) and seriousness . Suboptimal prescribing measures included unnecessary and inappropriate drug use ( Medication Appropriateness Index ) , inappropriate drug use ( Beers criteria ) , and underuse . RESULTS For serious adverse drug reactions , there were no inpatient geriatric unit effects during the inpatient or outpatient follow-up periods . Outpatient geriatric clinic care result ed in a 35 % reduction in the risk of a serious adverse drug reaction compared with usual care ( adjusted relative risk = 0.65 ; 95 % confidence interval : 0.45 to 0.93 ) . Inpatient geriatric unit care reduced unnecessary and inappropriate drug use and underuse significantly during the inpatient period ( P < 0.05 ) . Outpatient geriatric clinic care reduced the number of conditions with omitted drugs significantly during the outpatient period ( P < 0.05 ) . CONCLUSION Compared with usual care , outpatient geriatric evaluation and management reduces serious adverse drug reactions , and inpatient and outpatient geriatric evaluation and management reduces suboptimal prescribing , in frail elderly patients Inappropriate prescribing is particularly common in older patients and is associated with adverse drug events ( ADEs ) , hospitalization , and wasteful utilization of re sources . We r and omized 400 hospitalized patients aged ≥65 years to receive either the usual pharmaceutical care ( control ) or screening with STOPP/START criteria followed up with recommendations to their attending physicians ( intervention ) . The Medication Appropriateness Index ( MAI ) and Assessment of Underutilization ( AOU ) index were used to assess prescribing appropriateness , both at the time of discharge and for 6 months after discharge . Unnecessary polypharmacy , the use of drugs at incorrect doses , and potential drug – drug and drug – disease interactions were significantly lower in the intervention group at discharge ( absolute risk reduction 35.7 % , number needed to screen to yield improvement in MAI = 2.8 ( 95 % confidence interval 2.2–3.8 ) ) . Underutilization of clinical ly indicated medications was also reduced ( absolute risk reduction 21.2 % , number needed to screen to yield reduction in AOU = 4.7 ( 95 % confidence interval 3.4–7.5 ) ) . Significant improvements in prescribing appropriateness were sustained for 6 months after discharge OBJECTIVE To evaluate the effects of pharmacist-conducted medication therapy review ( MTR ) and intervention on the quality of care of patients in a family medicine clinic . DESIGN Prospect i ve , observational , cohort study . SETTING Family medicine clinic in Minnesota during 2000 - 2001 . PATIENTS Patients were enrolled in a statewide nonprofit managed care organization ; selected patients were seen by a clinical pharmacist . INTERVENTION Following MTR , medication-related problems ( MRPs ) were identified and resolved . MAIN OUTCOME MEASURES MRPs identified and resolved , improvement in clinical status , achievement of therapeutic goals , important medication use , and reduction in number of medications . RESULTS 92 patients were included in the study , with a total of 203 patient encounters . MRPs were identified in 90 % of patients , with a total of 250 identified . Overall status of medical conditions improved in 45 % of patients , 46 % stayed the same , and 9 % declined ( P < 0.001 ) . Significant improvement in status was found for hypertension ( P = 0.007 ) , dyslipidemia ( P = 0.002 ) , and asthma ( P = 0.011 ) . Significant improvement was seen for aspirin use for myocardial infa rct ion prevention ( 50 % vs. 93 % , P = 0.031 ) and inhaled steroids for asthma ( 36 % vs. 64 % , P = 0.031 ) . The number of medications was reduced from an average of 3.92 to 3.04 ( P < 0.001 ) per patient . CONCLUSION MTR and intervention by a pharmacist positively affected quality of care in this family medicine clinic OBJECTIVE To assess whether home-based medication review by a pharmacist for at-risk older patients in a primary care setting can reduce hospital admissions . DESIGN R and omised controlled trial comparing home-based medication review with st and ard care . SETTING Home-based medication review of 136 patients registered with one general practice . METHOD Study participants were over 80 years of age , living at home , taking four or more medicines , and had at least one additional medicines-related risk factor . The intervention comprised two home visits by a community pharmacist who educated the patient/carer about their medicines , noted any pharmaceutical care issues , assessed need for an adherence aid , and subsequently met with the lead GP to agree on actions . MAIN OUTCOME MEASURE Total non-elective hospital admissions within 6 months . Secondary outcomes included number of deaths , care home admissions and quality of life ( EQ-5d ) . Impact on number of medicines prescribed was also assessed . RESULTS At 6 months , no difference in hospital admissions ( 21 intervention versus 20 control P = 0.80 ) , and no difference in care home admissions or deaths were detected between groups . There was a small ( non-significant ) decrease in quality of life in the intervention group . There was a statistically significant reduction in the mean number of medicines prescribed ( -0.87 items in favour of the intervention group , 95 % confidence interval -1.66 to -0.08 , P = 0.03 ) . CONCLUSIONS No positive impact on clinical outcomes or quality of life was demonstrated , however , this intervention did appear to reduce prescribing . This is in line with other evidence and suggests that this form of intervention may not have a clear health gain , but may lead to modest savings in terms of reduced prescribing . Future research should focus on whether such a prescribing effect would make this type of intervention cost effective BACKGROUND Older people in nursing and residential homes often have complex disabilities and behavioural disturbances . Recent publicity has highlighted the dangers of medication in this group , and controls over prescribing have been suggested . AIMS To investigate the effect of a review of medication by a pharmacist . METHOD An 8-month prospect i ve trial of an active medication review by a pharmacist was carried out on 330 residents in nursing homes in Manchester . RESULTS The intervention group experienced greater deterioration in cognitive function and behavioural disturbance than the control group , but the changes in depression and quality of life were similar for both groups . The number of drugs prescribed fell in the intervention group , but not in the control group , with a corresponding saving in drug costs . The number of deaths was significantly smaller in the intervention homes during the intervention period ( 4 v. 14 ) but not overall during the study period as a whole ( 26 v. 28 ) . CONCLUSION This clinical intervention reduced the number of medicines prescribed to elderly people in nursing homes , with minimal impact on their morbidity and mortality Background Failure to reconcile medications across transitions in care is an important source of potential harm to patients . Little is known about the predictors of unintentional medication discrepancies and how , when , and where they occur . Objective To determine the reasons , timing , and predictors of potentially harmful medication discrepancies . Design Prospect i ve observational study . Patients Admitted general medical patients . Measurements Study pharmacists took gold-st and ard medication histories and compared them with medical teams ’ medication histories , admission and discharge orders . Blinded teams of physicians adjudicated all unexplained discrepancies using a modification of an existing typology . The main outcome was the number of potentially harmful unintentional medication discrepancies per patient ( potential adverse drug events or PADEs ) . Results Among 180 patients , 2066 medication discrepancies were identified , and 257 ( 12 % ) were unintentional and had potential for harm ( 1.4 per patient ) . Of these , 186 ( 72 % ) were due to errors taking the preadmission medication history , while 68 ( 26 % ) were due to errors reconciling the medication history with discharge orders . Most PADEs occurred at discharge ( 75 % ) . In multivariable analyses , low patient underst and ing of preadmission medications , number of medication changes from preadmission to discharge , and medication history taken by an intern were associated with PADEs . Conclusions Unintentional medication discrepancies are common and more often due to errors taking an accurate medication history than errors reconciling this history with patient orders . Focusing on accurate medication histories , on potential medication errors at discharge , and on identifying high-risk patients for more intensive interventions may improve medication safety during and after hospitalization AIMS To examine the effectiveness of a multidisciplinary service model delivering medication review to patients at risk of medication misadventure in the community . METHODS The study was carried out in three Australian states ; Queensl and , New South Wales and Western Australia , and conducted as a r and omized , controlled effectiveness trial with the general practitioner ( GP ) as the unit of r and omization . In total , 92 GPs , 53 pharmacists and 400 patients enrolled in the study . The multidisciplinary service model consisted of GP education , patient home visits , pharmacist medication review s , primary healthcare team conferences , GP implementation of action plans in consultation with patients , and follow-up surgery visits for monitoring . Effectiveness was assessed using the four clinical value compass domains of ( i ) functional status , ( ii ) clinical outcomes , ( iii ) satisfaction and ( iv ) costs . The domains of functional status ( assessed by the health-related quality of life measure SF-36 subscales ) and clinical outcomes ( as assessed by adverse drug events ( ADEs ) , number of GP visits , hospital services and severity of illness ) were measured at baseline and endpoint . Satisfaction was measured by success in implementation and by participant satisfaction at endpoint , and costs ( as assessed using medication and healthcare service costs , less intervention costs ) were measured preintervention and during the trial . In addition , process evaluation was conducted for intervention patients , in which problems and recommendations from the medication review s were described . RESULTS The model was successfully implemented with 92 % of intervention GPs suggesting that the model had improved the care of participating patients , a view shared by 94 % of pharmacists . In addition , positive trends in clinical outcomes ( ADEs and severity of illness ) and costs ( an ongoing trend towards reduction in healthcare service costs ) were evident , although the trial was limited to a 6-month intervention time . No differences between intervention and control groups were identified for the health-related quality of life domain . The cost-effectiveness ratio for the intervention based on cost savings , reduced adverse events and improved health outcomes was small . The most common problems identified in the medication review s were potential adverse drug reactions , suboptimal monitoring and adherence/lack of concordance issues . In total , 54.4 % of recommendations were enacted , and 23.9 % were implemented precisely as recommended in the medication review . Follow-up evaluation showed that 70.9 % of actions had a positive outcome , 15.7 % no effect and 3.7 % had a negative outcome . CONCLUSIONS Most studies emphasize efficacy and the best achievable clinical outcomes rather than whether an intervention will be effective in practice . The current trial showed that three of the four domains in the clinical value compass showed trends of improvement or were indeed improved in the relatively short follow-up period of the trial , suggesting that a service based on this model could achieve similar benefits in practice . A domiciliary medication review programme similar to this model has now been implemented into national Australian practice , where GPs and pharmacists are reimbursed by the Australian government for the provision of these services BACKGROUND Poorly executed transfers of older patients from hospitals to long-term care facilities carry the risk of fragmentation of care , poor clinical outcomes , inappropriate use of emergency department services , and hospital readmission . OBJECTIVE This study was conducted to assess the impact of adding a pharmacist transition coordinator on evidence -based medication management and health outcomes in older adults undergoing first-time transfer from a hospital to a long-term care facility . METHODS This r and omized , single-blind , controlled trial enrolled hospitalized older adults awaiting transfer to a long-term residential care facility for the first time . Patients were r and omized either to receive the services of the pharmacist transition coordinator ( intervention group ) or to undergo the usual hospital discharge process ( control group ) . The intervention included medication-management transfer summaries from hospitals , timely coordinated medication review s by accredited community pharmacists , and case conferences with physicians and pharmacists . The primary outcome was the quality of prescribing , measured using the Medication Appropriateness Index ( MAI ) . Secondary outcomes were emergency department visits , hospital readmissions , adverse drug events , falls , worsening mobility , worsening behaviors , increased confusion , and worsening pain . RESULTS One hundred ten older adults ( 67 women , 43 men ; mean [ SD ] age , 82.7 [ 6.4 ] years ) were recruited from 3 metropolitan hospitals and assigned to 85 metropolitan long-term care facilities . Fifty-six patients were r and omized to the intervention group and 54 to the control group ; 44 patients in each group were evaluable at 8-week follow-up . There were no significant differences in baseline characteristics between treatment groups , with the exception of the number of medications discontinued during hospitalization : a mean of 1.1 more drugs was discontinued in the control group compared with the intervention group ( P = 0.011 ) . The majority of patients ( 35 [ 62.5 % ] in the intervention group , 41 [ 76.0 % ] in the control group ) changed physicians as part of the transition to a long-term care facility . At 8-week follow-up , there was no change in MAI from baseline in the intervention group , whereas it had worsened in the control group ( mean [ 95 % CI ] , 2.5 [ 1.4 - 3.7 ] vs 6.5 [ 3.9 - 9.1 ] , respectively ; P = 0.007 ) . Patients who received the intervention and were alive at follow-up exhibited a significant protective effect of the intervention against worsening pain ( relative risk ratio [ 95 % CI ] , 0.55 [ 0.32 - 0.94 ] ; P = 0.023 ) and hospital usage ( i.e. , the combination of emergency department visits and hospital readmissions ) ( 0.38 [ 0.15 - 0.99 ] ; P = 0.035 ) , but did not differ from control patients in terms of adverse drug events ( 1.05 [ 0.66 - 1.68 ] ) , falls ( 1.19 [ 0.71 - 1.99 ] ) , worsening mobility ( 0.39 [ 0.13 - 1.15 ] ) , worsening behaviors ( 0.52 [ 0.25 - 1.10 ] ) , or increased confusion ( 0.59 [ 0.28 - 1.22 ] ) . When data for patients who had died were included , the intervention had no effect on hospital usage in all patients ( 0.58 [ 0.28 - 1.21 ] ) . CONCLUSIONS Older people transferring from hospital to a long-term care facility are vulnerable to fragmentation of care and adverse events . In this study , use of a pharmacist transition coordinator improved aspects of inappropriate use of medicines across health sectors Objective : To describe the frequency and types of drug-related problems ( DRPs ) in hospitalised patients , and to identify risk factors for DRPs and the drugs most frequently causing them . Methods From May to December 2002 , 827 patients from six internal medicine and two rheumatology departments in five hospitals in Norway were included in this study . We recorded demographic data , drugs used , relevant medical history , laboratory data and clinical /pharmacological risk factors , i.e. reduced renal function , reduced liver function , heart failure , diabetes , compliance problems , drugs with a narrow therapeutic index and drug allergy . DRPs were documented after review ing medical records and participation in multidisciplinary team discussion s. An independent quality assessment team retrospectively assessed the DRPs in a r and omly selected number of the study population . Results Of the patients , 81 % had DRPs , and an average of 2.1 clinical ly relevant DRPs was recorded per patient . The DRPs most frequently recorded were dose-related problems ( 35.1 % of the patients ) followed by need for laboratory tests ( 21.6 % ) , non-optimal drugs ( 21.4 % ) , need for additional drugs ( 19.7 % ) , unnecessary drugs ( 16.7 % ) and medical chart errors ( 16.3 % ) . The patients used an average of 4.6 drugs at admission . A multivariate analysis showed that the number of drugs at admission and the number of clinical /pharmacological risk factors were both independent risk factors for the occurrence of DRPs , whereas age and gender were not . The drugs most frequently causing a DRP were warfarin , digitoxin and prednisolone , with calculated risk ratios 0.48 , 0.42 and 0.26 , respectively . The drug groups causing most DRPs were B01A-antithrombotic agents , M01A-non-steroidal anti-inflammatory agents , N02A-opioids and C09A-angiotensin converting enzyme inhibitors , with risk ratios of 0.22 , 0.49 , 0.21 and 0.35 , respectively . Conclusions The majority of hospitalised patients in our study had DRPs . The number of drugs used and the number of clinical /pharmacological risk factors significantly and independently influenced the risk for DRPs . Procedures for identification of , and intervention on , actual and potential DRPs , along with awareness of drugs carrying a high risk for DRPs , are important elements of drug therapy and may contribute to diminishing drug-related morbidity and mortality BACKGROUND drug intake is associated with the risk of drug-related problems ( DRPs ) , e.g. the intake of PIM . OBJECTIVE the proportion of potentially inappropriate medication ( PIM ) taken by elderly people was analysed . DESIGN community-based , prospect i ve cohort study . SETTING ambulatory health-care sector in a German rural area . SUBJECTS seven hundred and forty-four patients with age > 65 years and regular intake of drugs . METHODS comprehensive home medication review ( HMR ) provided by specially qualified assistants of GP practice s using electronic case reporting forms ( eCRFs ) , and GP 's diagnoses were extracted from patients ' health records . Up date d Beers ' list of Fick et al. was used to detect PIM for patients > 65 years and drug-condition interaction . RESULTS a total of 18 % ( n= 134 ) of the patients received 163 inappropriate drugs . Out of these drugs , most prevalent PIM were benzodiazepine derivates ( n= 45 ) . Out of all drugs , 25 drug-condition interactions were identified . The intake of PIM was slightly associated with self-reported falls (: 0.1074 ; P= 0.0244 ) . Multivariate logistic regression showed significant results for the number of taken substances ( OR = 1.176 ; 95 % CI 1.121 - 1.234 , P < 0.001 ) . CONCLUSIONS a high proportion of patients taking PIM in a community-based setting were investigated . Statistical associations with self-reported falls were found . Confounding may influence data . Further research to investigate findings is needed Seamless care is the desirable continuity of care delivered to a patient in the healthcare system across the spectrum of caregivers and their environments . Medication Reconciliation is one component of seamless pharmaceutical care . A r and omized controlled trial , carried out over nine months with a six-month follow-up period , investigated the impact of a pharmacist-directed seamless care service . Intervention patients admitted to one of two general medicine units were subjected to a comprehensive seamless care discharge process as they were discharged from a regional , academically affiliated hospital in Moncton , NB . The number , type and potential clinical impact of drug-therapy problems for seamless monitoring ( DTPsm ) and drug-therapy inconsistencies and omissions ( DTIOs ) in hospital discharge medications were measured . A total of 253 patients , with 134 patients in the intervention group and 119 in the control group , completed the study . An average of 3.59 DTPsm per intervention patient , with 72.1 % of these being scored as having a significant or very significant clinical impact level , were communicated to community pharmacists . Ninety-nine DTIOs were identified and resolved in intervention patients before discharge . A retrospective medical chart review demonstrated that the intervention resolved almost all DTIOs . In conclusion , a pharmacist-directed seamless care service had a significant impact on drug-related clinical outcomes and processes of care WHAT IS KNOWN AND OBJECTIVE Interventions involving medication reconciliation and review by clinical pharmacists can reduce drug-related problems and improve therapeutic outcomes . The objective of this study was to examine the impact of routine admission medication reconciliation and inpatient medication review on emergency department ( ED ) revisits after discharge . Secondary outcomes included the combined rate of post-discharge hospital revisits or death . METHODS This prospect i ve , controlled study included all patients hospitalized in three internal medicine wards in a university hospital , between 1 January 2006 and 31 May 2008 . Medication reconciliation on admission and inpatient medication review , conducted by clinical pharmacists in a multiprofessional team , were implemented in these wards at different times during 2007 and 2008 ( intervention periods ) . A discharge medication reconciliation was undertaken in all the study wards , during both control and intervention periods . Patients were included in the intervention group ( n = 1216 ) if they attended a ward with medication reconciliation and review , whether they had received the intervention or not . Control patients ( n = 2758 ) attended the wards before implementation of the intervention . RESULTS AND DISCUSSION No impact of medication reconciliation and review s on ED revisits [ hazard ratio ( HR ) , 0.95 ; 95 % confidence interval ( CI ) , 0.86 - 1.04]or event-free survival ( HR , 0.96 ; 95 % CI , 0.88 - 1.04 ) was demonstrated . In the intervention group , 594 patients ( 48.8 % ) visited the ED , compared with 1416 ( 51.3 % ) control patients . In total , 716 intervention ( 58.9 % ) and 1688 ( 61.2 % ) control patients experienced any event ( ED visit , hospitalization or death ) . Because the time to a subsequent ED visit was longer for the control as well as the intervention groups in 2007 than in 2006 ( P < 0.05 ) , we re-examined this cohort of patients ; the proportion of patients revisiting the ED was similar in both groups in 2007 ( P = 0.608 ) . WHAT IS NEW AND CONCLUSION Routine implementation of medication reconciliation and review s on admission and during the hospital stay did not appear to have any impact on ED revisits , re-hospitalizations or mortality over 6-month follow-up BACKGROUND Medication reconciliation can prevent some adverse drug events ( ADEs ) . Our prospect i ve study explored whether an easily replicable nurse-pharmacist led medication reconciliation process could efficiently and inexpensively prevent potential ADEs . METHODS Nurses at a 1000 bed urban , tertiary care hospital developed the home medication list ( HML ) through patient interview . If a patient was not able to provide a written HML or recall medications , the nurses review ed the electronic record along with other sources . The nurses then compared the HML to the patient 's active inpatient medications and judged whether the discrepancies were intentional or potentially unintentional . This was repeated at discharge as well . If the prescriber changed the order when contacted about a potential unintentional discrepancy , it was categorized as unintentional and rated on a 1 - 3 potential harm scale . RESULTS The study included 563 patients . HML information gathering averaged 29 minutes . Two hundred twenty-five patients ( 40 % ; 95 % confidence interval [ CI ] , 36%-44 % ) had at least 1 unintended discrepancy on admission or discharge . One hundred sixty-two of the 225 patients had an unintended discrepancy ranked 2 or 3 on the harm scale . It cost $ 113.64 to find 1 potentially harmful discrepancy . Based on the 2008 cost of an ADE , preventing 1 discrepancy in every 290 patient encounters would offset the intervention costs . We potentially averted 81 ADEs for every 290 patients . CONCLUSION Potentially harmful medication discrepancies occurred frequently at both admission and discharge . A nurse-pharmacist collaboration allowed many discrepancies to be reconciled before causing harm . The collaboration was efficient and cost-effective , and the process potentially improves patient safety BACKGROUND efficient strategies are needed to provide specialist advice in nursing homes to ensure quality medical care . We describe a case conference intervention involving a multidisciplinary team of health professionals . OBJECTIVES to evaluate the impact of multidisciplinary case conferences on the appropriateness of medications and on patient behaviours in high-level residential aged care facilities . DESIGN cluster-r and omised controlled trial . SETTING ten high-level aged care facilities . PARTICIPANTS 154 residents with medication problems and /or challenging behaviours were selected for case conference by residential care staff . INTERVENTION two multidisciplinary case conferences involving the resident 's general practitioner , a geriatrician , a pharmacist and residential care staff were held at the nursing home for each resident . MEASUREMENTS outcomes were assessed at baseline and 3 months . The primary outcome was the Medication Appropriateness Index ( MAI ) . The behaviour of each resident was assessed via the Nursing Home Behaviour Problem Scale . RESULTS 45 residents died before follow-up . Medication appropriateness improved in the intervention group [ MAI mean change 4.1 , 95 % confidence interval ( CI ) 2.1 - 6.1 ] compared with the control group ( MAI mean change 0.4 , 95 % CI -0.4 - 1.2 ; P < 0.001 ) . There was a significant reduction in the MAI for benzodiazepines ( mean change control -0.38 , 95 % CI -1.02 - 0.27 versus intervention 0.73 , 95 % CI 0.16 - 1.30 ; P = 0.017 ) . Resident behaviours were unchanged after the intervention and the improved medication appropriateness did not extend to other residents in the facility . CONCLUSION multidisciplinary case conferences in nursing homes can improve care . Outreach specialist services can be delivered without direct patient contact and achieve improvements in prescribing BACKGROUND : Previous studies have reported a positive impact of pharmacists on care of patients with chronic illnesses . The impact of the clinical pharmacist on hospital readmission in patients with acute coronary syndromes ( ACS ) has yet to be evaluated , as of this writing . OBJECTIVE : To evaluate the impact of the clinical pharmacist as a direct patient-care team member on cardiac-related readmission in patients admitted to the general cardiology unit with ACS . METHODS : A prospect i ve , nonr and omized observational study compared patients who received st and ard practice care with patients admitted to a service with a clinical pharmacist to provide care at the bedside . Patients admitted to and discharged from the general cardiology unit for ACS were included . The primary endpoint of the study was cardiac-related readmission at 30 days following hospital discharge . Secondary endpoints included length of stay and medication utilization . Interventions provided by the clinical pharmacist in the study group were documented . RESULTS : Cardiac readmission at 30 days was similar between the groups ( p = 0.59 % ) . In the subset of patients with unstable angina , readmission in the study group was significantly lower than in the control group ( 1.3 % vs 9.1 % ; p = 0.04 % ) . Patients in both groups were similarly managed using drug therapy and invasive coronary interventions . The medical staff 's rate of acceptance of recommendations provided by the pharmacist was 94.4 % . The most common interventions were medication education and identification of indicated therapy . CONCLUSIONS : The addition of pharmacists did not decrease readmission in patients with ACS . The finding of significant reduction in readmission in the subset of patients with unstable angina should be considered “ hypothesis generating ” for future r and omized studies to confirm the results Background : Medication errors are common upon hospital admission . Clinical pharmacist involvement in medication reconciliation is effective in identifying and rectifying medication errors . However , data is lacking on the economic impact , time requirements , and severity of errors resolved by clinical pharmacists . Objective : To determine the incidence of unintended admission medication discrepancies resolved by clinical pharmacists . Secondary objectives were to determine the type of discrepancies , potential severity , proximal cause , and economic impact of this clinical pharmacy program . Methods : This was a single-center , prospect i ve , observational study conducted at a major teaching medical institution . Following institutional review board approval , data collection was conducted over a 4-week period ( August 22 , 2011 , to September 16 , 2011 ) . Descriptive statistical methods were performed for all data analyses . Results : A total of 517 patients involving 5006 medications were included in this study . More than 25 % ( n = 132 ) of patients had at least 1 error associated with a medication ordered on hospital admission . Pharmacists resolved a total of 467 admission medication errors ( 3.5 ± 2.3 errors/patient ) . The most common type of medication error resolved was medication omission ( 79.6 % ) . In regard to severity , 46 % of medication errors were considered significant or serious . Overall , the mean total time was 44.4 ± 21.8 minutes per medication reconciliation . This clinical pharmacy program was estimated to carry a net present value of $ 5.7 million over 5 years . Conclusion : Clinical pharmacist involvement within a multidisciplinary health care team during the admission medication reconciliation process demonstrated a significant improvement in patient safety and an economic benefit Background The prevalence and cost of hospital readmissions have gained attention . The ability to identify patients at high risk for hospital readmission has implication s for quality and costs of care . Medication errors have been shown to increase the risk for readmission . Objective To study the impact of a pharmacist-based predischarge medication reconciliation and counseling program on 30-day readmission rates and determine whether polypharmacy and problem medications are important screening criteria . Methods A prospect i ve , nonr and omized cohort study performed at a single medical-surgical unit with telemetry capability at a single academic medical center . The participants were 729 patients , aged 18 years and older , who were discharged between July 1 and October 29 , 2010 . The intervention was pharmacist medication reconciliation and counseling based on a screening tool . The primary outcome was 30-day readmission rate . Secondary outcomes were the presence of polypharmacy and problem medications and their relationship with observed 30-day readmission rate , including calculation of a problem med/polypharmacy score . Results The pharmacy review group ( n = 537 ) had a lower 30-day readmission rate than the group receiving usual care ( n = 192 ) ( 16.8 % vs 26.0 % ; odds ratio [ OR ] 0.572 ; 95 % CI , 0.387 - 0.852 ; P = .006 ) . Polypharmacy , defined as either 5 or more or 10 or more scheduled medications , alone and in combination with at least one problem medication had higher 30-day readmission rates . A score of no factors present exhibited good negative predictive value . Conclusions Medication reconciliation and counseling by a pharmacist reduced the 30-day readmission rate . Polypharmacy and problem medications appear to have value individually and together . A pharmacist , guided by a screening tool in predischarge medication reconciliation , is one option to effectively reduce 30-day readmissions BACKGROUND The inaccurate recording of medicines on admission to hospital is an important cause of medication error . Medication reconciliation has been used to identify and correct these errors . OBJECTIVE To determine if a multimodal intervention involving medication reconciliation with real-time feedback and education would reduce the number of errors made by medical staff when recording medicines at the time of admission to hospital . DESIGN Observational study . PARTICIPANTS Patients admitted to the general medical wards of a teaching hospital were studied prospect ively . Patients ≥75 years of age and on ≥5 medications were identified as the ‘ target group.’INTERVENTIONAfter admission , a second medication history was taken , and discrepancies were identified and communicated to the medical teams . An educational intervention to encourage prescribers to obtain accurate medication histories was conducted at the same time . MEASUREMENTS The discrepancy rate was measured before and after the intervention . MAIN RESULTS There were 470 admissions in the ‘ target group . ’ Three hundred and thirty-eight of the admissions ( 71.9 % ) had one or more unintentional discrepancies . Although many discrepancies had little potential to cause harm , 33 % were rated as clinical ly significant . During the study the discrepancy rate ( prior to reconciliation ) fell from 2.6 ( SD 2.6 ) to 1.0 ( SD 1.1 ) per admission ( p < 0.0001 ) . This decline in discrepancy rate remained significant ( p = 0.001 ) even when only clinical ly important discrepancies were included . The proportion of admissions with one or more clinical ly important discrepancies also decreased during the study from 46 % to 24 % ( p = 0.023 ) . CONCLUSIONS Errors in the recording of medicines at the time of hospital admission are common . Combining the feedback provided by medication reconciliation with prescriber education reduced the error rate . This approach may be useful when the re sources are not available to perform medication reconciliation for all patients admitted to hospital BACKGROUND Medication discrepancies may occur during transitions from community to acute care hospitals . The elderly are at risk for such discrepancies due to multiple comorbidities and complex medication regimens . Medication reconciliation involves verifying medication use and identifying and rectifying discrepancies . OBJECTIVE The aim of this study was to describe the prevalences and types of medication discrepancies in acutely ill older patients . METHODS Patients who were ≥ 70 years and were admitted to any of 3 acute care for elders ( ACE ) units over a period of 2 nonconsecutive months in 2008 were prospect ively enrolled . Medication discrepancies were classified as intentional , undocumented intentional , and unintentional . Unintentional medication discrepancies were classified by a blinded rater for potential to harm . This study was primarily qualitative , and descriptive ( univariate ) statistics are presented . RESULTS Sixty-seven patients ( 42 women ; mean [ SD ] age , 84.0 [ 6.5 ] years ) were enrolled . There were 37 unintentional prescription-medication discrepancies in 27 patients ( 40.3 % ) and 43 unintentional over-the-counter ( OTC ) medication discrepancies in 19 patients ( 28.4 % ) , which translates to Medication Reconciliation Success Index ( MRSI ) of 89 % for prescription medications and 59 % for OTC medications . The overall MRSI was 83 % . More than half of the prescription-medication discrepancies ( 56.8 % ) were classified as potentially causing moderate/severe discomfort or clinical deterioration . CONCLUSION Despite a fairly high overall MRSI in these patients admitted to ACE units , a substantial proportion of the prescription-medication discrepancies were associated with potential harm OBJECTIVES There are conflicting results in studies of pharmacists undertaking medication review s for older people . With increasing promotion and funding for ' medication review s ' there is a need for them to be st and ardised , and to determine their effectiveness and the feasibility of providing them from a community pharmacy . The objective was to determine whether involvement of community pharmacists undertaking clinical medication review s , working with general practitioners , improved medicine-related therapeutic outcomes for patients . METHODS A r and omised controlled trial was carried out in people 65 years and older on five or more prescribed medicines . Community pharmacists undertook a clinical medication review ( Comprehensive Pharmaceutical Care ) and met with the patient 's general practitioner to discuss recommendations about possible medicine changes . The patients were followed-up 3-monthly . The control group received usual care . The main outcome measures were Quality of Life ( SF-36 ) and Medication Appropriateness Index . KEY FINDINGS A total of 498 patients were enrolled in the study . The quality -of-life domains of emotional role and social functioning were significantly reduced in the intervention group compared to the control group . The Medication Appropriateness Index was significantly improved in the intervention group . Only 39 % of the 44 pharmacists who agreed to participate in the study provided adequate data , which was a limitation of the study and indicated potential barriers to the generalisability of the study . CONCLUSION Clinical medication review s in collaboration with general practitioners can have a positive effect on the Medication Appropriateness Index . However , pharmacist withdrawal from the study suggests that community pharmacy may not be an appropriate environment from which to exp and clinical medication review s in primary care Background : As patients move across transition points of care , medication discrepancies are likely to occur . In the emergency department ( ED ) , patients are vulnerable to medication discrepancies because they are in an environment in which rapid decisions need to be made under high levels of stress . Objective : To identify the patient- , environment- , and medication-related factors involving unexplained medication discrepancies across transition points after ED presentation . Methods : Using a retrospective chart review design , a stratified , r and om sampling of data was undertaken over a 12-month period . Information was obtained from an electronic administrative data base and medical records as patients moved from the ED to another transition point of care . Medication discrepancies were classified into 2 outcome groups : ( 1 ) no discrepancies and situations in which discrepancies were adequately explained and ( 2 ) discrepancies that had no adequate explanation . Results : For the 12-month period , 210 r and omly selected patients were included ; 73 ( 34.8 % ) had at least one unexplained medication discrepancy . Binary logistic regression modeling showed 4 factors that were statistically significant in determining the incidence of at least one unexplained medication discrepancy . Benefit card holders ( individuals who receive benefits from government insurance programs comparable to the US-based Medicare and Medicaid initiatives , which include the elderly , the disabled , low income earners , and unemployed persons ) had 3.73 greater odds of experiencing an unexplained medication discrepancy ( 95 % CI 1.72 to 8.07 ; p = 0.001 ) . Patients prescribed 5 or more drugs at discharge from the ED had 12.22 greater odds of having at least one unexplained medication discrepancy ( 95 % CI 5.52 to 27.08 ; p < 0.001 ) . Patients who were first seen by a physician within 1 hour of a change in working shift had 3.70 greater odds of having an unexplained medication discrepancy ( 95 % CI 1.67 to 8.18 ; p = 0.001 ) . For each additional minute of wait time for a physician , the odds of having an unexplained medication discrepancy increased by a factor of 1.01 ( 95 % CI 1.00 to 1.01 ; p = 0.042 ) . Conclusions : Patient- , environment- , and drug-related factors contribute to the risk of medication discrepancies across transition points from the ED Background Medication discrepancies at the time of hospital discharge are common and can result in error , patient/carer inconvenience or patient harm . Providing accurate medication information to the next care provider is necessary to prevent adverse events . Aims To investigate the quality and consistency of medication details generated for such transfer from an Irish teaching hospital . Methods This was an observational study of 139 cardiology patients admitted over a 3 month period during which a pharmacist prospect ively recorded details of medication inconsistencies . Results A discrepancy in medication documentation at discharge occurred in 10.8 % of medication orders , affecting 65.5 % of patients . While patient harm was assessed , it was only felt necessary to contact three ( 2 % ) patients . The most common inconsistency was drug omission ( 20.9 % ) . Conclusions Inaccuracy of medication information at hospital discharge is common and compromises quality of care |
13,777 | 29,689,079 | Conclusions This meta- analysis does not establish that KFAC is superior to PC in increasing muscle-evoked torque and lessening discomfort level . | Objective This study aim ed to determine whether kilohertz-frequency alternating current ( KFAC ) is superior to low-frequency pulsed current ( PC ) in increasing muscle-evoked torque and lessening discomfort . | The purpose of this study was to test the torque generating capabilities of three commercially available neuromuscular electrical stimulators ( NMES ) having different current characteristics . Twenty healthy adults were positioned in sitting on an isokinetic dynamometer . Maximum voluntary isometric knee extension torque was determined . Subsequently , two 10-sec , maximally tolerated contractions were elicited with each machine . The order of stimulation was r and omized and there were 2-minute rest periods between contractions . Electrically elicited torque values were expressed as a percentage of the maximal voluntary isometric torque ( % MVIT ) . Analysis of variance with one repeated measure showed a significant difference among % MVIT produced by the stimulators . NMES 2 ( Nemectrodyn 7 ) produced significantly less % MVIT than either NMES 1 ( Electrostim 180 - 2 ) or NMES 3 ( Chattanooga VMS ) . In all but three cases , NMES 2 's maximal current output was reached . Although all three devices were capable of producing % MVIT that has been shown to be sufficient for strengthening , it appears that NMES 2 does not have the capacity to provide " overload " as strength increases . J Orthop Sports Phys Ther 1989;10(8):297 - 301 The aim of the study was to investigate the uniformity of the muscle motor point location for lower limb muscles in healthy subjects . Fifty-three subjects of both genders ( age range : 18–50 years ) were recruited . The muscle motor points were identified for the following ten muscles of the lower limb ( dominant side ) : vastus medialis , rectus femoris , and vastus lateralis of the quadriceps femoris , biceps femoris , semitendinosus , and semimembranosus of the hamstring muscles , tibialis anterior , peroneus longus , lateral and medial gastrocnemius . The muscle motor point was identified by scanning the skin surface with a stimulation pen electrode and corresponded to the location of the skin area above the muscle in which an electrical pulse evoked a muscle twitch with the least injected current . For each investigated muscle , 0.15 ms square pulses were delivered through the pen electrode at low current amplitude ( < 10 mA ) and frequency ( 2 Hz ) . 16 motor points were identified in the 10 investigated muscles of almost all subjects : 3 motor points for the vastus lateralis , 2 motor points for rectus femoris , vastus medialis , biceps femoris , and tibialis anterior , 1 motor point for the remaining muscles . An important inter-individual variability was observed for the position of the following 4 out of 16 motor points : vastus lateralis ( proximal ) , biceps femoris ( short head ) , semimembranosus , and medial gastrocnemius . Possible implication s for electrical stimulation procedures and electrode positioning different from those commonly applied for thigh and leg muscles are discussed This study compared between alternating and pulsed current electrical muscle stimulation ( EMS ) for muscle oxygenation and blood volume during isometric contractions . Nine healthy men ( 23–48 years ) received alternating current EMS ( 2500 Hz ) modulated at 75 Hz on the knee extensors of one leg , and pulsed current EMS ( 75 Hz ) for the other leg separated by 2 weeks in a r and omised , counter-balanced order . Pulse duration ( 400 μs ) , on – off ratio ( 5–15 s ) and other stimulation parameters were matched between conditions and 30 isometric contractions were induced at the knee joint angle of 100 ° ( 0 ° full extension ) . Changes in tissue oxygenation index ( ∆TOI ) and total hemoglobin volume ( ∆tHb ) of vastus lateralis and medialis muscles over 30 contractions were assessed by a near-infrared spectroscopy , and were compared between conditions by a two-way repeated measures ANOVA . Peak torque produced during EMS increased over 30 contractions in response to the increase in the stimulation intensity for pulsed current , but not for the alternating current EMS . The torque during each isometric contraction was less stable in alternating than pulsed current EMS . The changes in ∆TOI amplitude during relaxation phases and ∆tHb amplitude were not significantly different between conditions . However , the decreases in ∆TOI amplitude during contraction phases from baseline were significantly ( P < 0.05 ) greater for the pulsed current than alternating current from the 18th contraction ( −15.6 ± 2.3 vs. −8.9 ± 1.8 % ) to 30th contraction ( −10.7 ± 1.8 vs. −4.8 ± 1.5 % ) . These results suggest that the muscles were less activated in the alternating current EMS when compared with the pulsed current EMS BACKGROUND AND PURPOSE Neuromuscular electrical stimulation is used by physical therapists to improve muscle performance . Optimal forms of stimulation setting s are yet to be determined , as are possible sex-related differences in responsiveness to electrical stimulation . The objectives of the study were : ( 1 ) to compare the ability of 3 different waveforms to generate isometric contractions of the quadriceps femoris muscles of individuals without known impairments , ( 2 ) to compare muscle fatigue caused by repeated contractions induced by these same waveforms , and ( 3 ) to examine the effect of sex on muscle force production and fatigue induced by electrical stimulation . SUBJECTS Fifteen women and 15 men ( mean age=29.5 years , SD=5.4 , range=22 - 38 ) participated in the study . METHODS A portable battery-operated stimulator was used to generate either a monophasic or biphasic rectangular waveform . A stimulator that was plugged into an electrical outlet was used to generate a 2,500-Hz alternating current . Phase duration , frequency , and on-off ratios were kept identical for both stimulators . Participants did not know the type of waveform being used . Torque was measured using a computerized dynamometer . A maximal voluntary isometric contraction ( MVIC ) of the right quadriceps femoris muscle set at 60 degrees of knee flexion was determined during the first session . In each of the 3 testing sessions , torque of contraction and fatigue elicited by one waveform were measured . Order of testing was r and omized . Torque elicited by electrical stimulation was expressed as a percentage of average MVIC . A mixed-model analysis of variance was used to determine the effect of stimulation and sex on strength of contraction and fatigue . Bonferroni-corrected post hoc tests were used to further distinguish between the effects of the 3 stimulus waveforms . RESULTS The results indicated that the monophasic and biphasic waveforms generated contractions with greater torque than the polyphasic waveform . These 2 waveforms also were less fatiguing . The torques from the maximally tolerated electrically elicited contractions were greater for the male subjects than for the female subjects . DISCUSSION AND CONCLUSION Muscle torque and fatigue of electrically induced contractions depend on the waveform used to stimulate the contraction , with monophasic and biphasic waveforms having an advantage over the polyphasic waveform . All tested waveforms elicited , on average , stronger contractions in male subjects than in female subjects when measured as a percentage of MVIC Objective The aim of this study was to investigate the effect of neuromuscular electrical stimulation burst duty cycle ( BDC ) and current type ( sinusoidal alternating current [ sAC ] vs. rectangular alternating current [ rAC ] ) on the electrically induced isometric torque ( EIT ) and discomfort . Pulsed current ( PC ) stimulation , which corresponds to one pulse rAC , was included in testing . Design A repeated- measures design was used . The left quadriceps of 22 healthy subjects ( mean ± SD age , 33 ± 8 yrs ) were stimulated alternately with sAC and rAC current bursts ( 4-kHz carrier frequency ; 71 bursts per second burst frequency ) to produce isometric contractions . A range of BDCs were tested for sAC ( 7%–50 % ) and rAC ( 2%–18 % ) stimulation at fixed intensities while EIT and discomfort were recorded . BDC presentation order was r and omized . Results Overall , both current types elicited peak EIT at ∼14 % BDC ( range , 7%–21 % ) . Significantly more EIT was produced by rAC than by sAC stimulation ( P < 0.005 ) . Discomfort increased with BDC and was similar for both current types . Conclusions The study confirmed previous findings that conventional sAC stimulation ( 50 % BDC ) and pulsed current stimulation ( rAC with 2 % BDC ) used in sports and rehabilitation produce similar EIT levels . However , rAC stimulation at low BDC ( 7%–18 % ) was more effective ( + 35 % torque produced with similar discomfort ) than pulsed current or conventional sAC Background and Purpose . A r and omized controlled trial to compare 2 forms of monophasic pulsed currents with 2 forms of burst-modulated , kilohertz-frequency alternating current ( “ Russian current ” and “ Aussie current ” ) was conducted to establish whether different amounts of wrist extensor torque were produced and whether discomfort varied with stimulus type . Subjects . The 32 subjects were adults who were healthy and were drawn from a population of staff and students at La Trobe University . Methods . Each subject received all 4 currents . Maximal electrically induced torque ( MEIT ) of the wrist extensors was measured for each stimulus type . Relative discomfort of stimulation also was assessed . Results . Russian current elicited lower mean torque than those elicited by Aussie current and monophasic pulsed currents . The Russian and Aussie currents elicited significantly less discomfort than the 2 monophasic pulsed currents . Discussion and Conclusion . When force production and relative discomfort were jointly used as the criteria , Aussie current was found to be more effective than either of the monophasic pulsed currents or Russian current stimulation In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if a body of evidence is associated with a high risk of publication bias . Even when individual studies included in best- evidence summaries have a low risk of bias , publication bias can result in substantial overestimates of effect . Authors should suspect publication bias when available evidence comes from a number of small studies , most of which have been commercially funded . A number of approaches based on examination of the pattern of data are available to help assess publication bias . The most popular of these is the funnel plot ; all , however , have substantial limitations . Publication bias is likely frequent , and caution in the face of early results , particularly with small sample size and number of events , is warranted The aim of the study was to investigate the influence of two different transcutaneous neuromuscular electrical stimulation procedures on evoked muscle torque and local tissue oxygenation . In the first one ( MP mode ) , the cathode was facing the muscle main motor point and stimulus amplitude was set to the level eliciting the maximal myoelectrical activation according to the amplitude of the evoked electromyogram ( EMG ) ; in the second one ( RC mode ) , the electrodes were positioned following common reference charts for electrode placement while stimulus amplitude was set according to subject tolerance . Tibialis Anterior ( TA ) and Vastus Lateralis ( VL ) muscles of 10 subjects ( 28.4 ± 8.2 years ) were tested in specific dynamometers to measure the evoked isometric torque . The EMG and near-infrared spectroscopy probes were placed on muscle belly to detect the electrical activity and local metabolic modifications of the stimulated muscle , respectively . The stimulation protocol consisted of a gradually increasing frequency ramp from 2 to 50 Hz in 7.5 s. Compared to RC mode , in MP mode the contractile parameters ( peak twitch , tetanic torque , area under the torque build-up ) and the metabolic solicitation ( oxygen consumption and hyperemia due to metabolites accumulation ) result ed significantly higher for both TA and VL muscles . MP mode result ed also to be more comfortable for the subjects . Based on the assumption that proper mechanical and metabolic stimuli are necessary to induce muscle strengthening , our results witness the importance of an optimized , i.e. , comfortable and effective , stimulation to promote the aforementioned muscle adaptive modifications 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 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 Objective To test the hypotheses that , as compared with pulsed current with the same pulse duration , kilohertz frequency alternating current would not differ in terms of evoked-torque production and perceived discomfort , and as a result , it would show the same current efficiency . Design A repeated- measures design with 4 stimuli presented in r and om order was used to test 25 women : ( 1 ) 500-microsecond pulse duration , ( 2 ) 250-microsecond pulse duration , ( 3 ) 500-microsecond pulse duration and low carrier frequency ( 1 kHz ) , ( 4 ) 250-microsecond pulse duration and high carrier frequency ( 4 kHz ) . Isometric peak torque of quadriceps muscle was measured using an isokinetic dynamometer . Discomfort was measured using a visual analog scale . Results Currents with long pulse duration s induced approximately 21 % higher evoked torque than short pulse duration s. In addition , currents with 500 microseconds delivered greater amounts of charge than stimulation patterns using 250-microsecond pulse duration s ( P < 0.05 ) . All currents presented similar discomfort . There was no difference on stimulation efficiency with the same pulse duration . Conclusions Both kilohertz frequency alternating current and pulsed current , with the same pulse duration , have similar efficiency for inducing isometric knee extension torque and discomfort . However , neuromuscular electrical stimulation ( NMES ) with longer pulse duration induces higher NMES-evoked torque , regardless of the carrier frequency . Pulse duration is an important variable that should receive more attention for an optimal application of NMES in clinical setting ABSTRACT PEDro is produced by the Centre for Evidence -Based Physiotherapy ( CEBP ) , located in Sydney , Australia . PEDro is intended to be used to gain “ rapid access to bibliographic details and abstract s of r and omized controlled trials , systematic review s and evidence -based clinical practice guidelines in physiotherapy.”1 This column will provide some background information on the data base , as well as cover the basics of search ing its content BACKGROUND Some r and omised controlled trials ( RCTs ) done in German-speaking Europe are published in international English- language journals and others in national German- language journals . We assessed whether authors are more likely to report trials with statistically significant results in English than in German . METHODS We studied pairs of RCT reports , matched for first author and time of publication , with one report published in German and the other in English . Pairs were identified from reports round in a manual search of five leading German- language journals and from reports published by the same authors in English found on Medline . Quality of methods and reporting were assessed with two different scales by two investigators who were unaware of authors ' identities , affiliations , and other characteristics of trial reports . Main study endpoints were selected by two investigators who were unaware of trial results . Our main outcome was the number of pairs of studies in which the levels of significance ( shown by p values ) were discordant . FINDINGS 62 eligible pairs of reports were identified but 19 ( 31 % ) were excluded because they were duplicate publications . A further three pairs ( 5 % ) were excluded because no p values were given . The remaining 40 pairs were analysed . Design characteristics and quality features were similar for reports in both language s. Only 35 % of German- language articles , compared with 62 % of English- language articles , reported significant ( p < 0.05 ) differences in the main endpoint between study and control groups ( p = 0.002 by McNemar 's test ) . Logistic regression showed that the only characteristic that predicted publication in an English- language journal was a significant result . The odds ratio for publication of trials with significant results in English was 3.75 ( 95 % CI 1.25 - 11.3 ) . INTERPRETATION Authors were more likely to publish RCTs in an English- language journal if the results were statistically significant . English language bias may , therefore , be introduced in review s and meta-analyses if they include only trials reported in English . The effort of the Cochrane Collaboration to identify as many controlled trials as possible , through the manual search of many medical journals published in different language s will help to reduce such bias STUDY DESIGN Single-blind , block-r and omization crossover design . OBJECTIVE To compare the knee extensor muscle torque production elicited with 2500-Hz burst-modulated alternating current ( BMAC ) and with a monophasic pulsed current ( MPC ) at the maximum tolerated stimulation intensity . BACKGROUND Neuromuscular electrical stimulation ( NMES ) is often used for strengthening the quadriceps following knee surgery . Strength gains are dependent on muscle torque production , which is primarily limited by discomfort . Burst-modulated alternating current stimulation is a clinical ly popular waveform for NMES . Prior research has established that MPC with a relatively long pulse duration is effective for high muscle torque production . METHODS Participants in this study were 20 adults with no history of knee injury . A crossover design was used to r and omize the order in which each participant 's dominant or nondominant lower extremity received NMES and the waveform ( MPC or BMAC ) this limb received . Stimulation intensity was incrementally increased until participants reached their maximum tolerance . The torque produced was converted to a percentage of each participant 's maximum volitional isometric contraction of the respective limb . RESULTS A general linear model for a 2-treatment , 2-period crossover design was utilized to analyze the results . The mean ± SD electrically induced percent maximum volitional isometric contraction at maximal participant tolerance was 49.5 % ± 19.6 % for MPC and 29.8 % ± 12.4 % for BMAC . This difference was statistically significant ( P = .002 ) after accounting for treatment order and limb , which had no effect on torque production . CONCLUSION Neuromuscular stimulation using MPC may be more efficacious than using BMAC to achieve a high torque output in patients with quadriceps weakness Background : Low-frequency pulsed currents ( LPCs ) and kilohertz-frequency alternating currents ( KACs ) are used clinical ly to augment muscle contractions . Treatment effectiveness may be enhanced by selecting stimulation parameters that evoke the strongest contractions with minimal discomfort and fatigue . Objective : The objective of this study was to compare maximally induced strength ( force-producing capacity ) of contractions , muscle fatigue , and discomfort associated with an LPC and with 3 KACs differing in frequency and duration of burst modulation . Design : This was a repeated- measures trial , with r and omized order of current presentation . Setting : The study was conducted in the physical therapy laboratory at the University of Haifa . Subjects : Twenty-six volunteers without impairments , with a mean age of 27.4 years ( SD=5.0 , range=21–45 ) , participated . Intervention : All currents were applied in separate sessions to the wrist extensors of each subject . Currents consisted of an LPC with a 50-Hz pulse frequency and 3 KACs with a 2.5-kHz carrier frequency , including the “ Russian current ” ( RC ) burst modulated at 50 Hz with 25 cycles per burst and 2 currents burst modulated at 20 or 50 Hz with 10 cycles per burst . Measurement : The maximal electrically induced isometric force , the force integral of 21 electrically induced consecutive contractions , and the degree of discomfort were recorded . Results : Force of contraction was not affected by type of current . The LPC was least fatiguing , and the RC was most fatiguing , with the 2 other KACs having an intermediate effect . Degree of discomfort was higher with the KAC modulated at 20 Hz . Conclusions : When comfort , strength , and fatigue are considered jointly , the LPC is advantageous . Electrically induced fatigue is affected by the number of cycles per second , rather than the number of bursts per second |
13,778 | 22,400,019 | IOERT represents a feasible technique with acceptable surgical time and minimal toxicity . | Intraoperative electron beam radiotherapy ( IOERT ) for prostate cancer ( PC ) is a radiotherapeutic technique , giving high doses of radiation during radical prostatectomy ( RP ) .
This paper presents the published treatment approaches for intraoperative radiotherapy analyzing functional outcome , morbidity , and oncological outcome in patients with clinical intermediate-high-risk prostate cancer . | PURPOSE Recent studies have suggested an alpha/beta ratio in prostate cancer of 1.5 - 3 Gy , which is lower than that assumed for late-responsive normal tissues . Therefore the administration of a single , intraoperative dose of irradiation should represent a convenient irradiation modality in prostate cancer . MATERIAL S AND METHODS Between February 2002 and June 2004 , 34 patients with localized prostate cancer with only one risk factor ( Gleason score > or = 7 , Clinical Stage [ cT ] > or = 2c , or prostate-specific antigen [ PSA ] of 11 - 20 ng/mL ) and without clinical evidence of lymph node metastases were treated with radical prostatectomy ( RP ) and intraoperative radiotherapy on the tumor bed . A dose-finding procedure based on the Fibonacci method was employed . Dose levels of 16 , 18 , and 20 Gy were selected , which are biologically equivalent to total doses of about 60 - 80 Gy administered with conventional fractionation , using an alpha/beta ratio value of 3 . RESULTS At a median follow-up of 41 months , 24 ( 71 % ) patients were alive with an undetectable PSA value . No patients died from disease , whereas 2 patients died from other malignancies . Locoregional failures were detected in 3 ( 9 % ) patients , 2 in the prostate bed and 1 in the common iliac node chain outside the radiation field . A PSA rise without local or distant disease was observed in 7 ( 21 % ) cases . The overall 3-year biochemical progression-free survival rate was 77.3 % . CONCLUSIONS Our dose-finding study demonstrated the feasibility of intraoperative radiotherapy in prostate cancer also at the highest administered dose PURPOSE We evaluated patients at our institution who underwent radical prostatectomy for clinical stage T3 prostate cancer to determine their long-term clinical outcomes . MATERIAL S AND METHODS We review ed our prospect i ve surgical data base and identified 176 men who underwent radical retropubic prostatectomy for clinical stage T3 prostate cancer from 1983 to 2003 . Clinical and pathological data were review ed and evaluated in a Cox proportional hazards model to determine preoperative predictors of biochemical recurrence . Clinical progression following biochemical recurrence was evaluated and clinical failure was defined as the development of clinical metastases or progression to hormone refractory prostate cancer . RESULTS Of the 176 patients with cT3 prostate cancer 64 ( 36 % ) received neoadjuvant hormonal therapy . At a mean followup of 6.4 years 84 ( 48 % ) patients had disease recurrence with a median time to biochemical recurrence of 4.6 years . The actuarial 10-year probability of freedom from recurrence was 44 % . On multivariate analysis biopsy Gleason score , pretreatment serum prostate specific antigen and year of surgery were independent predictors of biochemical recurrence . Neoadjuvant hormonal therapy was not a significant predictor of biochemical recurrence . Following biochemical recurrence clinical failure developed in 30 of 84 ( 36 % ) men with a median time of 11 years . Overall the 5 , 10 and 15-year probabilities of death from prostate cancer were 6 % , 15 % and 24 % , respectively . CONCLUSIONS More than half ( 52 % ) of our patients remained free of disease recurrence following radical prostatectomy . In our series neoadjuvant hormonal therapy offered no advantage with respect to disease recurrence . Radical prostatectomy remains an integral component in the treatment of select patients with clinical stage T3 prostate cancer BACKGROUND To present the technique and dose distribution of intraoperative radiotherapy ( IORT ) for prostate cancer . PATIENTS AND METHODS Pelvic lymphadenectomy , prostate IORT and radical retropubic prostatectomy was performed in 11 prostate cancer patients . Prostate thickness and rectum depth were measured with intraoperative ultrasound . IORT was delivered by a mobile linear accelerator in the operating room ( electron beam , 12 Gy at 90 % isodose ) . RESULTS The mean preoperative probability of organ-confined disease was 10 % ( Memorial Sloan Kettering Cancer Center nomograms ) . Mean prostate thickness , width and length were 3.4 cm , 4.6 and 4.9 cm , respectively . Mean rectum depth was 3.3 cm . Mean doses to the posterior prostate capsule , 5-mm lateral prostate margins and at the subsequent uretheral stump area were 4.6 Gy , 8 . 7 Gy and 11.3 Gy , respectively . Maximum mean rectal dose was 4.9 Gy . CONCLUSION IORT appeared a feasible approach for prostate cancer , showing a satisfactory dose coverage to the prostate bed with relatively low rectal dose . However , high variability in dose distribution calls for further study of patient selection criteria and dosimetry Radiotherapy and and rogen deprivation in combination after local surgery ( RADICALS ) : A new Medical Research Council/National Cancer Institute of Canada phase III trial of adjuvant treatment after radical prostatectomy Chris Parker , Matthew R. Sydes 1 , Charles Catton 2 , Howard Kynaston 3 , John Logue , Claire Murphy 1 , Rachel C. Morgan 1 , Kilian Mellon 5 , Chris Morash 6 , Wendy Parulekar 7 , Mahesh K.B. Parmar 1 , Heather Payne 8 , Colleen Savage 7 , Jim Stansfeld 9 and Noel W. Clarke 10 ( The RADICALS Trial Management Group ) Academic Unit of Radiotherapy & Oncology , Institute of Cancer Research and the Royal , Marsden NHS Foundation Trust , Sutton , Surrey , 1 Medical Research Council ( MRC ) Clinical Trials Unit , London , UK , 2 Princess Margaret Hospital , Toronto , Ontario , Canada , 3 Department of Urology , University Hospital of Wales , Heath Park , Cardiff , 4 Christie Hospital NHS Trust , Manchester , UK , 5 Urology Section , University of Leicester , UK , 6 University of Ottawa , The Ottawa Hospital General Campus , Ottawa , 7 National Cancer Institute of Canada ( NCIC ) Clinical Trials Group , Kingston , Ontario , Canada , 8 Department of Oncology , University College Hospital , London , UK , 9 Hon . Treasurer , PCaSO Prostate Cancer Network , Emsworth , Hants , UK , 10 Salford Royal Hospitals NHS Trust , Salford , BACKGROUND We did a r and omised phase III trial comparing external irradiation alone and external irradiation combined with an analogue of luteinising-hormone releasing hormone ( LHRH ) to investigate the added value of long-term and rogen suppression in locally advanced prostate cancer . METHODS Between 1987 and 1995 , 415 patients were r and omly assigned radiotherapy alone or radiotherapy plus immediate and rogen suppression . Eligible patients had T1 - 2 tumours of WHO grade 3 or T3 - 4 N0 - 1 M0 tumours ; the median age of participants was 71 years ( range 51 - 80 ) . In both treatment groups , 50 Gy radiation was delivered to the pelvis over 5 weeks , and 20 Gy over 2 weeks as a prostatic boost . Goserelin ( 3.6 mg subcutaneously every 4 weeks ) was started on the first day of irradiation and continued for 3 years ; cyproterone acetate ( 150 mg orally ) was given for 1 month starting 1 week before the first goserelin injection . The primary endpoint was clinical disease-free survival . Analyses were by intention to treat . FINDINGS 412 patients had evaluable data , with median follow-up of 66 months ( range 1 - 126 ) . 5-year clinical disease-free survival was 40 % ( 95 % CI 32 - 48 ) in the radiotherapy-alone group and 74 % ( 67 - 81 ) in the combined-treatment group ( p=0.0001 ) . 5-year overall survival was 62 % ( 52 - 72 ) and 78 % ( 72 - 84 ) , respectively ( p=0.0002 ) and 5-year specific survival 79 % ( 72 - 86 ) and 94 % ( 90 - 98 ) . INTERPRETATION Immediate and rogen suppression with an LHRH analogue given during and for 3 years after external irradiation improves disease-free and overall survival of patients with locally advanced prostate cancer CONTEXT Despite a stage-shift to earlier cancer stages and lower tumor volumes for prostate cancer , pathologically advanced disease is detected at radical prostatectomy in 38 % to 52 % of patients . However , the optimal management of these patients after radical prostatectomy is unknown . OBJECTIVE To determine whether adjuvant radiotherapy improves metastasis-free survival in patients with stage pT3 N0 M0 prostate cancer . DESIGN , SETTING , AND PATIENTS R and omized , prospect i ve , multi-institutional , US clinical trial with enrollment between August 15 , 1988 , and January 1 , 1997 ( with data base frozen for statistical analysis on September 21 , 2005 ) . Patients were 425 men with pathologically advanced prostate cancer who had undergone radical prostatectomy . INTERVENTION Men were r and omly assigned to receive 60 to 64 Gy of external beam radiotherapy delivered to the prostatic fossa ( n = 214 ) or usual care plus observation ( n = 211 ) . MAIN OUTCOME MEASURES Primary outcome was metastasis-free survival , defined as time to first occurrence of metastatic disease or death due to any cause . Secondary outcomes included prostate-specific antigen ( PSA ) relapse , recurrence-free survival , overall survival , freedom from hormonal therapy , and postoperative complications . RESULTS Among the 425 men , median follow-up was 10.6 years ( interquartile range , 9.2 - 12.7 years ) . For metastasis-free survival , 76 ( 35.5 % ) of 214 men in the adjuvant radiotherapy group were diagnosed with metastatic disease or died ( median metastasis-free estimate , 14.7 years ) , compared with 91 ( 43.1 % ) of 211 ( median metastasis-free estimate , 13.2 years ) of those in the observation group ( hazard ratio [ HR ] , 0.75 ; 95 % CI , 0.55 - 1.02 ; P = .06 ) . There were no significant between-group differences for overall survival ( 71 deaths , median survival of 14.7 years for radiotherapy vs 83 deaths , median survival of 13.8 years for observation ; HR , 0.80 ; 95 % CI , 0.58 - 1.09 ; P = .16 ) . PSA relapse ( median PSA relapse-free survival , 10.3 years for radiotherapy vs 3.1 years for observation ; HR , 0.43 ; 95 % CI , 0.31 - 0.58 ; P<.001 ) and disease recurrence ( median recurrence-free survival , 13.8 years for radiotherapy vs 9.9 years for observation ; HR , 0.62 ; 95 % CI , 0.46 - 0.82 ; P = .001 ) were both significantly reduced with radiotherapy . Adverse effects were more common with radiotherapy vs observation ( 23.8 % vs 11.9 % ) , including rectal complications ( 3.3 % vs 0 % ) , urethral strictures ( 17.8 % vs 9.5 % ) , and total urinary incontinence ( 6.5 % vs 2.8 % ) . CONCLUSIONS In men who had undergone radical prostatectomy for pathologically advanced prostate cancer , adjuvant radiotherapy result ed in significantly reduced risk of PSA relapse and disease recurrence , although the improvements in metastasis-free survival and overall survival were not statistically significant . Trial Registration clinical trials.gov Identifier : NCT00394511 |
13,779 | 29,033,608 | In each subgroup divided by areas , the prognostic significance still remained highly significant .
The proportion of methylation in each group was in inverse proportion to the corresponding HR in the univariate and multivariate analyses of PFS .
However , from the perspective of OS , compared with data from Europe and the US , higher methylation rates in Asia did not bring better returns | BACKGROUND O6-methylguanine-DNA methyltransferase ( MGMT ) is an independent predictor of therapeutic response and potential prognosis in patients with glioblastoma multiforme ( GBM ) .
However , its significance of clinical prognosis in different continents still needs to be explored . | O(6)-methylguanine DNA-methyltransferase ( MGMT ) promoter methylation status is a prognostic factor in newly diagnosed glioblastoma patients . However , it is not yet clear whether , and if so how , MGMT methylation status may change . Moreover , it is unknown whether the prognostic role of this epigenetic feature is retained during the disease course . A retrospective analysis was made using a data base of 614 glioblastoma patients treated prospect ively from January 2000 to August 2008 . We evaluated only patients who met the following inclusion criteria : age > or = 18 years ; performance status 0 - 2 ; histological diagnosis of glioblastoma at both first and second surgery for recurrence ; postoperative treatment consisting of : ( i ) radiotherapy ( RT ) followed by adjuvant temozolomide ( TMZ ) until 2005 and ( ii ) TMZ concurrent with and adjuvant to RT after 2005 ; a time interval > or = 3 months between first and second surgery . MGMT status was evaluated at first and second surgery in all 44 patients ( M : F 32:12 , median age : 49 years , range : 27 - 67 years ) . In 38 patients ( 86.4 % ) , MGMT promoter status was assessable at both first and second surgery . MGMT methylation status , changed in 14 patients ( 37 % ) of second surgery sample s and more frequently in methylated than in unmethylated patients ( 61.5 % vs 24 % , P = .03 ) . The median survival was significantly influenced only by MGMT methylation status determined at first surgery ( P = .04 ) . Significant changes in MGMT methylation status during the course of GBM occur more frequently in MGMT methylated than unmethylated cases . MGMT methylation status determined at first surgery appears to be of prognostic value ; however , it is not predictive of outcome following second surgery Hypermethylation in the promoter region of the MGMT gene encoding the DNA repair protein O6-methylguanine-DNA methyltransferase is among the most important prognostic factors for patients with glioblastoma and predicts response to treatment with alkylating agents like temozolomide . Hence , the MGMT status is widely determined in most clinical trials and frequently requested in routine diagnostics of glioblastoma . Since various different techniques are available for MGMT promoter methylation analysis , a generally accepted consensus as to the most suitable diagnostic method remains an unmet need . Here , we assessed methylation-specific polymerase chain reaction ( MSP ) as a qualitative and semi-quantitative method , pyrosequencing ( PSQ ) as a quantitative method , and methylation-specific multiplex ligation-dependent probe amplification ( MS-MLPA ) as a semi-quantitative method in a series of 35 formalin-fixed , paraffin-embedded glioblastoma tissues derived from patients treated in a prospect i ve clinical phase II trial that tested up-front chemoradiotherapy with dose-intensified temozolomide ( UKT-05 ) . Our goal was to determine which of these three diagnostic methods provides the most accurate prediction of progression-free survival ( PFS ) . The MGMT promoter methylation status was assessable by each method in almost all cases ( n = 33/35 for MSP ; n = 35/35 for PSQ ; n = 34/35 for MS-MLPA ) . We were able to calculate significant cut-points for the continuous methylation signals at each CpG site analysed by PSQ ( range , 11.5 to 44.9 % ) and at one CpG site assessed by MS-MLPA ( 3.6 % ) indicating that a dichotomisation of continuous methylation data as a prerequisite for comparative survival analyses is feasible . Our results show that , unlike MS-MLPA , MSP and PSQ provide a significant improvement of predicting PFS compared with established clinical prognostic factors alone ( likelihood ratio tests : p<0.001 ) . Conclusively , taking into consideration prognostic value , cost effectiveness and ease of use , we recommend pyrosequencing for analyses of MGMT promoter methylation in high-throughput setting s and MSP for clinical routine diagnostics with low sample numbers BACKGROUND A r and omised trial published by the European Organisation for Research and Treatment of Cancer ( EORTC ) and the National Cancer Institute of Canada ( NCIC ) Clinical Trials Group ( trial 26981 - 22981/CE.3 ) showed that addition of temozolomide to radiotherapy in the treatment of patients with newly diagnosed glioblastoma significantly improved survival . We aim ed to undertake an exploratory sub analysis of the EORTC and NCIC data to confirm or identify new prognostic factors for survival in adult patients with glioblastoma , derive nomograms that predict an individual patient 's prognosis , and suggest stratification factors for future trials . METHODS Data from 573 patients with newly diagnosed glioblastoma who were r and omly assigned to radiotherapy alone or to the same radiotherapy plus temozolomide in the EORTC and NCIC trial were included in this sub analysis . Survival modelling was done in three patient population s : intention-to-treat population of all r and omised patients ( population 1 ) ; patients assigned temozolomide and radiotherapy ( population 2 , n=287 ) ; and patients assigned temozolomide and radiotherapy who had assessment of MGMT promoter methylation status and who had undergone tumour resection ( population 3 , n=103 ) . Cox proportional hazards models were fitted with and without O6-methylguanine-DNA methyltransferase ( MGMT ) promoter methylation status . Nomograms were developed to predict an individual patient 's median and 2-year survival probabilities . No nomogram was developed in the radiotherapy-alone group because combined treatment is now the new st and ard of care . FINDINGS Independent of the MGMT promoter methylation status , analysis in all r and omised patients ( population 1 ) identified combined treatment with temozolomide , more extensive tumour resection , younger age , Mini-Mental State Examination ( MMSE ) score of 27 or higher , and no corticosteroid treatment at baseline as independent prognostic factors correlated with improved survival outcome . In patients assigned temozolomide and radiotherapy ( population 2 ) , younger age , better performance status , more extensive tumour resection , and MMSE score of 27 or higher were associated with better survival . In patients who had tumours resected , who were assigned temozolomide and radiotherapy , and who had available MGMT promoter methylation status ( population 3 ) , methylated MGMT , better performance status , and MMSE score of 27 or higher were associated with improved survival . Nomograms were developed and are available at http://www.eortc.be/tools/g bmc alculator . INTERPRETATION MGMT promoter methylation status , age , performance status , extent of resection , and MMSE are suggested as eligibility or stratification factors for future trials in patients with newly diagnosed glioblastoma . Stratifying by MGMT promoter methylation status should be m and atory in all glioblastoma trials that use alkylating chemotherapy . Nomograms can be used to predict an individual patient 's prognosis , and they integrate pertinent molecular information that is consistent with a paradigm shift towards individualised patient management PURPOSE O6-methylguanine-methyltransferase ( MGMT ) promoter methylation has been shown to predict survival of patients with glioblastomas if temozolomide is added to radiotherapy ( RT ) . It is unknown if MGMT promoter methylation is also predictive to outcome to RT followed by adjuvant procarbazine , lomustine , and vincristine ( PCV ) chemotherapy in patients with anaplastic oligodendroglial tumors ( AOT ) . PATIENTS AND METHODS In the European Organisation for the Research and Treatment of Cancer study 26951 , 368 patients with AOT were r and omly assigned to either RT alone or to RT followed by adjuvant PCV . From 165 patients of this study , formalin-fixed , paraffin-embedded tumor tissue was available for MGMT promoter methylation analysis . This was investigated with methylation specific multiplex ligation-dependent probe amplification . RESULTS In 152 cases , an MGMT result was obtained , in 121 ( 80 % ) cases MGMT promoter methylation was observed . Methylation strongly correlated with combined loss of chromosome 1p and 19q loss ( P = .00043 ) . In multivariate analysis , MGMT promoter methylation , 1p/19q codeletion , tumor necrosis , and extent of resection were independent prognostic factors . The prognostic significance of MGMT promoter methylation was equally strong in the RT arm and the RT/PCV arm for both progression-free survival and overall survival . In tumors diagnosed at central pathology review as glioblastoma , no prognostic effect of MGMT promoter methylation was observed . CONCLUSION In this study , on patients with AOT MGMT promoter methylation was of prognostic significance and did not have predictive significance for outcome to adjuvant PCV chemotherapy . The biologic effect of MGMT promoter methylation or pathogenetic features associated with MGMT promoter methylation may be different for AOT compared with glioblastoma In 2011 , we reported a predominant prognostic/predictive role of MGMT promoter methylation status on progression-free survival ( PFS ) in unresectable glioblastoma patients undergoing upfront radiotherapy plus concomitant and maintenance temozolomide ( RTX/TMZ → TMZ ) . We , here , present the final results of this prospect i ve study focussing on the prognostic/predictive value of MGMT promoter methylation status for death risk stratification . Overall , 56 adult patients with unresectable , biopsy proven glioblastoma were prospect ively assigned to upfront RTX/TMZ → TMZ treatment between March 2006 and August 2008 . Last follow-up was performed in June 2016 . MGMT promoter methylation was determined using methylation-specific PCR ( MSP ) and sodium bisulfite sequencing . Analyses were done by intention to treat . Prognostic factors were obtained from proportional hazard models . At the time of the final analysis 55 patients showed progressive disease and 53 patients had died . MGMT promoter was methylated ( unmethylated ) in 30 ( 26 ) patients . Methylation of the MGMT promoter was the strongest favorable predictor for overall survival ( OS , median : 20.3 vs. 7.3 months , p < 0.001 , HR 0.30 , 95 % CI 0.16–0.55 ) , and PFS ( median : 15.0 vs. 6.1 months , p < 0.001 , HR 0.31 , 95 % CI 0.17–0.57 ) and was also associated with higher frequencies of treatment response and prolonged post-recurrence survival ( PRS , median : 4.5 vs. 1.4 months , p < 0.002 , HR 0.39 , 95 % CI 0.21–0.71 ) . Knowledge of MGMT promoter methylation status is essential for patients ’ counseling , prognostic evaluation , and for the design of future trials dealing with unresectable glioblastomas PURPOSE Glioblastomas are notorious for resistance to therapy , which has been attributed to DNA-repair proficiency , a multitude of deregulated molecular pathways , and , more recently , to the particular biologic behavior of tumor stem-like cells . Here , we aim ed to identify molecular profiles specific for treatment resistance to the current st and ard of care of concomitant chemoradiotherapy with the alkylating agent temozolomide . PATIENTS AND METHODS Gene expression profiles of 80 glioblastomas were interrogated for associations with resistance to therapy . Patients were treated within clinical trials testing the addition of concomitant and adjuvant temozolomide to radiotherapy . RESULTS An expression signature dominated by HOX genes , which comprises Prominin-1 ( CD133 ) , emerged as a predictor for poor survival in patients treated with concomitant chemoradiotherapy ( n = 42 ; hazard ratio = 2.69 ; 95 % CI , 1.38 to 5.26 ; P = .004 ) . This association could be vali date d in an independent data set . Provocatively , the HOX cluster was reminiscent of a " self-renewal " signature ( P = .008 ; Gene Set Enrichment Analysis ) recently characterized in a mouse leukemia model . The HOX signature and EGFR expression were independent prognostic factors in multivariate analysis , adjusted for the O-6-methylguanine-DNA methyltransferase ( MGMT ) methylation status , a known predictive factor for benefit from temozolomide , and age . Better outcome was associated with gene clusters characterizing features of tumor-host interaction including tumor vascularization and cell adhesion , and innate immune response . CONCLUSION This study provides first clinical evidence for the implication of a " glioma stem cell " or " self-renewal " phenotype in treatment resistance of glioblastoma . Biologic mechanisms identified here to be relevant for resistance will guide future targeted therapies and respective marker development for individualized treatment and patient selection PURPOSE The st and ard of care for anaplastic gliomas is surgery followed by radiotherapy . The NOA-04 phase III trial compared efficacy and safety of radiotherapy followed by chemotherapy at progression with the reverse sequence in patients with newly diagnosed anaplastic gliomas . PATIENTS AND METHODS Patients ( N = 318 ) were r and omly assigned 2:1:1 ( A : B1:B2 ) to receive conventional radiotherapy ( arm A ) ; procarbazine , lomustine ( CCNU ) , and vincristine ( PCV ; arm B1 ) ; or temozolomide ( arm B2 ) at diagnosis . At occurrence of unacceptable toxicity or disease progression , patients in arm A were treated with PCV or temozolomide ( 1:1 r and om assignment ) , whereas patients in arms B1 or B2 received radiotherapy . The primary end point was time to treatment failure ( TTF ) , defined as progression after radiotherapy and one chemotherapy in either sequence . RESULTS Patient characteristics in the intention-to-treat population ( n = 274 ) were balanced between arms . All histologic diagnoses were central ly confirmed . Median TTF ( hazard ratio [ HR ] = 1.2 ; 95 % CI , 0.8 to 1.8 ) , progression-free survival ( PFS ; HR = 1.0 ; 95 % CI , 0.7 to 1.3 , and overall survival ( HR = 1.2 ; 95 % CI , 0.8 to 1.9 ) were similar for arms A and B1/B2 . Extent of resection was an important prognosticator . Anaplastic oligodendrogliomas and oligoastrocytomas share the same , better prognosis than anaplastic astrocytomas . Hypermethylation of the O(6)-methylguanine DNA-methyltransferase ( MGMT ) promoter ( HR = 0.59 ; 95 % CI , 0.36 to 1.0 ) , mutations of the isocitrate dehydrogenase ( IDH1 ) gene ( HR = 0.48 ; 95 % CI , 0.29 to 0.77 ) , and oligodendroglial histology ( HR = 0.33 ; 95 % CI , 0.2 to 0.55 ) reduced the risk of progression . Hypermethylation of the MGMT promoter was associated with prolonged PFS in the chemotherapy and radiotherapy arm . CONCLUSION Initial radiotherapy or chemotherapy achieved comparable results in patients with anaplastic gliomas . IDH1 mutations are a novel positive prognostic factor in anaplastic gliomas , with a favorable impact stronger than that of 1p/19q codeletion or MGMT promoter methylation Purpose : In the setting of a prospect i ve clinical trial , we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase ( MGMT ) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide . Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy . Experimental Design : The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation . The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR . Results : Inactivation of the MGMT gene by promoter methylation was associated with longer survival ( P = 0.0051 ; Log-rank test ) . At 18 months , survival was 62 % ( 16 of 26 ) for patients testing positive for a methylated MGMT promoter but reached only 8 % ( 1 of 12 ) in absence of methylation ( P = 0.002 ; Fisher ’s exact test ) . In the presence of other clinical ly relevant factors , methylation of the MGMT promoter remains the only significant predictor ( P = 0.017 ; Cox regression ) . Conclusions : This prospect i ve clinical trial identifies MGMT-methylation status as an independent predictor for glioblastoma patients treated with a methylating agent . The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implication s for the design of future trials and supports efforts to deplete MGMT by O-6-benzylguanine , a noncytotoxic substrate of this enzyme Background The benefits of new innovations in glioblastoma therapies should not be curtailed as a result of delays in commencement of radiation therapy , caused by clinical circumstances as well as diagnostic procedures . This study evaluates whether delays in chemo-radiotherapy after surgery , while determining O6-methylguanine-DNA-methyltransferase ( MGMT ) promoter status , affect the survival rates of patients with glioblastoma ( GBM ) . Methods Our sample comprised 50 GBM patients in a retrospective analysis of three prospect i ve studies that focused on combined radiotherapy and required MGMT promoter-status testing as inclusion criteria . Results were compared with a reference group of 127 favourable GBM cases ( Karnofsky performance-status scale ≥ 70 ) , in which the patients underwent st and ard postoperative chemo-radiotherapy with temozolomide . Survival time was calculated using the Kaplan-Meier method , and a multivariate analysis of the delays between surgical and radiotherapy procedures was performed using the Cox regression model . Results The study group ’s median overall survival time was 16.2 months ( with a range of 2 to 56 months ) , versus the reference group ’s survival time of 18.2 months ( with a range of 1 to 92 months ) ( p = 0.64 ) . The delay between surgery and radiotherapy was increased by 8 days in the study patients ( p < 0.001 ) , with a median delay of 35 days ( range : 18–49 days ) corresponding to the typical 27-day delay ( range : 5–98 days ) for those in the reference group . Univariate and multivariate analyses did not show any negative association between survival time and delaying radiation therapy to determine MGMT-promoter status ; commencement of radiation therapy sooner than 24 days after surgery was the threshold for significantly decreased overall survival ( p = 0.01 ) and progression-free ( p = 0.03 ) survival . Conclusion Delaying postoperative chemoradiation for GBM patients —carried out in order to determine MGMT-promoter status — did not have a negative impact on survival time . Indeed , the data of the present study shows that initiating radiation therapy sooner than 24 days after surgery has a negative impact on progression and survival BACKGROUND Radiotherapy is the st and ard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined . We did a r and omised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma . METHODS Between May 15 , 2005 , and Nov 2 , 2009 , we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma , age older than 65 years , and a Karnofsky performance score of 60 or higher . Patients were r and omly assigned 100 mg/m(2 ) temozolomide , given on days 1 - 7 of 1 week on , 1 week off cycles , or radiotherapy of 60·0 Gy , administered over 6 - 7 weeks in 30 fractions of 1·8 - 2·0 Gy . The primary endpoint was overall survival . We assessed non-inferiority with a 25 % margin , analysed for all patients who received at least one dose of assigned treatment . This trial is registered with Clinical Trials.gov , number NCT01502241 . FINDINGS Of 584 patients screened , we enrolled 412 . 373 patients ( 195 r and omly allocated to the temozolomide group and 178 to the radiotherapy group ) received at least one dose of treatment and were included in efficacy analyses . Median overall survival was 8·6 months ( 95 % CI 7·3 - 10·2 ) in the temozolomide group versus 9·6 months ( 8·2 - 10·8 ) in the radiotherapy group ( hazard ratio [ HR ] 1·09 , 95 % CI 0·84 - 1·42 , p(non-inferiority)=0·033 ) . Median event-free survival ( EFS ) did not differ significantly between the temozolomide and radiotherapy groups ( 3·3 months [ 95 % CI 3·2 - 4·1 ] vs 4·7 [ 4·2 - 5·2 ] ; HR 1·15 , 95 % CI 0·92 - 1·43 , p(non-inferiority)=0·043 ) . Tumour MGMT promoter methylation was seen in 73 ( 35 % ) of 209 patients tested . MGMT promoter methylation was associated with longer overall survival than was unmethylated status ( 11·9 months [ 95 % CI 9·0 to not reached ] vs 8·2 months [ 7·0 - 10·0 ] ; HR 0·62 , 95 % CI 0·42 - 0·91 , p=0·014 ) . EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy ( 8·4 months [ 95e% CI 5·5 - 11·7 ] vs 4·6 [ 4·2 - 5·0 ] ) , whereas the opposite was true for patients with no methylation of the MGMT promoter ( 3·3 months [ 3·0 - 3·5 ] vs 4·6 months [ 3·7 - 6·3 ] ) . The most frequent grade 3 - 4 intervention-related adverse events were neutropenia ( 16 patients in the temozolomide group vs two in the radiotherapy group ) , lymphocytopenia ( 46 vs one ) , thrombocytopenia ( 14 vs four ) , raised liver-enzyme concentrations ( 30 vs 16 ) , infections ( 35 vs 23 ) , and thromboembolic events ( 24 vs eight ) . INTERPRETATION Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma . MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making . FUNDING Merck Sharp & Dohme Glioblastoma ( GBM ) is the most common and aggressive primary brain tumor . The identification of novel molecular prognostic markers of GBM has recently been an area of great interest in neuro-oncology . The methylation status of the MGMT gene promoter is currently a promising molecular prognostic marker , but some controversial data have precluded its clinical use . We analyzed MGMT methylation by methylation-specific PCR in 90 GBM patients from four Portuguese hospitals , uniformly treated with radiotherapy combined with concomitant and adjuvant temozolomide ( Stupp protocol ) . The Kaplan-Meier method was used to construct survival curves , and the log-rank test and a Cox-regression model were used to analyze patient survival . The methylation status of MGMT was successfully determined in 89 % ( 80/90 ) of the tumors . The frequency of tumoral MGMT promoter methylation was 47.5 % . The median overall survivals ( OSs ) were 16 months ( 95 % CI 12.2 - 19.8 ) and 13 months ( 95 % CI 13.3 - 18.7 ) for patients whose tumors had a methylated or unmethylated MGMT , respectively . Univariate and multivariate analyses did not show any statistically significant association between MGMT methylation status and patient OS ( P=0.583 by the log-rank test ; P=0.617 by the Cox-regression test ) or progression-free survival ( P=0.775 by the log-rank test ; P=0.691 by the Cox-regression test ) . None of the patient clinical features were significantly correlated with survival . This is the first study to report the frequency of MGMT methylation among Portuguese GBM patients . Our data did not show statistically significant associations between MGMT promoter methylation and the outcome of GBM patients treated with temozolomide . Additional robust prospect i ve studies are warranted to clarify whether the MGMT status should be used in clinical decisions Background Patients with non-resectable glioblastoma generally exhibit a poor prognosis , even after radiotherapy plus concomitant and adjuvant temozolomide ( XRT/TMZ→TMZ ) . Unfortunately , no data are available concerning the predictive value of O6-methylguanine-DNA methyltransferase ( MGMT ) promoter methylation for this important sub population . For clarification , a prospect i ve study was conducted . Methods Adult patients with a non-resectable glioblastoma were included . A molecular stereotactic biopsy technique was used for tumour characterisation combining histopathological diagnosis with small sample size adjusted methylation-specific PCR ( MSP ) and sodium bisulfite sequencing . Treatment included XRT ( 60 Gy in 30 fractions)/TMZ ( daily dose of 75 mg/m2)→TMZ ( 150–200 mg/m2 per day for 5 days of every28-day cycle ) . The primary end point was progression-free survival ( PFS ) . Secondary endpoints were overall survival ( OS ) and treatment response ( TR ) . Patients were categorised in the Radiation Therapy Oncology Group (RTOG)-recursive partitioning analysis ( RPA ) Classes III ( N=4 ) , IV ( N=12 ) , V ( N=28 ) and VI ( N=12 ) . Results and discussion The success rates of MSP and sequence analyses were 100 % . The MGMT promoter was methylated in 30/56 tumours , which was associated with an increased PFS ( median 56 versus 20 weeks ; hazard ratio 0.15 ; range 0.07 to 0.33 ; p<0.0001 ) , higher frequency of TR ( 93.3 % vs 46.2 % ; p=0.0008 ) and increased OS ( median 104 vs 28 weeks ; hazard ratio 0.18 ; range 0.08 to 0.38 ; p<0.0001 ) . The transient perioperative morbidity was 1.8 % . Conclusion MGMT promoter methylation has a predominant favourable influence even for the important sub population with non-resectable glioblastoma . The molecular stereotactic biopsy technique is safe and effective for predictive evaluation and helps to avoid both over- and undertreatment OBJECTIVES Elderly Glioblastoma multiforme ( GBM ) patients have a worse prognosis and receive variable treatments . MGMT gene promoter methylation is linked with improved survival in GBM . We examined treatments administered and survival including in relation to MGMT methylation status in elderly GBM patients . PATIENTS AND METHODS Patients ≥65 years with diagnosed GBM between 1/01/2007 and 30/04/2009 and undergoing either a biopsy , subtotal ( STR ) or gross total resection ( GTR ) were included . The collected information included MGMT status [ methylated ( ME ) vs. unmethylated ( UN ) ] and survival data . p<0.05 was considered significant . RESULTS 59 patients were identified with median age at diagnosis being 72.68 years ( 65.72 - 85.04 ) . Treatment included surgery ( 25 GTR , 8 STR , 26 biopsy ) , chemoradiation ( 22 ) and radiotherapy alone ( 20 ) . Overall median overall survival ( MOS ) was 219 days . MOS with chemoradiation was 316 days vs. 143 days without it ( p=0.011 ) . 47 patients had definite MGMT status ( 28 ME , 19 UN ) . In ME patients , 9/28 received temozolamide compared to 10/19 in UN category . Temozolamide administration in patients with definite MGMT status was based on WHO performance status ( p=0.007 ) . MOS in UN group was 308 days vs. 167 days in ME group ( p=0.068 ) . In a multivariate Cox model including use of temozolamide , WHO score and methylation status , only temozolamide use was significantly associated with a reduced risk for death ( HR 0.443 , 95 % CI 0.200 - 0.982 , p=0.045 ) . CONCLUSIONS In this small cohort of patients , chemoradiation in suitable elderly GBM patients seemed to afford a survival benefit . MGMT methylation was not associated with an improved survival with temozolamide being the only factor leading to a better survival . Temozolamide use should be considered irrespective of MGMT status in this population with future large prospect i ve studies needed to eluci date this further O6‐methylguanine‐DNA‐methyltransferase ( MGMT ) promoter methylation identifies a sub population of glioblastoma patients with more favorable prognosis and predicts a benefit from alkylating agent chemotherapy ( CT ) . Little is known about its prevalence and clinical significance in older glioblastoma patients . We studied 233 glioblastoma patients aged 70 years or more ( 144 males , 89 females , median age : 74 years , range : 70.0–86.6 years ) , who were prospect ively enrolled in the German Glioma Network , for MGMT promoter methylation by methylation‐specific PCR ( MSP ) in all patients and DNA pyrosequencing in 166 patients . MGMT data were correlated with patient outcome . Median progression‐free survival ( PFS ) was 4.8 months ( 95 % CI : 4.3–5.3 ) and median overall survival ( OS ) was 7.7 months ( 95 % CI : 6.3–9.0 ) . MGMT promoter methylation was detected by MSP in 134 patients ( 57.5 % ) . For the whole cohort , PFS was 5.2 versus 4.7 months ( p = 0.207 ) and OS was 8.4 versus 6.4 months ( p = 0.031 ) in patients with versus without MGMT promoter methylation . Patients with MGMT methylated tumors had longer PFS when treated with radiotherapy ( RT ) plus CT or CT alone compared to patients treated with RT alone . Patients with MGMT unmethylated tumors appeared to derive no survival benefit from CT , regardless of whether given at diagnosis together with RT or as a salvage treatment . Patients treated with RT plus CT or CT alone demonstrated longer OS when pyrosequencing revealed > 25 % MGMT methylated alleles . Taken together , MGMT promoter methylation may be a useful biomarker to stratify elderly glioblastoma patients for treatment with versus without alkylating agent CT BACKGROUND In 2004 , a r and omised phase III trial by the European Organisation for Research and Treatment of Cancer ( EORTC ) and National Cancer Institute of Canada Clinical Trials Group ( NCIC ) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy . We report the final results with a median follow-up of more than 5 years . METHODS Adult patients with newly diagnosed glioblastoma were r and omly assigned to receive either st and ard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide . The methylation status of the methyl-guanine methyl transferase gene , MGMT , was determined retrospectively from the tumour tissue of 206 patients . The primary endpoint was overall survival . Analyses were by intention to treat . This trial is registered with Clinical trials.gov , number NCT00006353 . FINDINGS Between Aug 17 , 2000 , and March 22 , 2002 , 573 patients were assigned to treatment . 278 ( 97 % ) of 286 patients in the radiotherapy alone group and 254 ( 89 % ) of 287 in the combined-treatment group died during 5 years of follow-up . Overall survival was 27.2 % ( 95 % CI 22.2 - 32.5 ) at 2 years , 16.0 % ( 12.0 - 20.6 ) at 3 years , 12.1 % ( 8.5 - 16.4 ) at 4 years , and 9.8 % ( 6.4 - 14.0 ) at 5 years with temozolomide , versus 10.9 % ( 7.6 - 14.8 ) , 4.4 % ( 2.4 - 7.2 ) , 3.0 % ( 1.4 - 5.7 ) , and 1.9 % ( 0.6 - 4.4 ) with radiotherapy alone ( hazard ratio 0.6 , 95 % CI 0.5 - 0.7 ; p<0.0001 ) . A benefit of combined therapy was recorded in all clinical prognostic subgroups , including patients aged 60 - 70 years . Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy . INTERPRETATION Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up . A few patients in favourable prognostic categories survive longer than 5 years . MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide . FUNDING EORTC , NCIC , Nélia and Amadeo Barletta Foundation , Schering-Plough BACKGROUND Epigenetic silencing of the MGMT ( O6-methylguanine-DNA methyltransferase ) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents . METHODS We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a r and omized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide . The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis . RESULTS The MGMT promoter was methylated in 45 percent of 206 assessable cases . Irrespective of treatment , MGMT promoter methylation was an independent favorable prognostic factor ( P<0.001 by the log-rank test ; hazard ratio , 0.45 ; 95 percent confidence interval , 0.32 to 0.61 ) . Among patients whose tumor contained a methylated MGMT promoter , a survival benefit was observed in patients treated with temozolomide and radiotherapy ; their median survival was 21.7 months ( 95 percent confidence interval , 17.4 to 30.4 ) , as compared with 15.3 months ( 95 percent confidence interval , 13.0 to 20.9 ) among those who were assigned to only radiotherapy ( P=0.007 by the log-rank test ) . In the absence of methylation of the MGMT promoter , there was a smaller and statistically insignificant difference in survival between the treatment groups . CONCLUSIONS Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide , whereas those who did not have a methylated MGMT promoter did not have such a benefit BACKGROUND Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor . Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with st and ard temozolomide chemoradiotherapy in newly diagnosed glioblastoma ( particularly in tumours with methylated MGMT promoter ) . We aim ed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter . METHODS In this multicentre , open-label , phase 3 study , we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries . Eligible patients ( newly diagnosed , histologically proven supratentorial glioblastoma , methylated MGMT promoter , and age ≥18 years ) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and central ly r and omised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly ( cilengitide group ) or temozolomide chemoradiotherapy alone ( control group ) . Patients and investigators were unmasked to treatment allocation . Maintenance temozolomide was given for up to six cycles , and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects . The primary endpoint was overall survival . We analysed survival outcomes by intention to treat . This study is registered with Clinical Trials.gov , number NCT00689221 . FINDINGS Overall , 3471 patients were screened . Of these patients , 3060 had tumour MGMT status tested ; 926 patients had a methylated MGMT promoter , and 545 were r and omly assigned to the cilengitide ( n=272 ) or control groups ( n=273 ) between Oct 31 , 2008 , and May 12 , 2011 . Median overall survival was 26·3 months ( 95 % CI 23·8 - 28·8 ) in the cilengitide group and 26·3 months ( 23·9 - 34·7 ) in the control group ( hazard ratio 1·02 , 95 % CI 0·81 - 1·29 , p=0·86 ) . None of the predefined clinical subgroups showed a benefit from cilengitide . We noted no overall additional toxic effects with cilengitide treatment . The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia ( 31 [ 12 % ] in the cilengitide group vs 26 [ 10 % ] in the control group ) , thrombocytopenia ( 28 [ 11 % ] vs 46 [ 18 % ] ) , neutropenia ( 19 [ 7 % ] vs 24 [ 9 % ] ) , leucopenia ( 18 [ 7 % ] vs 20 [ 8 % ] ) , and convulsion ( 14 [ 5 % ] vs 15 [ 6 % ] ) . INTERPRETATION The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes ; cilengitide will not be further developed as an anticancer drug . Nevertheless , integrins remain a potential treatment target for glioblastoma . FUNDING Merck KGaA , Darmstadt , Germany Epigenetic silencing of O6‐methylguanine‐DNA methyltransferase ( MGMT ) by promoter methylation can confer cancer cells with an increased sensitivity to alkylating chemotherapeutic agents and a higher susceptibility to TP53 transition mutations . The aim of our study was to assess the correlation of promoter methylation of the MGMT gene with TP53 mutations and the clinical characteristics of malignant astrocytomas . We analyzed the MGMT promoter methylation and TP53 mutations in 45 malignant astrocytomas ( 16 anaplastic astrocytomas and 29 glioblastomas multiforme ) treated prospect ively with 1‐(4‐amino‐2‐methyl‐5‐pyrimidinyl)methyl‐3‐2(2‐chloroethyl)‐3‐nitrosourea , interferon‐β and radiation therapy , and evaluated their clinical usefulness . MGMT promoter methylation was found in 17 ( 38 % ) of the 45 newly diagnosed malignant astrocytomas . A clear trend existed between MGMT methylation and G : C to A : T transition mutations of TP53 ( p = 0.0596 ) . Patients with MGMT‐methylated tumors displayed a greater chance of responding to adjuvant therapy as compared with those with MGMT‐unmethylated tumors ( p = 0.0393 ) . TP53 mutation was not significantly associated with the clinical response ( p = 0.1310 ) . While neither MGMT methylation nor TP53 mutation had a significant effect on prognosis of the whole population , the presence of MGMT methylation emerged as a significant predictor of a longer survival when exclusively analyzing 29 patients with glioblastomas multiforme . These findings highlight the importance of MGMT methylation as a specific predictive factor for responsiveness to nitrosourea chemotherapy A recent r and omized study conducted on newly diagnosed glioblastoma ( GBM ) patients demonstrated that concomitant and adjuvant temozolomide added to st and ard radiotherapy had a survival advantage compared with radiotherapy alone . The overall survival benefit of this aggressive treatment , however , was attenuated in older or poor performance status patients . The aim of the present study was to verify the activity and the toxicity of temozolomide administration concurrent and adjuvant to radiotherapy as first‐line treatment for elderly GBM patients , and to explore correlations between clinical outcome and O6 methylguanine‐DNA methyltransferase ( MGMT ) promoter methylation status OBJECT The purpose of this study was to determine whether increased local control and improved survival can be achieved in patients with glioblastoma multiformes ( GBMs ) who undergo aggressive resection , Gliadel wafer implantation , Gamma Knife radiosurgery ( GKS ) , and fractionated radiotherapy ( RT ) as the initial treatment . METHODS Thirty patients with radiographically suspected GBMs were screened for enrollment in a Phase I/II prospect i ve clinical trial . Twenty-seven patients were eligible and underwent gross-total resection and Gliadel wafer implantation . Gamma Knife radiosurgery ( 12 Gy at 50 % ) was administered to the resection cavity within 2 weeks of surgery . Patients then received st and ard fractionated RT ( total dose 60 Gy over 6 weeks ) . Temozolomide was prescribed for patients at the time of recurrence . Surveillance MR imaging , neurological examination , and quality -of-life evaluations were performed at 2-month intervals . To estimate the potential effects on the DNA repair mechanism , tumor tissue was analyzed with methylation-specific polymerase chain reaction analysis and immunohistochemical assays for MGMT gene promoter methylation and protein expression . RESULTS The median survival for all patients was 50 weeks and the 2-year survival rate was 22 % . When stratified into st and ard and high-risk patient groups , the median survivals were 76 and 33 weeks , respectively . Two patients remain alive at the time of this report with no clinical or radiographic evidence of disease at > 189 and 239 weeks posttreatment and excellent performance status . Local tumor control was achieved in 53 % of patients , and local failure occurred in 47 % . No acute early toxicity was noted ; however , delayed symptomatic radionecrosis occurred in 47 % of patients , which required repeated operations 9 - 24 months after the initial treatment . Delayed hydrocephalus requiring ventriculoperitoneal shunt placement occurred in 47 % of patients . There was a significant difference in survival between patients whose tumors contained the methylated and unmethylated MGMT promoter , 103 versus 45 weeks , respectively ( p = 0.0009 , log-rank test ) . CONCLUSIONS The combination of aggressive resection , Gliadel wafer implantation , and GKS in addition to st and ard fractionated RT in selected patients result ed in increased local control and increased survival compared with a historical control group treated with surgery and involved-field RT alone . Delayed focal radionecrosis was increased to 47 % in this series and was managed with steroids and repeated resection . Aggressive local tumor control with these multimodal therapies should be approached judiciously for a select group of high performance patients and the probability of developing symptomatic radionecrosis requiring surgery should be anticipated and fully disclosed to patients who undergo this treatment BACKGROUND Most patients with glioblastoma are older than 60 years , but treatment guidelines are based on trials in patients aged only up to 70 years . We did a r and omised trial to assess the optimum palliative treatment in patients aged 60 years and older with glioblastoma . METHODS Patients with newly diagnosed glioblastoma were recruited from Austria , Denmark , France , Norway , Sweden , Switzerl and , and Turkey . They were assigned by a computer-generated r and omisation schedule , stratified by centre , to receive temozolomide ( 200 mg/m(2 ) on days 1 - 5 of every 28 days for up to six cycles ) , hypofractionated radiotherapy ( 34·0 Gy administered in 3·4 Gy fractions over 2 weeks ) , or st and ard radiotherapy ( 60·0 Gy administered in 2·0 Gy fractions over 6 weeks ) . Patients and study staff were aware of treatment assignment . The primary endpoint was overall survival . Analyses were done by intention to treat . This trial is registered , number IS RCT N81470623 . FINDINGS 342 patients were enrolled , of whom 291 were r and omised across three treatment groups ( temozolomide n=93 , hypofractionated radiotherapy n=98 , st and ard radiotherapy n=100 ) and 51 of whom were r and omised across only two groups ( temozolomide n=26 , hypofractionated radiotherapy n=25 ) . In the three-group r and omisation , in comparison with st and ard radiotherapy , median overall survival was significantly longer with temozolomide ( 8·3 months [ 95 % CI 7·1 - 9·5 ; n=93 ] vs 6·0 months [ 95 % CI 5·1 - 6·8 ; n=100 ] , hazard ratio [ HR ] 0·70 ; 95 % CI 0·52 - 0·93 , p=0·01 ) , but not with hypofractionated radiotherapy ( 7·5 months [ 6·5 - 8·6 ; n=98 ] , HR 0·85 [ 0·64 - 1·12 ] , p=0·24 ) . For all patients who received temozolomide or hypofractionated radiotherapy ( n=242 ) overall survival was similar ( 8·4 months [ 7·3 - 9·4 ; n=119 ] vs 7·4 months [ 6·4 - 8·4 ; n=123 ] ; HR 0·82 , 95 % CI 0·63 - 1·06 ; p=0·12 ) . For age older than 70 years , survival was better with temozolomide and with hypofractionated radiotherapy than with st and ard radiotherapy ( HR for temozolomide vs st and ard radiotherapy 0·35 [ 0·21 - 0·56 ] , p<0·0001 ; HR for hypofractionated vs st and ard radiotherapy 0·59 [ 95 % CI 0·37 - 0·93 ] , p=0·02 ) . Patients treated with temozolomide who had tumour MGMT promoter methylation had significantly longer survival than those without MGMT promoter methylation ( 9·7 months [ 95 % CI 8·0 - 11·4 ] vs 6·8 months [ 5·9 - 7·7 ] ; HR 0·56 [ 95 % CI 0·34 - 0·93 ] , p=0·02 ) , but no difference was noted between those with methylated and unmethylated MGMT promoter treated with radiotherapy ( HR 0·97 [ 95 % CI 0·69 - 1·38 ] ; p=0·81 ) . As expected , the most common grade 3 - 4 adverse events in the temozolomide group were neutropenia ( n=12 ) and thrombocytopenia ( n=18 ) . Grade 3 - 5 infections in all r and omisation groups were reported in 18 patients . Two patients had fatal infections ( one in the temozolomide group and one in the st and ard radiotherapy group ) and one in the temozolomide group with grade 2 thrombocytopenia died from complications after surgery for a gastrointestinal bleed . INTERPRETATION St and ard radiotherapy was associated with poor outcomes , especially in patients older than 70 years . Both temozolomide and hypofractionated radiotherapy should be considered as st and ard treatment options in elderly patients with glioblastoma . MGMT promoter methylation status might be a useful predictive marker for benefit from temozolomide . FUNDING Merck , Lion 's Cancer Research Foundation , University of Umeå , and the Swedish Cancer Society PURPOSE This open-label , prospect i ve , single-arm , phase II study combined erlotinib with radiation therapy ( XRT ) and temozolomide to treat glioblastoma multiforme ( GBM ) and gliosarcoma . The objectives were to determine efficacy of this treatment as measured by survival and to explore the relationship between molecular markers and treatment response . PATIENTS AND METHODS Sixty-five eligible adults with newly diagnosed GBM or gliosarcoma were enrolled . We intended to treat patients not currently treated with enzyme-inducing antiepileptic drugs ( EIAEDs ) with 100 mg/d of erlotinib during XRT and 150 mg/d after XRT . Patients receiving EIAEDs were to receive 200 mg/d of erlotinib during XRT and 300 mg/d after XRT . After XRT , the erlotinib dose was escalated until patients developed tolerable grade 2 rash or until the maximum allowed dose was reached . All patients received temozolomide during and after XRT . Molecular markers of epidermal growth factor receptor ( EGFR ) , EGFRvIII , phosphatase and tensin homolog ( PTEN ) , and methylation status of the promotor region of the MGMT gene were analyzed from tumor tissue . Survival was compared with outcomes from two historical phase II trials . RESULTS Median survival was 19.3 months in the current study and 14.1 months in the combined historical control studies , with a hazard ratio for survival ( treated/control ) of 0.64 ( 95 % CI , 0.45 to 0.91 ) . Treatment was well tolerated . There was a strong positive correlation between MGMT promotor methylation and survival , as well as an association between MGMT promotor-methylated tumors and PTEN positivity shown by immunohistochemistry with improved survival . CONCLUSION Patients treated with the combination of erlotinib and temozolomide during and following radiotherapy had better survival than historical controls . Additional studies are warranted PURPOSE To evaluate long-term survival in a prospect i ve series of patients newly diagnosed with glioblastoma and treated with a combination of lomustine ( CCNU ) , temozolomide ( TMZ ) , and radiotherapy . PATIENTS AND METHODS Thirty-nine patients received radiotherapy of the tumor site only ( 60 Gy ) and CCNU/TMZ chemotherapy ( n = 31 received st and ard-dose CCNU , 100 mg/m2 on day 1 and TMZ 100 mg/m(2)/d on days 2 to 6 ; n = 8 received intensified-dose CCNU 110 mg/m(2 ) on day 1 and TMZ 150 mg/m(2 ) on days 2 to 6 ) for up to six courses . RESULTS In the whole cohort , the median overall survival ( mOS ) was 23.1 months ; 47.4 % survived for 2 years , and 18.5 % survived for 4 years . After a median follow-up of 41.5 months , mOS had not been reached in the intensified group and was significantly higher than in the st and ard group ( 22.6 months ; P = .024 ) . In the intensified group , four of eight patients survived for at least 56 months , two of them without recurrence . O(6)-methylguanine-DNA methyltransferase ( MGMT ) gene promotor methylation in the tumor tissue was associated with significantly longer mOS ( methylated , 34.3 months v nonmethylated , 12.5 months ) . A multivariate Cox proportional hazard model revealed MGMT status ( methylated v nonmethylated ; relative risk [ RR ] of death , 0.43 ; P = .003 ) and chemotherapy dose ( intensified v st and ard ; RR , 0.37 ; P = .012 ) as independent prognostic factors . WHO grade 4 hematoxicity was observed more frequently in the intensified group ( 57 % v 16 % ) . CONCLUSION The combination of radiotherapy , CCNU , and TMZ yielded promising long-term survival data in patients with newly diagnosed glioblastoma . Intensification of CCNU/TMZ chemotherapy may add an additional survival benefit , albeit with greater acute toxicity PURPOSE The prognostic value of genetic alterations characteristic of glioblastoma in patients treated according to present st and ards of care is unclear . PATIENTS AND METHODS Three hundred one patients with glioblastoma were prospect ively recruited between October 2004 and December 2006 at the clinical centers of the German Glioma Network . Two hundred fifty-eight patients had radiotherapy , 199 patients had temozolomide , 189 had both , and seven had another chemotherapy as the initial treatment . The tumors were investigated for TP53 mutation , p53 immunoreactivity , epidermal growth factor receptor , cyclin-dependent kinase CDK 4 or murine double minute 2 amplification , CDKN2A homozygous deletion , allelic losses on chromosome arms 1p , 9p , 10q , and 19q , O(6)-methylguanine methyltransferase ( MGMT ) promoter methylation , and isocitrate dehydrogenase 1 ( IDH1 ) mutations . RESULTS Median progression-free ( PFS ) and overall survival ( OS ) were 6.8 and 12.5 months . Multivariate analysis revealed younger age , higher performance score , MGMT promoter methylation , and temozolomide radiochemotherapy as independent factors associated with longer OS . MGMT promoter methylation was associated with longer PFS ( relative risk [ RR ] , 0.5 ; 95 % CI , 0.38 to 0.68 ; P < .001 ) and OS ( RR , 0.39 ; 95 % CI , 0.28 to 0.54 ; P < .001 ) in patients receiving temozolomide . IDH1 mutations were associated with prolonged PFS ( RR , 0.42 ; 95 % CI , 0.19 to 0.91 ; P = .028 ) and a trend for prolonged OS ( RR , 0.43 ; 95 % CI , 0.15 to 1.19 ; P = .10 ) . No other molecular factor was associated with outcome . CONCLUSION Molecular changes associated with gliomagenesis do not predict response to therapy in glioblastoma patients managed according to current st and ards of care . MGMT promoter methylation and IDH1 mutational status allow for stratification into prognostically distinct subgroups |
13,780 | 25,790,948 | Discussion : Overall response rate and disease control rate as well as 1-year survival rate in patients who received GS were superior to those treated with GEM alone .
Combination chemotherapy with GEM and S-1 may offer greater benefits in the treatment of pancreatic cancer than GEM alone , although the GS group had higher haematological toxicities .
Combination chemotherapy with GEM and S-1 might be an option of first-line chemotherapy for pancreatic cancer patients , at least in Asia .
Mini Abstract : This systematic review analysing r and omized controlled trials ( RCTs ) comparing S-1 combination chemotherapy versus GEM alone for locally advanced and metastatic pancreatic cancer demonstrated greater efficacy for S-1 combination in term of response , disease control and 1-year survival proportion | Abstract Introduction : After decades of research , pancreatic cancer is still a devastating disease .
The aim of this article was to assess the efficacy and safety of combination chemotherapy with gemcitabine ( GEM ) and S-1 ( GS ) therapy compared with GEM alone therapy in patients with locally advanced or metastatic pancreatic cancer . | Purpose To evaluate the efficacy and safety of the combination of gemcitabine ( GEM ) and S-1 ( GS ) in comparison to GEM alone ( G ) for unresectable pancreatic cancer . Methods In this multicenter r and omized phase II study , we r and omly assigned unresectable pancreatic cancer patients to either the GS group or the G group . The GS group regimen consists of intravenous 1,000 mg/m2 GEM during 30 min on days 1 and 8 , combined with 80 mg/m2 oral S-1 twice daily on days 1–14 , repeated every 3 weeks . On the other h and , the G group regimen consists of intravenous 1,000 mg/m2 GEM on days 1 , 8 , and 15 , repeated every 4 weeks . The primary endpoint was objective response rate ( ORR ) . Secondary end points included treatment toxicity , clinical response benefit , progression-free survival ( PFS ) , and overall survival . Results We registered 117 patients from 16 institutions between June 2007 and August , 2010 . The ORR of the GS group was 28.3 % , whereas that of the G group was 6.8 % . This difference was statistically significant ( P = 0.005 ) . The disease control rate was 64.2 % in the GS group and 44.1 % in the G group . Median PFS was 6.15 months in the GS group and 3.78 month in the G group . This was also statistically significant ( P = 0.0007 ) . Moreover , the median overall survival ( OS ) of the GS group was significantly longer than that of the G group ( 13.7 months vs. 8.0 months ; P = 0.035 ) . The major grade 3–4 adverse events were neutropenia ( 54.7 % in the GS group and 22.0 % in the G group ) , thrombocytopenia ( 15.1 % in the GS group and 5.1 % in the G group ) , and skin rash ( 9.4 % in the GS group ) . Conclusions The GS group showed stronger anticancer activity than the G group , suggesting the need for a large r and omized phase III study to confirm GS advantages in a specific subset 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 : This r and omised phase II trial compared gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer . Methods : Patients were r and omly assigned to 4-week treatment with gemcitabine alone ( 1000 , mg m−2 gemcitabine by 30-min infusion on days 1 , 8 , and 15 ) or gemcitabine and S-1 combination therapy ( 1000 , mg m−2 gemcitabine by 30-min infusion on days 1 and 15 and 40 mg m−2 S-1 orally twice daily on days 1–15 ) . The primary end point was progression-free survival ( PFS ) . Results : Between July 2006 and February 2009 , 106 patients were enrolled . The PFS in gemcitabine and S-1 combination arm was significantly longer than in gemcitabine arm ( 5.4 vs 3.6 months ) , with a hazard ratio of 0.64 ( P=0.036 ) . Overall survival ( OS ) for gemcitabine and S-1 combination was longer than that for gemcitabine monotherapy ( 13.5 vs 8.8 months ) , with a hazard ratio of 0.72 ( P=0.104 ) . Overall , grade 3 or 4 adverse events were similar in both arms . Conclusion : Gemcitabine and S-1 combination therapy demonstrated longer PFS in advanced pancreatic cancer . Improved OS duration of 4.7 months was found for gemcitabine and S-1 combination therapy , though this was not statistically significant Abstract Purpose To evaluate the efficacy and safety of combined gemcitabine and S-1 as first-line chemotherapy for patients with locally advanced or metastatic pancreatic cancer . Methods This study included patients who had been diagnosed with unresectable , locally advanced or metastatic adenocarcinoma arising from the pancreas , which was histologically or cytologically confirmed and involved at least 1 unidimensionally measurable lesion . The regimen consisted of intravenous 1,000 mg/m2 gemcitabine on day 1 and 8 combined with oral S-1 on days 1–14 every 21 days . The dosage of S-1 was based on the body surface area ( BSA ) as follows : 40 mg bid ( total 80 mg/day ) for a BSA of < 1.25 , 50 mg bid ( total 100 mg/day ) for a BSA of ≥1.25 but < 1.5 , and 60 mg bid ( total 120 mg/day ) for a BSA of ≥1.5 . Treatment consisted of at least 2 courses unless rapid disease progression was noted . The primary end points were the response and disease control rates , and the secondary end points were toxicity and survival . Results Thirty-seven patients were enrolled between August 2005 and December 2010 . The median number of chemotherapy cycles was 4 ( range 1–28 cycles ) . Response to treatment could be evaluated in 31 patients . None of the patients showed complete response , but 5 achieved partial response . The response rate was thus 13.5 % [ 95 % confidence interval ( CI ) 2.7–24.3 % ] in the intent-to-treat population . Sixteen patients ( 43.2 % ; 95 % CI 27–59.5 % ) showed stable disease , and the overall disease control rate was 56.8 % ( 95 % CI 40.6–72.9 % ) . For all 37 patients , the median progression-free survival was 4.6 months ( 95 % CI 1.8–7.6 month ) , and the median overall survival was 9.4 month ( 95 % CI 5.8–12.6 month ) . Chemotherapy-related grade 3/4 hematological toxicities were neutropenia ( 36.1 % ) , leucopenia ( 22.2 % ) , and anemia ( 13.9 % ) . The non-hematological toxicities were generally mild . Conclusions Combination chemotherapy with gemcitabine and S-1 was effective , convenient , and safe in patients with advanced pancreatic cancer PURPOSE The purpose of this trial was to evaluate the role of radiation therapy with concurrent gemcitabine ( GEM ) compared with GEM alone in patients with localized unresectable pancreatic cancer . PATIENTS AND METHODS Patients with localized unresectable adenocarcinoma of the pancreas were r and omly assigned to receive GEM alone ( at 1,000 mg/m(2)/wk for weeks 1 to 6 , followed by 1 week rest , then for 3 of 4 weeks ) or GEM ( 600 mg/m(2)/wk for weeks 1 to 5 , then 4 weeks later 1,000 mg/m(2 ) for 3 of 4 weeks ) plus radiotherapy ( starting on day 1 , 1.8 Gy/Fx for total of 50.4 Gy ) . Measurement of quality of life using the Functional Assessment of Cancer Therapy-Hepatobiliary question naire was also performed . RESULTS Of 74 patients entered on trial and r and omly assigned to receive GEM alone ( arm A ; n = 37 ) or GEM plus radiation ( arm B ; n = 34 ) , patients in arm B had greater incidence of grade s 4 and 5 toxicities ( 41 % v 9 % ) , but grade s 3 and 4 toxicities combined were similar ( 77 % in A v 79 % in B ) . No statistical differences were seen in quality of life measurements at 6 , 15 to 16 , and 36 weeks . The primary end point was survival , which was 9.2 months ( 95 % CI , 7.9 to 11.4 months ) and 11.1 months ( 95 % CI , 7.6 to 15.5 months ) for arms A and B , respectively ( one-sided P = .017 by stratified log-rank test ) . CONCLUSION This trial demonstrates improved overall survival with the addition of radiation therapy to GEM in patients with localized unresectable pancreatic cancer , with acceptable toxicity Purpose The aim of this study was to evaluate efficacy and safety of gemcitabine plus S-1 ( GS ) combination chemotherapy in patients with unresectable pancreatic cancer . Methods Patients were r and omly assigned to receive GS ( oral S-1 60 mg/m2 daily on days 1–15 every 3 weeks and gemcitabine 1,000 mg/m2 on days 8 and 15 ) or gemcitabine ( 1,000 mg/m2 on days 1 , 8 , and 15 every 4 weeks ) . The primary endpoint was progression-free survival ( PFS ) . Results One hundred and one patients were r and omly assigned . PFS was significantly longer in the GS arm with an estimated hazard ratio ( HR ) of 0.65 ( 95 % CI 0.43–0.98 ; P = 0.039 ; median 5.3 vs 3.8 months ) . Objective response rate ( ORR ) was also better in the GS arm ( 21.6 vs 6 % , P = 0.048 ) . Median survival was 8.6 months for GS and 8.6 months for GEM ( HR 0.93 ; 95 % CI 0.61–1.41 ; P = 0.714 ) . Grade 3–4 neutropenia ( 44 vs 19.6 % , P = 0.011 ) and thrombocytopenia ( 26 vs 8.7 % , P = 0.051 ) were more frequent in the GS arm . Conclusions GS therapy improved PFS and ORR with acceptable toxicity profile in patients with unresectable pancreatic cancer PURPOSE Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms . To date , no treatment has had a significant impact on the disease . In early studies with gemcitabine , patients with pancreas cancer experienced an improvement in disease-related symptoms . Based on those findings , a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer . PATIENTS AND METHODS One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were r and omized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest , then weekly x 3 every 4 weeks thereafter ( 63 patients ) , or to fluorouracil ( 5-FU ) 600 mg/m2 once weekly ( 63 patients ) . The primary efficacy measure was clinical benefit response , which was a composite of measurements of pain ( analgesic consumption and pain intensity ) , Karnofsky performance status , and weight . Clinical benefit required a sustained ( > or = 4 weeks ) improvement in at least one parameter without worsening in any others . Other measures of efficacy included response rate , time to progressive disease , and survival . RESULTS Clinical benefit response was experienced by 23.8 % of gemcitabine-treated patients compared with 4.8 % of 5-FU-treated patients ( P = .0022 ) . The median survival duration s were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients , respectively ( P = .0025 ) . The survival rate at 12 months was 18 % for gemcitabine patients and 2 % for 5-FU patients . Treatment was well tolerated . CONCLUSION This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced , symptomatic pancreas cancer . Gemcitabine also confers a modest survival advantage over treatment with 5-FU BACKGROUND The long-term prognosis for localized pancreatic cancer ( PC ) remains poor . Three r and omized trials ( GEST phase III , JACCRO PC-01 phase II and GEMSAP phase II ) evaluated gemcitabine ( Gem ) with or without S-1 for patients with metastatic and locally advanced PC . A pooled analysis based on published data examined whether Gem with S-1 ( GS ) is superior to Gem alone in overall survival ( OS ) in patients with locally advanced PC . METHODS Data were extracted on 193 patients : 31 ( JACCRO ) , 28 ( GEMSAP ) , and 134 ( GEST ) . OS was used for primary endpoint and progression-free survival ( PFS ) was used for secondary endpoint . A general variance-based method was used to estimate the pooled HR and 95 % CI between GS ( n = 96 ) and Gem ( n = 97 ) . RESULTS Meta- analysis demonstrated that the overall risk of death was significantly different between the two chemotherapies ( hazard ratio = 0.673 , 95 % confidence interval : 0.488 - 0.929 , P = 0.016 ) . The median PFSs for GS and GEM in the JACCRO , GEMSAP , and GEST studies were 12.0 , 12.6 , and 10.7 months , and 4.1 , 8.1 , and 6.2 months , respectively ( P = 0.001 ) . The r and om-effect pooled estimate for 165 patients showed the objective response rate ( ORR ) in the GS group ( 28.4 % ) was better in the Gem group ( 8.3 % , P = 0.001 ) . CONCLUSIONS GS improved ORR , PFS and OS in patients with locally advanced PC over Gem alone . GS could become one of the front-line chemotherapeutic agents BACKGROUND Pancreatic ductal adenocarcinoma ( PDAC ) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease . To improve the st and ard therapy with gemcitabine , we initiated a prospect i ve r and omised phase-II trial with gemcitabine ( GEM ) versus gemcitabine plus sunitinib ( SUNGEM ) based on data of in vitro trials and phase-I data for the combination treatment . The rational of adding sunitinib was its putative antiangiogenic mechanism of action . METHODS A total of 106 eligible patients with locally advanced , unresectable or metastatic PDAC without previous system therapy were r and omised to receive GEM at a dosage of 1.000mg/m(2 ) d1 , 8 , 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2 ) d1 + 8 and sunitinib 50 mg p.o . d1 - 14 , q21d . The primary end-point was progression free survival ( PFS ) , secondary end-points were overall survival ( OS ) , toxicity and overall response rate ( ORR ) . RESULTS The confirmatory analysis of PFS was based on the intend-to-treat ( ITT ) population ( N=106 ) . The median PFS was 13.3 weeks ( 95 % confidence interval ( 95%-CI ) : 10.4 - 18.1 weeks ) for GEM and 11.6 weeks for SUNGEM ( 95%-CI : 7.0 - 18.0 weeks ; p=0.78 one-sided log-rank ) . The ORR was 6.1 % ( 95%-CI : 0.7 - 20.2 % ) for GEM and for 7.1 % ( 95%-CI : 0.9 - 23.5 % ) for SUNGEM ( p=0.87 ) . The median time to progression ( TTP ) was 14.0 weeks ( 95%-CI : 12.4 - 22.3 weeks ) for GEM and 18.0 weeks ( 95%-CI : 11.3 - 19.3 weeks ) for SUNGEM ( p=0.60 ; two-sided log-rank ) . The median OS was 36.7 weeks ( 95%-CI : 20.6 - 49.0 weeks ) for the GEM arm and 30.4 weeks ( 95%-CI : 18.1 - 37.6 weeks ) for the SUNGEM ( p=0.78 , one-sided log-rank ) . In regard to toxicities , suspected SAEs were reported in 53.7 % in the GEM arm and 71.2 % in the SUNGEM arm . Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1 % versus 27.8 % in the GEM arm ( p=0.045 , two sided log-rank ) . CONCLUSIONS The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity BACKGROUND The role of chemoradiation with systemic chemotherapy compared with chemotherapy alone in locally advanced pancreatic cancer ( LAPC ) is uncertain . PATIENTS AND METHODS One hundred and nineteen patients with LAPC , World Health Organization performance status of zero to two were r and omly assigned to either the induction CHRT group ( 60 Gy , 2 Gy/fraction ; concomitant 5-fluorouracil infusion , 300 mg/m(2)/day , days 1 - 5 for 6 weeks ; cisplatin , 20 mg/m(2)/day , days 1 - 5 during weeks 1 and 5 ) or the induction gemcitabine group ( GEM : 1000 mg/m(2 ) weekly for 7 weeks ) . Maintenance gemcitabine ( 1000 mg/m(2 ) weekly , 3/4 weeks ) was given in both arms until disease progression or toxicity . RESULTS Overall survival was shorter in the CHRT than in GEM arm [ median survival 8.6 ( 99 % confidence interval 7.1 - 11.4 ) and 13 months ( 8.7 - 18.1 ) , P = 0.03 ] . One-year survival was , respectively , 32 % and 53 % . These results were confirmed in a per- protocol analysis for patients who received 75 % or more of the planned dose of radiotherapy . More overall grade s 3 - 4 toxic effects were recorded in the CHRT arm , both during induction ( 36 versus 22 % ) and maintenance ( 32 versus 18 % ) . CONCLUSION This intensive induction schedule of CHRT was more toxic and less effective than gemcitabine alone |
13,781 | 28,925,488 | In order to perform odds ratio we observed a decrease in late gastrointestinal toxicity for patients treated with hypofractionated schemes compared to CV treated ones .
Among patients who underwent conventional treatment , SIB seemed to decrease acute genitourinary side effects ; SIB-Hypo treated patients suffered less toxicity than patients treated with hypofractionated- sequential boost schemes .
Hypo-SIB schemes would seem less toxic in terms of acute gastrointestinal and late genitourinary side effects than CV-SIB . | OBJECTIVE The aim of our report was to review the literature concerning the toxicity of radiation therapy in patients treated for high-risk prostate cancer , and to evaluate the differences in toxicity between conventional fractionation and hypofractionated treatments , in view of different techniques used in high-risk prostate cancer patients . | PURPOSE To perform a r and omized trial comparing 70 and 80 Gy radiotherapy for prostate cancer . PATIENTS AND METHODS A total of 306 patients with localized prostate cancer were r and omized . No and rogen deprivation was allowed . The primary endpoint was biochemical relapse according to the modified 1997-American Society for Therapeutic Radiology and Oncology and Phoenix definitions . Toxicity was grade d using the Radiation Therapy Oncology Group 1991 criteria and the late effects on normal tissues-subjective , objective , management , analytic scales ( LENT-SOMA ) scales . The patients ' quality of life was scored using the European Organization for Research and Treatment of Cancer Quality of Life Question naire 30-item cancer-specific and 25-item prostate-specific modules . RESULTS The median follow-up was 61 months . According to the 1997-American Society for Therapeutic Radiology and Oncology definition , the 5-year biochemical relapse rate was 39 % and 28 % in the 70- and 80-Gy arms , respectively ( p = .036 ) . Using the Phoenix definition , the 5-year biochemical relapse rate was 32 % and 23.5 % , respectively ( p = .09 ) . The subgroup analysis showed a better biochemical outcome for the higher dose group with an initial prostate-specific antigen level > 15 ng/mL. At the last follow-up date , 26 patients had died , 10 of their disease and none of toxicity , with no differences between the two arms . According to the Radiation Therapy Oncology Group scale , the Grade 2 or greater rectal toxicity rate was 14 % and 19.5 % for the 70- and 80-Gy arms ( p = .22 ) , respectively . The Grade 2 or greater urinary toxicity was 10 % at 70 Gy and 17.5 % at 80 Gy ( p = .046 ) . Similar results were observed using the LENT-SOMA scale . Bladder toxicity was more frequent at 80 Gy than at 70 Gy ( p = .039 ) . The quality -of-life question naire results before and 5 years after treatment were available for 103 patients with no differences found between the 70- and 80-Gy arms . CONCLUSION High-dose radiotherapy provided a better 5-year biochemical outcome with slightly greater toxicity PURPOSE To evaluate the acute toxicities of hypofractionated accelerated radiotherapy ( RT ) using a concomitant intensity-modulated RT boost in conjunction with elective pelvic nodal irradiation for high-risk prostate cancer . METHODS AND MATERIAL S This report focused on 66 patients entered into this prospect i ve Phase I study . The eligible patients had clinical ly localized prostate cancer with at least one of the following high-risk features ( Stage T3 , Gleason score > or=8 , or prostate-specific antigen level > 20 ng/mL ) . Patients were treated with 45 Gy in 25 fractions to the pelvic lymph nodes using a conventional four-field technique . A concomitant intensity-modulated radiotherapy boost of 22.5 Gy in 25 fractions was delivered to the prostate . Thus , the prostate received 67.5 Gy in 25 fractions within 5 weeks . Next , the patients underwent 3 years of adjuvant and rogen ablative therapy . Acute toxicities were assessed using the Common Terminology Criteria for Adverse Events , version 3.0 , weekly during treatment and at 3 months after RT . RESULTS The median patient age was 71 years . The median pretreatment prostate-specific antigen level and Gleason score was 18.7 ng/L and 8 , respectively . Grade 1 - 2 genitourinary and gastrointestinal toxicities were common during RT but most had settled at 3 months after treatment . Only 5 patients had acute Grade 3 genitourinary toxicity , in the form of urinary incontinence ( n = 1 ) , urinary frequency/urgency ( n = 3 ) , and urinary retention ( n = 1 ) . None of the patients developed Grade 3 or greater gastrointestinal or Grade 4 or greater genitourinary toxicity . CONCLUSION The results of the present study have indicated that hypofractionated accelerated RT with a concomitant intensity-modulated RT boost and pelvic nodal irradiation is feasible with acceptable acute toxicity The objectives of this study were to evaluate dosimetric quality and acute toxicity of volumetric-modulated arc therapy ( VMAT ) and daily image guidance in high-risk prostate cancer patients . A total of 100 consecutive high-risk prostate cancer patients treated with definitive VMAT with prophylactic whole-pelvic radiotherapy ( WPRT ) were enrolled . All patients were treated with a double-arc VMAT plan delivering 52 Gy to the prostate planning target volume ( PTV ) , while simultaneously delivering 46.8 Gy to the pelvic nodal PTV in 26 fractions , followed by a single-arc VMAT plan delivering 26 Gy to the prostate PTV in 13 fractions . Image-guided RT was performed with daily cone-beam computed tomography . Dose – volume parameters for the PTV and the organs at risk ( OARs ) , total number of monitor units ( MUs ) and treatment time were evaluated . Acute toxicity was assessed using the Common Terminology Criteria for Adverse Events , version 4.0 . All dosimetric parameters met the present plan acceptance criteria . Mean MU and treatment time were 471 and 146 s for double-arc VMAT , respectively , and were 520 and 76 s for single-arc VMAT , respectively . No Grade 3 or higher acute toxicity was reported . Acute Grade 2 proctitis , diarrhea , and genitourinary toxicity occurred in 12 patients ( 12 % ) , 6 patients ( 6 % ) and 13 patients ( 13 % ) , respectively . The present study demonstrated that VMAT for WPRT in prostate cancer results in favorable PTV coverage and OAR sparing with short treatment time and an acceptable rate of acute toxicity . These findings support the use of VMAT for delivering WPRT to high-risk prostate cancer patients PURPOSE To report acute toxicity result ing from radiotherapy ( RT ) dose escalation and hypofractionation using intensity-modulated RT ( IMRT ) treatment combined with and rogen suppression in high-risk prostate cancer patients . METHODS AND MATERIAL S Sixty patients with a histological diagnosis of high-risk prostatic adenocarcinoma ( having either a clinical Stage of > or = T3a or an initial prostate-specific antigen [ PSA ] level of > or = 20 ng/ml or a Gleason score of 8 to 10 or a combination of a PSA concentration of > 15 ng/ml and a Gleason score of 7 ) were enrolled . RT prescription was 68 Gy in 25 fractions ( 2.72 Gy/fraction ) over 5 weeks to the prostate and proximal seminal vesicles . The pelvic lymph nodes and distal seminal vesicles concurrently received 45 Gy in 25 fractions . The patients were treated with helical TomoTherapy-based IMRT and underwent daily megavoltage CT image-guided verification prior to each treatment . Acute toxicity scores were recorded weekly during RT and at 3 months post-RT , using Radiation Therapy Oncology Group acute toxicity scales . RESULTS All patients completed RT and follow up for 3 months . The maximum acute toxicity scores were as follows : 21 ( 35 % ) patients had Grade 2 gastrointestinal ( GI ) toxicity ; 4 ( 6.67 % ) patients had Grade 3 genitourinary ( GU ) toxicity ; and 30 ( 33.33 % ) patients had Grade 2 GU toxicity . These toxicity scores were reduced after RT ; there were only 8 ( 13.6 % ) patients with Grade 1 GI toxicity , 11 ( 18.97 % ) with Grade 1 GU toxicity , and 5 ( 8.62 % ) with Grade 2 GU toxicity at 3 months follow up . Only the V60 to the rectum correlated with the GI toxicity . CONCLUSION Dose escalation using a hypofractionated schedule to the prostate with concurrent pelvic lymph node RT and long-term and rogen suppression therapy is well tolerated acutely . Longer follow up for outcome and late toxicity is required OBJECTIVE Accuracy of biopsy scheme depends on different parameters . Prostate-specific antigen ( PSA ) level and digital rectal examination ( DRE ) influenced the detection rate and suggested the biopsy scheme to approach each patient . Another parameter is the prostate volume . Sampling accuracy tends to decrease progressively with an increasing prostate volume . We prospect ively observed detection cancer rate in suspicious prostate cancer ( PCa ) and improved by applying a protocol biopsy according to prostate volume ( PV ) . PATIENTS AND METHODS Clinical data and pathological features of these 1356 patients were analysed and included in this study . This protocol is a combined scheme that includes transrectal ( TR ) 12-core PBx ( TR12PBx ) for PV ≤ 30 cc , TR 14-core PBx ( TR14PBx ) for PV > 30 cc but < 60 cc , TR 18-core PBx ( TR18PBx ) for PV ≥ 60 cc . RESULTS Out of a total of 1356 patients , in 111 ( 8.2 % ) PCa was identified through TR12PBx scheme , in 198 ( 14.6 % ) through TR14PBx scheme and in 253 ( 18.6 % ) through TR18PBx scheme . The PCa detection rate was increased by 44 % by adding two TZ cores ( TR14PBx scheme ) . The TR18PBx scheme increased this rate by 21.7 % vs. TR14PBx scheme . The diagnostic yield offered by TR18PBx was statistically significant compared to the detection rate offered by the TR14PBx scheme ( p < 0.003 ) . The biopsy Gleason score and the percentage of core involvement were comparable between PCa detected by the TR14PBx scheme diagnostic yield and those detected by the TR18PBx scheme ( p = 0.362 ) . CONCLUSIONS The only PV parameter , in our opinion , can be significant in choosing the best biopsy scheme to approach in a first setting of biopsies increasing PCa detection rate Abstract Background A prospect i ve clinical trial was conducted to evaluate the feasibility of a novel approach to the treatment of patients with high risk prostate cancer ( HRPC ) through the use of a nomogram to tailor radiotherapy target volumes . Methods Twenty seven subjects with HRPC were treated with a mildly hypofractionated radiotherapy regimen using image-guided IMRT technique between Jun/2013-Jan/2015.A set of vali date d prognostic factors were inputted into the Memorial-Sloan-Kettering Cancer Center ( MSKCC ) prostate cancer nomogram to estimate risk of loco-regional spread ( LRS ) . The nomogram risk estimates for extra-capsular extension ( ECE ) , seminal vesicles involvement ( SVI ) , and pelvic lymph nodes involvement ( LNI ) were used to adapt radiotherapy treatment volumes based on a risk threshold of ≥15 % in all cases . A planning guide was used to delineate target volumes and organs at risk ( OAR ) . Up to three dose levels were administered over 28 fractions ; 70Gy for gross disease in the prostate + /− seminal vesicles ( 2.5Gy/fraction ) , 61.6Gy for sub clinical peri-prostatic disease ( 2.2Gy/fraction ) and 50.4Gy to pelvic nodes ( 1.8Gy/fraction ) . Data regarding protocol adherence , nomogram use , radiotherapy dose distribution , and acute toxicity were collected . Results Nomogram use 100 % of patients were treated for ECE , 88.9 % for SVI , and 70.4 % for LNI . The three areas at risk of LRS were appropriately treated according to the study protocol in 98.8 % cases . The MSKCC nomogram estimates for LRS differed significantly between the time of recruitment and analysis . Contouring protocol compliance Compliance with the trial contouring protocol for up to seven target volumes was 93.0 % ( 159/171 ) . Compliance with protocol for small bowel contouring was poor ( 59.3 % ) . Dose constraints compliance Compliance with dose constraints for target volumes was 97.4 % ( 191/196 ) . Compliance with dose constraints for OAR was 88.2 % ( 285/323 ) . Acute toxicity There were no grade 3 acute toxicities observed . 20/27 ( 74.1 % ) and 6/27 ( 22.2 % ) patients experienced a grade 2 genitourinary and gastrointestinal toxicity respectively . Conclusions We have demonstrated the feasibility of this novel risk-adapted radiation treatment protocol for HRPC . This study has identified key learning points regarding this approach , including the importance of st and ardization and updating of risk quantification tools , and the utility of an observer to verify their correct use . Trial registration ClincialTrials.gov identifier NCT01418040.Hunter New Engl and Human Research Ethics Committee ( HNEHREC ) reference number Background Definitive , percutaneous irradiation of the prostate and the pelvic lymph nodes in high-risk prostate cancer is the alternative to prostatectomy plus lymphadenectomy . To date , the role of whole pelvis radiotherapy ( WPRT ) has not been clarified especially taking into consideration the benefits of high conformal IMRT ( intensity modulated radiotherapy ) of complex-shaped target volumes . Methods From 2009 to 2012 , 40 patients of high-risk prostate cancer with an increased risk of microscopic lymph node involvement were enrolled into this prospect i ve phase II trial . Patients received at least two months of antihormonal treatment ( AT ) before radiotherapy continuing for at least 2 years . Helical IMRT ( tomotherapy ) of the pelvic lymph nodes ( 51.0 Gy ) with a simultaneous integrated , moderate hypofractionated boost ( single dose of 2.25 Gy ) to the prostate ( 76.5 Gy ) was performed in 34 fractions . PSA levels , prostate-related symptoms and quality of life were assessed at regular intervals for 24 months . Results Of the 40 patients enrolled , 38 finished the treatment as planned . Overall acute toxicity rates were low and no acute grade 3 or 4 gastrointestinal ( GI ) and genitourinary ( GU ) toxicity occurred . 21.6 % of patients experienced acute grade 2 but no late grade ≥2 GI toxicity . Regarding GU side effects , results showed 48.6 % acute grade 2 and 6.4 % late grade 2 toxicity . After a median observation time of 23.4 months the PLATIN 1 trial can be considered as sufficiently safe meeting the prospect ively defined aims of the trial . With 34/37 patients free of a PSA recurrence it shows promising efficacy . Conclusion Tomotherapy of the pelvic lymph nodes with a simultaneous integrated boost to the prostate can be performed safely and without excessive toxicity . The combined irradiation of both prostate and pelvic lymph nodes seems to be as well tolerated as the irradiation of the prostate alone . Trial registration Trial Numbers : ARO 2009–05 , Clinical Trials.gov : NCT01903408 PURPOSE To report clinical outcomes in patients treated with image guided proton therapy ( PT ) for localized prostate cancer . METHODS AND MATERIAL S The medical records of 1327 men were review ed . Each man was enrolled on an outcomes tracking study . Dual enrollment on a prospect i ve clinical trial was allowed . Each patient was treated for localized prostate cancer with PT at our institution between 2006 and 2010 . Ninety-eight percent of patients received 78 Gy ( radiobiological equivalent [ RBE ] ) or higher ; 18 % received and rogen deprivation therapy ( ADT ) . The 5-year freedom from biochemical progression ( FFBP ) , distant metastasis-free survival , and cause-specific survival rates are reported for each risk group . Data on patient-reported quality of life and high- grade toxicities were prospect ively collected and reported . A multivariate analysis was performed to identify clinical predictors of biochemical failure and urologic toxicity . RESULTS The median follow-up time was 5.5 years . The 5-year FFBP rates were 99 % , 94 % , and 74 % in low-risk , intermediate-risk , and high-risk patients , respectively . The actuarial 5-year rates of late grade 3 + Common Terminology Criteria for Adverse Events , version 4.0 , gastrointestinal ( GI ) and genitourinary ( GU ) toxicity were 0.6 % and 2.9 % , respectively . Multivariate analysis showed a significant correlation between grade 3 + GU toxicity and pretreatment prostate reductive procedures ( P<.0001 ) , prostate volume ( P=.0085 ) , pretreatment α-blockers ( P=.0067 ) , diabetes ( P=.0195 ) , and dose-volume histogram parameters ( P=.0208 ) . The median International Prostate Symptom Scores pretreatment scores and scores at 5 years after treatment were 7 and 7 , respectively . The mean Exp and ed Prostate Cancer Index Composite ( EPIC ) scores significantly declined for sexual summary for patients not receiving ADT ( from 67 to 53 ) between baseline and 5 years . CONCLUSIONS Image guided PT provided excellent biochemical control rates for patients with localized prostate cancer . The actuarial rates of high- grade toxicity were low after PT . From pretreatment to 5 years of follow-up , a significant decline was found only in mean EPIC sexual summary scores . Prospect i ve clinical studies are needed to determine the comparative effectiveness of PT and other radiation treatment strategies BACKGROUND In 2007 , we began the r and omised phase 3 multicentre HYPRO trial to investigate the effect of hypofractionated radiotherapy compared with conventionally fractionated radiotherapy on relapse-free survival in patients with prostate cancer . Here , we examine whether patients experience differences in acute gastrointestinal and genitourinary adverse effects . METHODS In this r and omised non-inferiority phase 3 trial , done in seven radiotherapy centres in the Netherl and s , we enrolled intermediate-risk or high-risk patients aged between 44 and 85 years with histologically confirmed stage T1b-T4 NX-0MX-0 prostate cancer , a PSA concentration of 60 ng/mL or lower , and WHO performance status of 0 - 2 . A web-based application was used to r and omly assign ( 1:1 ) patients to receive either st and ard fractionation with 39 fractions of 2 Gy in 8 weeks ( five fractions per week ) or hypofractionation with 19 fractions of 3·4 Gy in 6·5 weeks ( three fractions per week ) . R and omisation was done with minimisation procedure , stratified by treatment centre and risk group . The primary endpoint is 5-year relapse-free survival . Here we report data for the acute toxicity outcomes : the cumulative incidence of grade 2 or worse acute and late genitourinary and gastrointestinal toxicity . Non-inferiority of hypofractionation was tested separately for genitourinary and gastrointestinal acute toxic effects , with a null hypothesis that cumulative incidences of each type of adverse event were not more than 8 % higher in the hypofractionation group than in the st and ard fractionation group . We scored acute genitourinary and gastrointestinal toxic effects according to RTOG-EORTC criteria from both case report forms and patients ' self- assessment question naires , at baseline , twice during radiotherapy , and 3 months after completion of radiotherapy . Analyses were done in the intention-to-treat population . Patient recruitment has been completed . This study is registered with www.controlled-trials.com , number IS RCT N85138529 . FINDINGS Between March 19 , 2007 , and Dec 3 , 2010 , 820 patients were r and omly assigned to treatment with st and ard fractionation ( n=410 ) or hypofractionation ( n=410 ) . 3 months after radiotherapy , 73 ( 22 % ) patients in the st and ard fractionation group and 75 ( 23 % ) patients in the hypofractionation group reported grade 2 or worse genitourinary toxicity ; grade 2 or worse gastrointestinal toxicity was noted in 43 ( 13 % ) patients in the st and ard fractionation group and in 42 ( 13 % ) in the hypofractionation group . Grade 4 acute genitourinary toxicity was reported for two patients , one ( < 1 % ) in each group . No grade 4 acute gastrointestinal toxicities were observed . We noted no significant difference in cumulative incidence by 120 days after radiotherapy of grade 2 or worse acute genitourinary toxicity ( 57·8 % [ 95 % CI 52·9 - 62·7 ] in the st and ard fractionation group vs 60·5 % ( 55·8 - 65·3 ) in the hypofractionation group ; difference 2·7 % , 90 % CI -2·99 to 8·48 ; odds ratio [ OR ] 1·12 , 95 % CI 0·84 - 1·49 ; p=0·43 ) . The cumulative incidence of grade 2 or worse acute gastrointestinal toxicity by 120 days after radiotherapy was higher in patients given hypofractionation ( 31·2 % [ 95 % CI 26·6 - 35·8 ] in the st and ard fractionation group vs 42·0 % [ 37·2 - 46·9 ] in the hypofractionation group ; difference 10·8 % , 90 % CI 5·25 - 16·43 ; OR 1·6 ; p=0·0015 ; non-inferiority not confirmed ) . INTERPRETATION Hypofractionated radiotherapy was not non-inferior to st and ard fractionated radiotherapy in terms of acute genitourinary and gastrointestinal toxicity for men with intermediate-risk and high-risk prostate cancer . In fact , the cumulative incidence of grade 2 or worse acute gastrointestinal toxicity was significantly higher in patients given hypofractionation than in those given st and ard fractionated radiotherapy . Patients remain in follow-up for efficacy endpoints . FUNDING The Dutch Cancer Society INTRODUCTION This trial r and omly assessed short-term adjuvant hormonal therapy added to radiotherapy ( RT ) for intermediate- and high-risk ( UICC 1997 cT2a or cT1b-c with high PSA or Gleason score ) localised prostate cancer . We report acute toxicity ( CTCAE v2 ) assessed weekly during RT in relation to radiation parameters . PATIENTS AND METHODS Centres selected the RT dose ( 70 , 74 or 78Gy ) and RT technique . Statistical significance is at 0.05 . RESULTS Of 791 patients , 652 received 3D-CRT ( 70Gy : 195 , 74Gy : 376 , 78Gy : 81 ) and 139 received IMRT ( 74Gy : 28 , 78Gy : 111 ) . During RT , grade 3 gastrointestinal ( GI ) and genitourinary ( GU ) toxicities were reported by 7 ( 0.8 % ) and 50 ( 6.3 % ) patients , respectively . No grade 4 was reported . The risk of grade 2 GI toxicity increased significantly with increasing D50%-rectum ( p=0.004 ) and that of grade 2 GU toxicity correlated only to Dmax-bladder ( p=0.051 ) . 3D-RT technique , increasing total dose and V95 % > 400 cc increased D50 % and Dmax . One month after RT , only 14 patients ( 1.8 % ) reported grade 3 toxicity . AST did not seem to influence the risk of GU or GI acute toxicity . CONCLUSION RT up to 78Gy was well tolerated . Dmax-bladder and D50%-rectum influenced the risk of grade 2 GU toxicity and GI toxicity , respectively . Both were lower with IMRT but remained high for an irradiated RT volume>400 cc for 3D-RT and for a dose of 78Gy . Hormonal treatment did not influence acute toxicity BACKGROUND AND PURPOSE Urinary toxicity plays a major role in the quality of life ( QOL ) of patients treated with external beam radiotherapy as primary therapy for prostate cancer . In this study we report on : ( 1 ) Incidence of acute and late GU toxicity after intensity modulated radiotherapy ( IMRT ) for prostate cancer at Ghent University Hospital ( GUH ) . ( 2 ) Time evolution of pre-IMRT and IMRT-induced acute and late GU toxicity . MATERIAL S AND METHODS At GUH , 260 patients with a follow-up of > or = 12 months were treated with IMRT for prostate cancer . The incidence and evolution of GU toxicity were recorded . RESULTS Acute grade s 3 , 2 and 1 GU toxicity occurred in 8 % , 42 % and 42 % of the patients , respectively . Late grade s 3 , 2 and 1 GU toxicity occurred in 3 % , 19 % and 40 % of the patients , respectively . During therapy baseline grade 1 symptoms increased into grade 2 acute GU toxicity in 48 % . After 1 and 2 years , 60 % and 70 % of the patients , respectively , had less GU symptoms when compared to the pre-treatment status . CONCLUSION IMRT induces mild GU toxicity . There is an improvement in pre-IMRT obstructive miction disorders PURPOSE To determine the potential advantage of and rogen ablation following st and ard external-beam radiation therapy in patients with locally advanced ( clinical or pathologic T3 ; clinical or pathologic node positive ) carcinoma of the prostate . METHODS AND MATERIAL S In 1987 the RTOG initiated a Phase III trial of long-term adjuvant goserelin in definitively irradiated patients with carcinoma of the prostate . A total of 977 patients were accrued to the study of which 945 remain analyzable : 477 on the adjuvant hormone arm ( Arm I ) ; and 468 on the radiation only arm ( Arm II ) with hormones initiated at relapse . The initial results were reported in the Journal of Clinical Oncology in 1997 . RESULTS With a median follow up of 5.6 years for all patients and 6.0 years for living patients local failure at 8 years was 23 % for Arm I and 37 % for Arm II ( p < 0.0001 ) . Distant metastasis was likewise favorably impacted with the immediate use of hormonal manipulation with a distant metastasis rate in Arm I of 27 % and 37 % in Arm II ( p < 0.0001 ) . Disease-free survival ( NED survival ) and NED survival with PSA of 1.5 ng/mL ( bNED ) or less were both statistically significant in favor of the immediate hormone arm ( both p < 0.0001 ) . Cause-specific failure was not statistically different with a cause-specific failure of 16 % for Arm I and 21 % in Arm II ( p = 0.23 ) . Overall survival was likewise not statistically different between two arms , with a 49 % overall survival at 8 years in Arm I and 47 % in Arm II ( p = 0.36 ) . Subset analysis of central ly review ed Gleason 8 - 10 patients who did not undergo prostatectomy showed that for patients receiving radiation therapy plus adjuvant hormones there was a statistically significant improvement in both absolute ( p = 0.036 ) and cause-specific survival ( p = 0.019 ) . CONCLUSIONS Use of long-term adjuvant and rogen deprivation in addition to definitive radiation therapy results in a highly significant improvement in regards to local control , freedom from distant metastasis , and biochemical free survival in unfavorable prognosis patients with carcinoma of the prostate OBJECTIVE To compare outcomes of open ( O- ) , laparoscopic ( L- ) and robot-assisted laparoscopic ( RAL- ) radical prostatectomy ( RP ) performed by the same surgeon . PATIENTS AND METHODS From May 1999 to April 2012 , 484 RPs were performed by a single surgeon . Patients ' data including age , body-mass index , serum prostate specific antigen ( PSA ) level , Gleason score of prostate biopsy and prostatectomy specimen , preoperative prostate and specimen volumes , clinical and pathologic stages , operation time , estimated blood loss ( EBL ) , catheterization time , blood transfusion rate were recorded . Prospect ively collected data was evaluated retrospectively by statistical analyses . RESULTS Of 484 radical prostatectomies , ORP ( 50 ) , LRP ( 308 ) and RALRP ( 79 ) done by the same surgeon were included into study . Mean ages were 63.8 , 62.7 and 60.3 years for ORP , LRP and RALRP respectively . Operation times for ORP , LRP and RALRP were 255 , 208 and 242 minutes . EBL and hospitalization time were 602 , 526 , 234 mL , and 9.1 , 3.2 , 3.2 days for ORP , LRP and RALRP , respectively . While a significant advantage was found for EBL and complication rates in RALRP and for operation time in LRP , significant disadvantages were found in terms of catheterization time , hospitalization time , decrease in hemoglobin and blood transfusion in ORP . However , preoperative prostate volume and serum PSA level , oncologic outcomes and positive surgical margins were nearly similar in all operative techniques . CONCLUSIONS Minimally invasive techniques such as LRP and RALRP are promising techniques with comparable outcomes with ORP . Shorter catheterization time , less blood loss and fewer complication rates can be provided by RALRP PURPOSE To initiate a phase 1/2 trial to examine the tolerability of a condensed combined-modality protocol for high-risk prostate cancer . METHODS AND MATERIAL S Men scoring ≥3 on the Vulnerable Elderly Scale ( VES ) or refusing conventionally fractionated treatment for high-risk prostate cancer were eligible to participate . And rogen suppression was delivered for 12 months , and radiation therapy was delivered using 25 Gy to pelvic nodes delivered synchronously with 40 Gy to the prostate given as 1 fraction per week over 5 weeks . The phase 1 component included predetermined stopping rules based on 6-month treatment-related toxicity , with trial suspension specified if there were ≥6 of 15 patients ( 40 % ) or ≥3 of 15 ( 20 % ) who experienced grade ≥2 or ≥3 gastrointestinal ( GI ) or genitourinary ( GU ) toxicity , respectively . RESULTS Sixteen men were enrolled , with 7 men meeting the criteria of VES ≥3 and 9 men having a VES <3 but choosing the condensed treatment . One man was not treated owing to discovery of a synchronous primary rectal cancer . Four patients ( 26 % ) experienced grade ≥2 toxicity at 6 weeks after treatment . There were 9 of 15 ( 60 % ) who experienced grade ≥2 GI or GU toxicity and 4 of 15 ( 26 % ) grade ≥3 GI or GU toxicity at 6 months , and 5 of 15 ( 30 % ) grade ≥2 GI and GU toxicity at 6 months . A review of the 15 cases did not identify any remedial changes , thus the phase 1 criteria were not met . CONCLUSION This novel condensed treatment had higher than anticipated late toxicities and was terminated before phase 2 accrual . Treatment factors , such as inclusion of pelvic lymph node radiation therapy , planning constraints , and treatment margins , or patient factors related to the specific frail elderly population may be contributing Purpose To assess the clinical efficacy and toxicity of whole pelvic intensity-modulated radiotherapy ( WP-IMRT ) for high-risk prostate cancer . Material s and Methods Patients with high-risk prostate cancer treated between 2008 and 2013 were review ed . The study included patients who had undergone WP-IMRT with image guidance using electronic portal imaging devices and /or cone-beam computed tomography . The endorectal balloon was used in 93 % of patients . Patients received either 46 Gy to the whole pelvis plus a boost of up to 76 Gy to the prostate in 2 Gy daily fractions , or 44 Gy to the whole pelvis plus a boost of up to 72.6 Gy to the prostate in 2.2 Gy fractions . Results The study cohort included 70 patients , of whom 55 ( 78 % ) had a Gleason score of 8 to 10 and 50 ( 71 % ) had a prostate-specific antigen level > 20 ng/mL. The and rogen deprivation therapy was combined in 62 patients . The biochemical failure-free survival rate was 86.7 % at 2 years . Acute any grade gastrointestinal ( GI ) and genitourinary ( GU ) toxicity rates were 47 % and 73 % , respectively . The actuarial rate of late grade 2 or worse toxicity at 2 years was 12.9 % for GI , and 5.7 % for GU with no late grade 4 toxicity . Conclusion WP-IMRT was well tolerated with no severe acute or late toxicities , result ing in at least similar biochemical control to that of the historic control group with a small field . The long-term efficacy and toxicity will be assessed in the future , and a prospect i ve r and omized trial is needed to verify these findings Background The α/β ratio for prostate cancer is postulated being in the range of 0.8 to 2.2 Gy , giving rise to the hypothesis that there may be a therapeutic advantage to hypofractionation . To do so , we carried out a r and omized trial comparing hypofractionated and conventionally fractionated image-guided intensity modulated radiotherapy ( IG-IMRT ) in high-risk prostate cancer . Here , we report on acute toxicity and quality of life ( QOL ) for the first 124 r and omized patients . Methods The trial compares 76 Gy in 38 fractions ( 5 fractions/week ) ( Arm 1 ) to 63 Gy in 20 fractions ( 4 fractions/week ) ( Arm 2 ) ( IG-IMRT ) . Prophylactic pelvic lymph node irradiation with 46 Gy in 23 fractions sequentially ( Arm 1 ) and 44 Gy in 20 fractions simultaneously ( Arm 2 ) was applied . All patients had long term and rogen deprivation therapy ( ADT ) started before RT . Both physician-rated acute toxicity and patient-reported QOL using EPIC question naire are described . Results There were no differences in overall maximum acute gastrointestinal ( GI ) or genitourinary ( GU ) toxicity . Compared to conventional fractionation ( Arm 1 ) , GI and GU toxicity both developed significantly earlier but also disappeared earlier in the Arm 2 , reaching significant differences from Arm 1 at week 8 and 9 . In multivariate analyses , only parameter shown to be related to increased acute Grade ≥1 GU toxicity was the study Arm 2 ( p = 0.049 ) . There were no statistically significant differences of mean EPIC scores in any domain and sub-scales . The clinical ly relevant decrease ( CRD ) in EPIC urinary domain was significantly higher in Arm 2 at month 1 with a faster recovery at month 3 as compared to Arm 1 . Conclusions Hypofractionation at 3.15 Gy per fraction to 63 Gy within 5 weeks was well tolerated . The GI and GU physician-rated acute toxicity both developed earlier but recovered faster using hypofractionation . There was a correlation between acute toxicity and bowel and urinary QOL outcomes . Longer follow-up is needed to determine the significance of these associations with late toxicity PURPOSE Toxicity concerns have limited pelvic nodal prescriptions to doses that may be suboptimal for controlling microscopic disease . In a prospect i ve trial , we tested whether image-guided intensity-modulated radiation therapy ( IMRT ) can safely deliver escalated nodal doses while treating the prostate with hypofractionated radiotherapy in 5½ weeks . METHODS AND MATERIAL S Pelvic nodal and prostatic image-guided IMRT was delivered to 53 National Comprehensive Cancer Network ( NCCN ) high-risk patients to a nodal dose of 56 Gy in 2-Gy fractions with concomitant treatment of the prostate to 70 Gy in 28 fractions of 2.5 Gy , and 50 of 53 patients received and rogen deprivation for a median duration of 12 months . RESULTS The median follow-up time was 25.4 months ( range , 4.2 - 57.2 ) . No early Grade 3 Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events v.3.0 genitourinary ( GU ) or gastrointestinal ( GI ) toxicities were seen . The cumulative actuarial incidence of Grade 2 early GU toxicity ( primarily alpha blocker initiation ) was 38 % . The rate was 32 % for Grade 2 early GI toxicity . None of the dose-volume descriptors correlated with GU toxicity , and only the volume of bowel receiving ≥30 Gy correlated with early GI toxicity ( p = 0.029 ) . Maximum late Grade s 1 , 2 , and 3 GU toxicities were seen in 30 % , 25 % , and 2 % of patients , respectively . Maximum late Grade s 1 and 2 GI toxicities were seen in 30 % and 8 % ( rectal bleeding requiring cautery ) of patients , respectively . The estimated 3-year biochemical control ( nadir + 2 ) was 81.2 ± 6.6 % . No patient manifested pelvic nodal failure , whereas 2 experienced paraaortic nodal failure outside the field . The six other clinical failures were distant only . CONCLUSIONS Pelvic IMRT nodal dose escalation to 56 Gy was delivered concurrently with 70 Gy of hypofractionated prostate radiotherapy in a convenient , re source -efficient , and well-tolerated 28-fraction schedule . Pelvic nodal dose escalation may be an option in any future exploration of potential benefits of pelvic radiation therapy in high-risk prostate cancer patients OBJECTIVES We analysed the acute toxicity observed in the European Organisation for Research and Treatment of Cancer ( EORTC ) r and omised trial 22863 comparing conventional external irradiation with or without an agonist analogue of gonadotropin-releasing hormone in high-risk prostate cancer patients . METHODS Four hundred five patients that received a dose of at least 30 Gy were considered evaluable for acute toxicity assessment . Toxicity was grouped in a few categories : general , genito-urinary , and lower gastro-intestinal . Univariate and multivariate analyses were performed using the World Health Organisation ( WHO ) toxicity score and grouping together toxicity scores in different bimodal and trimodal groups . RESULTS Overall , our data show that age , previous surgery and irradiation dose are important predictive factors for acute toxicity , but not the use of combined hormone therapy . Fifteen percent of patients suffered of moderate to severe acute toxicity ( WHO G3-G4 ) . Life threatening toxicity was observed in six cases ( 1.5 % ) . CONCLUSIONS The assessment of toxicity combining in different groups the original five scores scale produced conflicting results similar to those commonly reported in literature . Interpretation of the role of pre-treatment factors with uneven distribution in the study requires careful evaluation . These data obtained with conventional curative irradiation of high-risk prostate cancer patients are proposed for comparison with results achieved using modern state-of-the-art irradiation techniques BACKGROUND The optimum duration of and rogen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined . We aim ed to determine whether long-term and rogen deprivation was superior to short-term and rogen deprivation when combined with high-dose radiotherapy . METHODS In this open-label , multicentre , phase 3 r and omised controlled trial , patients were recruited from ten university hospitals throughout Spain . Eligible patients had clinical stage T1c-T3b N0M0 prostate adenocarcinoma with intermediate-risk and high-risk factors according to 2005 National Comprehensive Cancer Network criteria . Patients were r and omly assigned ( 1:1 ) using a computer-generated r and omisation schedule to receive either 4 months of and rogen deprivation combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy ( range 76 - 82 Gy ; short-term and rogen deprivation group ) or the same treatment followed by 24 months of adjuvant and rogen deprivation ( long-term and rogen deprivation group ) , stratified by prostate cancer risk group ( intermediate risk vs high risk ) and participating centre . Patients assigned to the short-term and rogen deprivation group received 4 months of neoadjuvant and concomitant and rogen deprivation with subcutaneous goserelin ( 2 months before and 2 months combined with high-dose radiotherapy ) . Anti- and rogen therapy ( flutamide 750 mg per day or bicalutamide 50 mg per day ) was added during the first 2 months of treatment . Patients assigned to long-term suppression continued with the same luteinising hormone-releasing hormone analogue every 3 months for another 24 months . The primary endpoint was biochemical disease-free survival . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT02175212 . FINDINGS Between Nov 7 , 2005 , and Dec 20 , 2010 , 178 patients were r and omly assigned to receive short-term and rogen deprivation and 177 to receive long-term and rogen deprivation . After a median follow-up of 63 months ( IQR 50 - 82 ) , 5-year biochemical disease-free survival was significantly better among patients receiving long-term and rogen deprivation than among those receiving short-term treatment ( 90 % [ 95 % CI 87 - 92 ] vs 81 % [ 78 - 85 ] ; hazard ratio [ HR ] 1·88 [ 95 % CI 1·12 - 3·15 ] ; p=0·01 ) . 5-year overall survival ( 95 % [ 95 % CI 93 - 97 ] vs 86 % [ 83 - 89 ] ; HR 2·48 [ 95 % CI 1·31 - 4·68 ] ; p=0·009 ) and 5-year metastasis-free survival ( 94 % [ 95 % CI 92 - 96 ] vs 83 % [ 80 - 86 ] ; HR 2·31 [ 95 % CI 1·23 - 3·85 ] ; p=0·01 ) were also significantly better in the long-term and rogen deprivation group than in the short-term and rogen deprivation group . The effect of long-term and rogen deprivation on biochemical disease-free survival , metastasis-free survival , and overall survival was more evident in patients with high-risk disease than in those with low-risk disease . Grade 3 late rectal toxicity was noted in three ( 2 % ) of 177 patients in the long-term and rogen deprivation group and two ( 1 % ) of 178 in the short-term and rogen deprivation group ; grade 3 - 4 late urinary toxicity was noted in five ( 3 % ) patients in each group . No deaths related to treatment were reported . INTERPRETATION Compared with short-term and rogen deprivation , 2 years of adjuvant and rogen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer , particularly those with high-risk disease , with no increase in late radiation toxicity . Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of and rogen deprivation . FUNDING Spanish National Health Investigation Fund , AstraZeneca CONTEXT Clinical ly localized prostate cancer is very prevalent among US men , but recurrence after treatment with conventional radiation therapy is common . OBJECTIVE To evaluate the hypothesis that increasing the radiation dose delivered to men with clinical ly localized prostate cancer improves disease outcome . DESIGN , SETTING , AND PATIENTS R and omized controlled trial of 393 patients with stage T1b through T2b prostate cancer and prostate-specific antigen ( PSA ) levels less than 15 ng/mL r and omized between January 1996 and December 1999 and treated at 2 US academic institutions . Median age was 67 years and median PSA level was 6.3 ng/mL. Median follow-up was 5.5 ( range , 1.2 - 8.2 ) years . INTERVENTION Patients were r and omized to receive external beam radiation to a total dose of either 70.2 Gy ( conventional dose ) or 79.2 Gy ( high dose ) . This was delivered using a combination of conformal photon and proton beams . MAIN OUTCOME MEASURE Increasing PSA level ( ie , biochemical failure ) 5 years after treatment . RESULTS The proportions of men free from biochemical failure at 5 years were 78.8 % [ corrected ] ( 95 % confidence interval , 73.1%-84.6 % ) [ corrected ] for conventional-dose and 91.3 % [ corrected ] ( 95 % confidence interval , 87.2%-95.4 % ) [ corrected ] for high-dose therapy ( P<.001 ) , a 59 % [ corrected ] reduction in the risk of failure . The advantage to high-dose therapy was statistically significant [ corrected ] in both the low-risk subgroup [ corrected ] ( risk reduction , 84 % [ P<.001 ] ) [ corrected ] There has been no significant difference in overall survival rates between the treatment groups . Only 1 % of patients receiving conventional-dose and 2 % receiving high-dose radiation experienced acute urinary or rectal morbidity of Radiation Therapy Oncology Group ( RTOG ) grade 3 or greater . So far , only 2 % and 1 % , respectively , have experienced late morbidity of RTOG grade 3 or greater . CONCLUSIONS Men with clinical ly localized prostate cancer have a lower risk of biochemical failure if they receive high-dose rather than conventional-dose conformal radiation . This advantage was achieved without any associated increase in RTOG grade 3 acute or late urinary or rectal morbidity PURPOSE To report the long-term results of a r and omized radiotherapy dose escalation trial for prostate cancer . METHODS AND MATERIAL S From 1993 to 1998 , a total of 301 patients with stage T1b to T3 prostate cancer were accrued to a r and omized external beam dose escalation trial using 70 Gy versus 78 Gy . The median follow-up is now 8.7 years . Kaplan-Meier analysis was used to compute rates of prostate-specific antigen ( PSA ) failure ( nadir + 2 ) , clinical failure , distant metastasis , disease-specific , and overall survival as well as complication rates at 8 years post-treatment . RESULTS For all patients , freedom from biochemical or clinical failure ( FFF ) was superior for the 78-Gy arm , 78 % , as compared with 59 % for the 70-Gy arm ( p = 0.004 , and an even greater benefit was seen in patients with initial PSA > 10 ng/ml ( 78 % vs. 39 % , p = 0.001 ) . The clinical failure rate was significantly reduced in the 78-Gy arm as well ( 7 % vs. 15 % , p = 0.014 ) . Twice as many patients either died of prostate cancer or are currently alive with cancer in the 70-Gy arm . Gastrointestinal toxicity of grade 2 or greater occurred twice as often in the high dose patients ( 26 % vs. 13 % ) , although genitourinary toxicity of grade 2 or greater was less ( 13 % vs. 8 % ) and not statistically significantly different . Dose-volume histogram analysis showed that the complication rate could be significantly decreased by reducing the amount of treated rectum . CONCLUSIONS Modest escalation in radiotherapy dose improved freedom from biochemical and clinical progression with the largest benefit in prostate cancer patients with PSA > 10 ng/ml PURPOSE To report the acute and late toxicities of patients with high-risk localized prostate cancer treated using a concomitant hypofractionated , intensity-modulated radiotherapy boost combined with long-term and rogen deprivation therapy . METHODS AND MATERIAL S A prospect i ve Phase I-II study of patients with any of the following : clinical Stage T3 disease , prostate-specific antigen level ≥ 20 ng/mL , or Gleason score 8 - 10 . A dose of 45 Gy ( 1.8 Gy/fraction ) was delivered to the pelvic lymph nodes with a concomitant 22.5 Gy prostate intensity-modulated radiotherapy boost , to a total of 67.5 Gy ( 2.7 Gy/fraction ) in 25 fractions within 5 weeks . Image guidance was performed using three gold seed fiducials . The National Cancer Institute Common Terminology Criteria for Adverse Events , version 3.0 , and Radiation Therapy Oncology Group late morbidity scores were used to assess the acute and late toxicities , respectively . Biochemical failure was determined using the Phoenix definition . RESULTS A total of 97 patients were treated and followed up for a median of 39 months , with 88 % having a minimum of 24 months of follow-up . The maximal toxicity scores were recorded . The grade of acute gastrointestinal toxicity was Grade 0 in 4 % , 1 in 59 % , and 2 in 37 % . The grade of acute urinary toxicity was Grade 0 in 8 % , 1 in 50 % , 2 in 39 % , and 3 in 4 % . The grade of late gastrointestinal toxicity was Grade 0 in 54 % , 1 in 40 % , and 2 in 7 % . No Grade 3 or greater late gastrointestinal toxicities developed . The grade of late urinary toxicity was Grade 0 in 82 % , 1 in 9 % , 2 in 5 % , 3 in 3 % , and 4 in 1 % ( 1 patient ) . All severe toxicities ( Grade 3 or greater ) had resolved at the last follow-up visit . The 4-year biochemical disease-free survival rate was 90.5 % . CONCLUSIONS A hypofractionated intensity-modulated radiotherapy boost delivering 67.5 Gy in 25 fractions within 5 weeks combined with pelvic nodal radiotherapy and long-term and rogen deprivation therapy was well tolerated , with low rates of severe toxicity . The biochemical control rate at early follow-up has been promising . Additional follow-up is needed to determine the long-term biochemical control and prostate biopsy results PURPOSE To determine whether a dose of 78 Gy improves outcome compared with a conventional dose of 68 Gy for prostate cancer patients treated with three-dimensional conformal radiotherapy . PATIENTS AND METHODS Between June 1997 and February 2003 , stage T1b-4 prostate cancer patients were enrolled onto a multicenter r and omized trial comparing 68 Gy with 78 Gy . Patients were stratified by institution , age , (neo)adjuvant hormonal therapy ( HT ) , and treatment group . Four treatment groups ( with specific radiation volumes ) were defined based on the probability of seminal vesicle involvement . The primary end point was freedom from failure ( FFF ) . Failure was defined as clinical failure or biochemical failure , according to the American Society of Therapeutic Radiation Oncology definition . Other end points were freedom from clinical failure ( FFCF ) , overall survival ( OS ) , and toxicity . RESULTS Median follow-up time was 51 months . Of the 669 enrolled patients , 664 were included in the analysis . HT was prescribed for 143 patients . FFF was significantly better in the 78-Gy arm compared with the 68-Gy arm ( 5-year FFF rate , 64 % v 54 % , respectively ) , with an adjusted hazard ratio of 0.74 ( P = .02 ) . No significant differences in FFCF or OS were seen between the treatment arms . There was no difference in late genitourinary toxicity of Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer grade 2 or more and a slightly higher nonsignificant incidence of late gastrointestinal toxicity of grade 2 or more . CONCLUSION This multicenter r and omized trial shows a significantly improved FFF in prostate cancer patients treated with a higher dose of radiotherapy PURPOSE Assessment of and rogen deprivation therapy ( ADT ) benefits for prostate cancer treated with dose-escalated radiotherapy ( RT ) . METHODS AND MATERIAL S From 1991 to 2004 , 1,044 patients with intermediate- ( n = 782 ) or high-risk ( n = 262 ) prostate cancer were treated with dose-escalated RT at William Beaumont Hospital . Patients received external-beam RT ( EBRT ) alone , brachytherapy ( high or low dose rate ) , or high dose rate brachytherapy plus pelvic EBRT . Intermediate-risk patients had Gleason score 7 , prostate-specific antigen ( PSA ) 10.0 - 19.9 ng/mL , or Stage T2b-T2c . High-risk patients had Gleason score 8 - 10 , PSA ≥20 , or Stage T3 . Patients were additionally divided specifically by Gleason score , presence of palpable disease , and PSA level to further define subgroups benefitting from ADT . RESULTS Median follow-up was 5 years ; 420 patients received ADT + dose-escalated RT , and 624 received dose-escalated RT alone . For all patients , no advantages in any clinical endpoints at 8 years were associated with ADT administration . No differences in any endpoints were associated with ADT administration based on intermediate- vs. high-risk group or RT modality when analyzed separately . Patients with palpable disease plus Gleason ≥8 demonstrated improved clinical failure rates and a trend toward improved survival with ADT . Intermediate-risk patients treated with brachytherapy alone had improved biochemical control when ADT was given . CONCLUSION Benefits of ADT in the setting of dose-escalated RT remain poorly defined . This question must continue to be addressed in prospect i ve study AIM To compare toxicity profiles of two different intensity-modulated radiation therapy ( IMRT ) strategies in patients with high-risk prostate cancer . PATIENTS AND METHODS From May 2010 to September 2012 , 43 patients with high-risk prostate cancer were treated with IMRT and concurrent hormone therapy ; 23 patients were treated by conventional fractionation ( IMRT/C ) and 20 patients by simultaneous integrated boost ( IMRT/SIB ) . Acute and late toxicities were compared for each group . RESULTS Severe acute genitourinary toxicity was recorded in 8.6 % and 2 % of patients in the IMRT/C and IMRT/SIB group , respectively . Genitourinary toxicity G2 was observed in 39.1 % ( IMRT/C group ) and 25 % ( IMRT/SIB group ) of patients . Severe acute gastrointestinal toxicity was not observed ; Grade 2 acute gastrointestinal toxicity was recorded in 21.7 % ( IMRT/C group ) and 10 % ( IMRT/SIB group ) . Grade 2 late genitourinary toxicity was observed in 26 % ( IMRT/C group ) and 15 % ( IMRT/SIB group ) , whereas G2 late gastrointestinal toxicity in 34.5 % and 30 % of patients , respectively . No significant differences in incidence and severity of genitourinary and gastrointestinal toxicity were detected between the two IMRT treatment strategies . CONCLUSION IMRT/SIB was well-tolerated with favorable rates of acute and late toxicity , both genitourinary and gastrointestinal . Compared to IMRT/C , IMRT/SIB maintained the same efficacy and reduced the overall treatment time BACKGROUND The TROG 96.01 trial assessed whether 3-month and 6-month short-term neoadjuvant and rogen deprivation therapy ( NADT ) decreases clinical progression and mortality after radiotherapy for locally advanced prostate cancer . Here we report the 10-year results . METHODS Between June , 1996 , and February , 2000 , 818 men with T2b , T2c , T3 , and T4 N0 M0 prostate cancers were r and omly assigned to receive radiotherapy alone , 3 months of NADT plus radiotherapy , or 6 months of NADT plus radiotherapy . The radiotherapy dose for all groups was 66 Gy , delivered to the prostate and seminal vesicles ( excluding pelvic nodes ) in 33 fractions of 2 Gy per day ( excluding weekends ) over 6·5 - 7·0 weeks . NADT consisted of 3·6 mg goserelin given subcutaneously every month and 250 mg flutamide given orally three times a day . NADT began 2 months before radiotherapy for the 3-month NADT group and 5 months before radiotherapy for the 6-month NADT group . Primary endpoints were prostate-cancer-specific mortality and all-cause mortality . Treatment allocation was open label and r and omisation was done with a minimisation technique according to age , clinical stage , tumour grade , and initial prostate-specific antigen concentration ( PSA ) . Analysis was by intention-to-treat . The trial has been closed to follow-up and all main endpoint analyses are completed . The trial is registered with the Australian New Zeal and Clinical Trials Registry , number ACTRN12607000237482 . FINDINGS 802 men were eligible for analysis ( 270 in the radiotherapy alone group , 265 in the 3-month NADT group , and 267 in the 6-month NADT group ) after a median follow-up of 10·6 years ( IQR 6·9 - 11·6 ) . Compared with radiotherapy alone , 3 months of NADT decreased the cumulative incidence of PSA progression ( adjusted hazard ratio 0·72 , 95 % CI 0·57 - 0·90 ; p=0·003 ) and local progression ( 0·49 , 0·33 - 0·73 ; p=0·0005 ) , and improved event-free survival ( 0·63 , 0·52 - 0·77 ; p<0·0001 ) . 6 months of NADT further reduced PSA progression ( 0·57 , 0·46 - 0·72 ; p<0·0001 ) and local progression ( 0·45 , 0·30 - 0·66 ; p=0·0001 ) , and led to a greater improvement in event-free survival ( 0·51 , 0·42 - 0·61 , p<0·0001 ) , compared with radiotherapy alone . 3-month NADT had no effect on distant progression ( 0·89 , 0·60 - 1·31 ; p=0·550 ) , prostate cancer-specific mortality ( 0·86 , 0·60 - 1·23 ; p=0·398 ) , or all-cause mortality ( 0·84 , 0·65 - 1·08 ; p=0·180 ) , compared with radiotherapy alone . By contrast , 6-month NADT decreased distant progression ( 0·49 , 0·31 - 0·76 ; p=0·001 ) , prostate cancer-specific mortality ( 0·49 , 0·32 - 0·74 ; p=0·0008 ) , and all-cause mortality ( 0·63 , 0·48 - 0·83 ; p=0·0008 ) , compared with radiotherapy alone . Treatment-related morbidity was not increased with NADT within the first 5 years after r and omisation . INTERPRETATION 6 months of neoadjuvant and rogen deprivation combined radiotherapy is an effective treatment option for locally advanced prostate cancer , particularly in men without nodal metastases or pre-existing metabolic comorbidities that could be exacerbated by prolonged and rogen deprivation . FUNDING Australian Government National Health and Medical Research Council , Hunter Medical Research Institute , AstraZeneca , and Schering-Plough BACKGROUND We did a r and omised phase III trial comparing external irradiation alone and external irradiation combined with an analogue of luteinising-hormone releasing hormone ( LHRH ) to investigate the added value of long-term and rogen suppression in locally advanced prostate cancer . METHODS Between 1987 and 1995 , 415 patients were r and omly assigned radiotherapy alone or radiotherapy plus immediate and rogen suppression . Eligible patients had T1 - 2 tumours of WHO grade 3 or T3 - 4 N0 - 1 M0 tumours ; the median age of participants was 71 years ( range 51 - 80 ) . In both treatment groups , 50 Gy radiation was delivered to the pelvis over 5 weeks , and 20 Gy over 2 weeks as a prostatic boost . Goserelin ( 3.6 mg subcutaneously every 4 weeks ) was started on the first day of irradiation and continued for 3 years ; cyproterone acetate ( 150 mg orally ) was given for 1 month starting 1 week before the first goserelin injection . The primary endpoint was clinical disease-free survival . Analyses were by intention to treat . FINDINGS 412 patients had evaluable data , with median follow-up of 66 months ( range 1 - 126 ) . 5-year clinical disease-free survival was 40 % ( 95 % CI 32 - 48 ) in the radiotherapy-alone group and 74 % ( 67 - 81 ) in the combined-treatment group ( p=0.0001 ) . 5-year overall survival was 62 % ( 52 - 72 ) and 78 % ( 72 - 84 ) , respectively ( p=0.0002 ) and 5-year specific survival 79 % ( 72 - 86 ) and 94 % ( 90 - 98 ) . INTERPRETATION Immediate and rogen suppression with an LHRH analogue given during and for 3 years after external irradiation improves disease-free and overall survival of patients with locally advanced prostate cancer BACKGROUND AND PURPOSE To determine the efficacy and feasibility of carbon ion radiotherapy ( C-ion RT ) for prostate cancer . PATIENTS AND METHODS Between April 2000 and November 2003 , 175 patients received C-ion RT using a recommended dose fractionation ( 66.0 GyE/20 fractions ) established from prior studies . C-ion RT alone was performed for 33 patients constituting a low-risk group ( Stage < or = T2a and PSA < 20 ng/ml and Gleason score < or = 6 ) ; the remaining 142 high-risk patients received an additional and rogen deprivation therapy ( ADT ) . RESULTS The 4-year overall survival and bNED rates were 91 % and 87 % , respectively . Local control was achieved in all but one patient . The 4-year bNED rates were 87 % in the low-risk group and 88 % in the high-risk group . In very advanced diseases ( Stage > or= T3a or PSA > or= 20 ng/ml or Gleason score > or = 8) , there was significant difference in the bNED rate according to period of ADT administration ( ADT > or = 24 months : 93 % , ADT < 24 months : 73 % , p<0.01 ) . Grade 2 late toxicities developed in 4 patients ( 2 % ) for the rectum and 9 patients ( 5 % ) for the genitourinary system but no Grade 3 or higher toxicity was observed . CONCLUSIONS The effectiveness of C-ion RT for prostate cancer has been well confirmed . Based on these results , new study of a C-ion RT modified for the administration strategy of ADT according to the patient risk has been started by dividing patients into 3 groups , high-risk , intermediate-risk , and low-risk PURPOSE We assessed the outcome of a watchful-waiting protocol with selective delayed intervention by using clinical prostate-specific antigen ( PSA ) , or histologic progression as treatment indications for clinical ly localized prostate cancer . PATIENTS AND METHODS This was a prospect i ve , single-arm , cohort study . Patients were managed with an initial expectant approach . Definitive intervention was offered to those patients with a PSA doubling time of less than 3 years , Gleason score progression ( to 4 + 3 or greater ) , or unequivocal clinical progression . Survival analysis and Cox proportional hazard model were applied to the data . Results A total of 450 patients have been observed with active surveillance . Median follow-up was 6.8 years ( range , 1 to 13 years ) . Overall survival was 78.6 % . The 10-year prostate cancer actuarial survival was 97.2 % . Overall , 30 % of patients have been reclassified as higher risk and have been offered definitive therapy . Of 117 patients treated radically , the PSA failure rate was 50 % , which was 13 % of the total cohort . PSA doubling time of 3 years or less was associated with an 8.5-times higher risk of biochemical failure after definitive treatment compared with a doubling time of more than 3 years ( P < .0001 ) . The hazard ratio for nonprostate cancer to prostate cancer mortality was 18.6 at 10 years . CONCLUSION We observed a low rate of prostate cancer mortality . Among the patients who were reclassified as higher risk and who were treated , PSA failure was relatively common . Other-cause mortality accounted for almost all of the deaths . Additional studies are warranted to improve the identification of patients who harbor more aggressive disease despite favorable clinical parameters at diagnosis PURPOSE This trial was design ed to test the hypothesis that total and rogen suppression and whole pelvic radiotherapy ( WPRT ) followed by a prostate boost improves progression-free survival ( PFS ) by > or = 10 % compared with total and rogen suppression and prostate only RT ( PORT ) . This trial was also design ed to test the hypothesis that neoadjuvant hormonal therapy ( NHT ) followed by concurrent total and rogen suppression and RT improves PFS compared with RT followed by adjuvant hormonal therapy ( AHT ) by > or = 10 % . METHODS AND MATERIAL S Patients eligible for the study included those with clinical ly localized adenocarcinoma of the prostate and an elevated prostate-specific antigen level of < 100 ng/mL. Patients were stratified by T stage , prostate-specific antigen level , and Gleason score and were required to have an estimated risk of lymph node involvement of > 15 % . RESULTS The difference in overall survival for the four arms was statistically significant ( p = 0.027 ) . However , no statistically significant differences were found in PFS or overall survival between NHT vs. AHT and WPRT compared with PORT . A trend towards a difference was found in PFS ( p = 0.065 ) in favor of the WPRT + NHT arm compared with the PORT + NHT and WPRT + AHT arms . CONCLUSIONS Unexpected interactions appear to exist between the timing of hormonal therapy and radiation field size for this patient population . Four Phase III trials have demonstrated better outcomes when NHT was combined with RT compared with RT alone . The Radiation Therapy Oncology Group 9413 trial results have demonstrated that when NHT is used in conjunction with RT , WPRT yields a better PFS than does PORT . It also showed that when NHT + WPRT results in better overall survival than does WPRT + short-term AHT . Additional studies are warranted to determine whether the failure to demonstrate an advantage for NHT + WPRT compared with PORT + AHT is chance or , more likely , reflects a previously unrecognized biologic phenomenon BACKGROUND Several studies have reported a low α to β ratio for prostate cancer , suggesting that hypofractionation could enhance the biological tumour dose without increasing genitourinary and gastrointestinal toxicity . We tested this theory in the phase 3 HYPRO trial for patients with intermediate-risk and high-risk prostate cancer . We have previously reported acute incidence of genitourinary and gastrointestinal toxicity ; here we report data for late genitourinary and gastrointestinal toxicity . METHODS In this r and omised non-inferiority phase 3 trial , done in seven radiotherapy centres in the Netherl and s , we enrolled intermediate-risk or high-risk patients aged between 44 and 85 years with histologically confirmed stage T1b-T4 NX-0MX-0 prostate cancer , a prostate-specific antigen concentration of 60 ng/mL or lower , and WHO performance status of 0 - 2 . A web-based application was used to r and omly assign ( 1:1 ) patients to receive either st and ard fractionation with 39 fractions of 2 Gy in 8 weeks ( five fractions per week ) or hypofractionation with 19 fractions of 3·4 Gy in 6·5 weeks ( three fractions per week ) . R and omisation was done with the minimisation procedure , stratified by treatment centre and risk group . The primary endpoint was to detect a 10 % enhancement in 5-year relapse-free survival with hypofractionation . A key additional endpoint was non-inferiority of hypofractionation in cumulative incidence of grade 2 or worse acute and late genitourinary and gastrointestinal toxicity . We planned to reject inferiority of hypofractionation for late genitourinary toxicity if the estimated hazard ratio ( HR ) was less than 1·11 and for gastrointestinal toxicity was less than 1·13 . We scored toxicity with the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer ( RTOG/EORTC ) criteria from both physicians ' records ( clinical record form ) and patients ' self- assessment question naires . Analyses were done in the intention-to-treat population . Patient recruitment for the HYPRO trial was completed in 2010 . The trial was registered with www.controlled-trials.com , number IS RCT N85138529 . FINDINGS Between March 19 , 2007 , and Dec 3 , 2010 , 820 patients ( 410 in both groups ) were r and omly assigned . Analyses for late toxicity included 387 assessable patients in the st and ard fractionation group and 395 in the hypofractionation group . The median follow-up was 60 months ( IQR 51·2 - 67·3 ) . The data base for all analyses ( both groups and both genitourinary and gastrointestinal toxicities ) was locked on March 26 , 2015 . The incidence of grade 2 or worse genitourinary toxicity at 3 years was 39·0 % ( 95 % CI 34·2 - 44·1 ) in the st and ard fractionation group and 41·3 % ( 36·6 - 46·4 ) in the hypofractionation group . The estimated HR for the cumulative incidence of grade 2 or worse late genitourinary toxicity was 1·16 ( 90 % CI 0·98 - 1·38 ) , suggesting that non-inferiority could not be shown . The incidence of grade 2 or worse gastrointestinal toxicity at 3 years was 17·7 % ( 14·1 - 21·9 ) in st and ard fractionation and 21·9 % ( 18·1 - 26·4 ) hypofractionation . With an estimated HR of 1·19 ( 90 % CI 0·93 - 1·52 ) for the cumulative incidence of grade 2 or worse late gastrointestinal toxicity , we could not confirm non-inferiority of hypofractionation for cumulative late gastrointestinal toxicity . Cumulative grade 3 or worse late genitourinary toxicity was significantly higher in the hypofractionation group than in the st and ard fractionation group ( 19·0 % [ 95 % CI 15·2 - 23·2 ] vs 12·9 % [ 9·7 - 16·7 ] , respectively ; p=0·021 ) , but there was no significant difference between cumulative grade 3 or worse late gastrointestinal toxicity ( 2·6 % [ 95 % CI 1·2 - 4·7 ] ) in the st and ard fractionation group and 3·3 % [ 1·7 - 5·6 ] in the hypofractionation group ; p=0·55 ) . INTERPRETATION Our data could not confirm that hypofractionation was non-inferior for cumulative late genitourinary and gastrointestinal toxicity compared with st and ard fractionation . Before final conclusions can be made about the utility of hypofractionation , efficacy outcomes need to be reported . FUNDING The Dutch Cancer Society CONTEXT Comorbidities may increase the negative effects of specific anticancer treatments such as and rogen suppression therapy ( AST ) . OBJECTIVES To compare 6 months of AST and radiation therapy ( RT ) to RT alone and to assess the interaction between level of comorbidity and all-cause mortality . DESIGN , SETTING , AND PATIENTS At academic and community-based medical centers in Massachusetts , between December 1 , 1995 , and April 15 , 2001 , 206 men with localized but unfavorable-risk prostate cancer were r and omized to receive RT alone or RT and AST combined . All-cause mortality estimates stratified by r and omized treatment group and further stratified in a postr and omization analysis by the Adult Comorbidity Evaluation 27 comorbidity score were compared using a log-rank test . MAIN OUTCOME MEASURE Time to all-cause mortality . RESULTS As of January 15 , 2007 , with a median follow-up of 7.6 ( range , 0.5 - 11.0 ) years , 74 deaths have occurred . A significant increase in the risk of all-cause mortality ( 44 vs 30 deaths ; hazard ratio [ HR ] , 1.8 ; 95 % confidence interval [ CI ] , 1.1 - 2.9 ; P = .01 ) was observed in men r and omized to RT compared with RT and AST . However , the increased risk in all-cause mortality appeared to apply only to men r and omized to RT with no or minimal comorbidity ( 31 vs 11 deaths ; HR , 4.2 ; 95 % CI , 2.1 - 8.5 ; P < .001 ) . Among men with moderate or severe comorbidity , those r and omized to RT alone vs RT and AST did not have an increased risk of all-cause mortality ( 13 vs 19 deaths ; HR , 0.54 ; 95 % CI , 0.27 - 1.10 ; P = .08 ) . CONCLUSIONS The addition of 6 months of AST to RT result ed in increased overall survival in men with localized but unfavorable-risk prostate cancer . This result may pertain only to men without moderate or severe comorbidity , but this requires further assessment in a clinical trial specifically design ed to assess this interaction . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00116220 PURPOSE To assess feasibility , toxicity and biochemical relapse-free survival ( b-RFS ) for a group of organ confined ( OC ) Saudi prostate cancer patients treated by hypo-fractionated Volumetric Modulated Arc Radiation Therapy ( VMAT ) Simultaneous Integrated Boost ( SIB ) Elective Nodal Irradiation ( ENI ) whole pelvic radiotherapy ( WPRT ) . PATIENTS AND METHODS Between March 2009 and January 2014 , 29 OC prostate cancer patients ; median age 64years , PS 0 - 1 were treated in King Faisal Specialist Hospital - Riyadh , Kingdom of Saudi Arabia using VMAT-SIB-ENI-WPRT , to a total dose of 70Gy in 28 fractions . Twenty Four patients ( 83 % ) were treated with neo-adjuvant ; concurrent and rogen deprivation therapy ( ADT ) . Median follow-up ( FU ) was 42months ( range : 18 - 72months ) . RESULTS The 3-year actuarial b-RFS for low/intermediate and high risk groups were 100 % , and 48 % , respectively ( p=0.09 ) with a median FU period of 34months ( range : 14 - 53months ) . Gleason Score ( p=0.02 ) , and pretreatment PSA ( p=0.01 ) were predictive for biochemical failure on univariate analysis ; with no observed prostate cancer-related deaths . Grade 2 acute/late GI and GU toxicities were 28%/0 % and 17%/10 % respectively with no reported grade 3/4 toxicities . Four ( 50 % ) out of the 8 patients with baseline partial potency , retained sexual function on long term follow-up . CONCLUSIONS Hypo-fractionation dose escalation VMAT-SIB-ENI-WPRT using 2 arcs is a feasible technique for intermediate/high risk OC prostate cancer patients , with acceptable rates of acute/late toxicities , much favorable planning target volume ( PTV ) coverage , and shorter overall treatment time . Prospect i ve r and omized controlled trials are encouraged to confirm its equivalence to other fractionation schemes |
13,782 | 29,761,902 | The network meta- analysis ( NMA ) suggested a significant difference between the external and the conical connections ; this was less evident for the internal and conical ones .
Platform-switching ( PS ) seemed to positively affect bone levels , non-regarding the implant-connection it was applied to .
Within the limitations of this systematic review , it can be concluded that crestal bone levels are better maintained in the short-medium term when internal kinds of interface are adopted . | PURPOSE Different implant-abutment connections are available and it has been cl aim ed they could have an effect on marginal bone loss .
The aim of this review is to establish if implant connection configuration influences peri-implant bone loss ( PBL ) after functional loading .
METHODS A specific question was formulated according to the Population , Intervention , Control , and Outcome ( PICO ) : Does the type of implant-abutment connection ( external , internal , or conical ) have an influence on peri-implant bone loss ? | OBJECTIVES This r and omised , controlled multicentre trial aim ed at comparing two versions of a variable-thread dental implant design to a st and ard tapered dental implant design in cases of immediate functional loading for 36 months after loading . MATERIAL S AND METHODS 177 patients ( 325 implants ) were included at 12 study centres and r and omly allocated into one of three treatment groups : NAI ( variable-thread design , NobelActive internal connection ) , NAE ( variable-thread design , NobelActive external connection ) and , as control , NR ( st and ard tapered design , NobelReplace tapered groovy ) . Inclusion criteria concerned healed bony implant sites and feasibility for immediate loading . Clinical and radiographic examinations were performed at implant placement and after 3 , 6 , 12 , 24 and 36 months . The outcome measures were marginal bone remodelling ( primary outcome ) , implant survival and success , papilla score , plaque accumulation , and bleeding on probing . RESULTS 127 patients ( NAI : 45 , NAE : 41 , NR : 41 ) were followed-up and evaluated after 36 months . No significant differences in cumulative survival rates were seen for the groups ( NAI : 95.7 % ; NAE : 96.3 % ; NR : 96.6 % ) . In all groups , bone remodelling occurred during the first 3 months , with stable or even increasing bone levels after the initial remodelling period . The bone remodelling from insertion to 36 months for the NAI group ( -0.89 ± 1.65 mm ) was comparable ( P = 0.98 ) to that of the NR group ( -0.85 ± 1.32 mm ) . The NAE group showed comparable bone remodelling during the first year , with an increase in following years result ing in significantly less overall bone loss ( -0.16 ± 1.06 mm ) ( P = 0.041 ) . Overall improvement in papilla size was observed in all treatment groups . CONCLUSIONS Over 36 months , the results show stable or improving bone levels for all treatment groups after the initial bone remodelling seen during the first 3 months after placement . The variable- thread implants showed results comparable to those of st and ard tapered implants in cases of immediate function , and therefore can be considered as a treatment option for immediate loading OBJECTIVES The aim of this prospect i ve study was to assess the effects of abutment removal after 6 months on bone healing after the subcrestal placement of immediately restored , tapered implants in cases of partial posterior m and ibular edentulism . MATERIAL AND METHODS Each of the 24 patients with partial posterior m and ibular edentulism was consecutively treated with two immediately restored 3.5 mm diameter tapered implants . A total of 48 implants were placed in healed sites and immediately splinted with a temporary restoration , which was placed in such a way as to avoid occlusal contact . Twenty-four weeks after surgery , 12 patients underwent the st and ard prosthetic protocol : the abutments were removed and impressions were made directly on the implant platform . Twelve patients underwent the " one abutment at one time " protocol : impressions were made of the abutments using snap-on abutment copies . The final restoration was delivered approximately 6 months after implant insertion . Vertical and horizontal bone changes were assessed using periapical radiographs immediately after surgery and at 6- , 12- , 24- and 36-month follow-up examinations . RESULTS All implants osseointegrated and were clinical ly stable at the 6-month follow-up . No statistically significant difference was evidence d between the two groups regarding the measurement of vertical bone healing . A small but significant horizontal bone loss was evidence d in the hard tissue portion over the implant platform in the period of time between the 6-month and 1-year follow-up in the control group . CONCLUSIONS The non-removal of an abutment placed at the time of surgery results in a statistically significant reduction of the horizontal bone remodeling around the immediately restored , subcrestally placed , tapered implant in cases of partial posterior m and ibular edentulism PURPOSE To compare the clinical and radiological outcomes of two implant design s with different prosthetic interfaces and neck configurations . MATERIAL S AND METHODS Thirty-four partially edentate patients r and omly received at least one NobelActive implant ( Nobel Biocare , Göteborg , Sweden ) with back-tapered collar , internal conical connection and platform shifting design , and one NobelSpeedy implant ( Nobel Biocare ) with external hexagon and flat-to-flat implant-abutment interface according to a split-mouth design . Follow-up continued to 3 years post-loading . The primary outcome measures were the success rates of the implants and prostheses , and the occurrence of any surgical and prosthetic complications during the entire follow-up . Secondary outcome measures were : horizontal and vertical peri-implant marginal bone level ( MBL ) changes , resonance frequency analysis values at implant placement and loading ( 4 months ) , sulcus bleeding index ( SBI ) and plaque score ( PS ) . RESULTS No drop-out occurred . No implants and prostheses failures were observed to the 3-year follow-up . MBL changes were statistically significant different with better results for the NobelActive implants for both horizontal and vertical measurements ( P = 0.000 ) . After 3 years post-loading , the NobelActive implants underwent a mean vertical bone resorption of 0.66 mm , compared with 1.25 mm for the NobelSpeedy Groovy implants ( P = 0.000 ) ; the mean horizontal bone resorption was 0.19 mm for the NobelActive implants and 0.60 mm for the NobelSpeedy Groovy implants ( P = 0.000 ) . A high ISQ value was found for both implants , and no statistically significant difference was found for ISQ mean values between interventions ( P = 0.941 at baseline ; P = 0.454 at implantabutment connection ; P = 0.120 at prosthesis delivery ) . All implants showed good periodontal health at the 3-year-in-function visit , with no significant differences between groups . CONCLUSION The results of this research suggest that in well-maintained patients , the MBL changes could be affected by the different implant design . After 4 months of unloaded healing , as well as after 3 years in function , both implants provided good results , however vertical and horizontal bone loss had statistically significant differences between the two groups ( difference of 0.58 ± 0.10 mm for the vertical MBL , and 0.4 ± 0.05 mm for the horizontal MBL ) , with lower values in the Nobel Active implants , compared to the NobelSpeedy Groovy implants OBJECTIVE To carry out a comparative study of two implants with different neck features and prostheses platform connection ( machined with external connection and rough-surfaced with switching platform ) upon peri-implant marginal bone loss , before and after functional loading . MATERIAL AND METHODS A r and omized , prospect i ve radiological study was made . Eighteen totally edentulous patients were selected . Subjects were divided into two groups according to the type of implant neck used : ( a ) Osseous ( ® ) , with machined surface , without microthreads , external connection , and without platform switching ; and ( b ) Inhex ( ® ) , with treated surface , microthreads , internal connection , and platform switching . Mesial and distal marginal bone loss was measured . Implant success was assessed according to the criteria of Buser . Control timepoints were as follows : ( a ) at implant placement ; ( b ) at prosthesis placement ; ( c ) 6 months after loading ; ( d ) 12 months after loading . RESULTS Fifteen patients that received 120 dental implants were included : 47 % Osseous ( ® ) group and 53 % Inhex ( ® ) group . Global mean marginal bone loss with Osseous ( ® ) was 0.27 ± 0.43 mm and 0.38 ± 0.51 mm as determined 6 and 12 months after prosthetic loading , respectively , whereas in the case of Inhex ( ® ) was 0.07 ± 0.13 and 0.12 ± 0.17 mm . These differences were statistically significant ( P = 0.047 ) . Difference between Osseous ( ® ) and Inhex ( ® ) in maxilla ( P = 0.272 ) and m and ibular ( P = 0.462 ) bone loss were not statistically significant . CONCLUSIONS Bone loss after 6 and 12 months proved statistically significant between two groups , with comparatively greater loss in the case of Osseous ( ® ) implants vs. Inhex ( ® ) implants . Regardless the heterogeneity of the two groups ( neck shape , microthreads , surface texture ) , the implant-abutment connection appears to be a significant factor on peri-implant crestal bone levels . Anyway , in both groups , the values obtained were within normal ranges described in the literature BACKGROUND Peri-implant bone loss seems to occur following implant placement/loading regardless of all the efforts to eliminate it . Several factors , including surgical trauma , biologic width establishment , lack of passive fit of the superstructures , implant-abutment microgap , and occlusal overloading , may increase peri-implant bone loss . Over the years , new interface design s were introduced and clinical studies suggest that internal conical connection and platform shifting may be advantageous for marginal bone preservation . PURPOSE To compare clinical and radiological outcomes of two implant design s with different prosthetic interfaces and neck configurations in a r and omized , controlled , split-mouth clinical trial . MATERIAL S AND METHODS Thirty-four partially edentate patients r and omly received at least one internal conical connection with back-tapered collar and platform shifting design or external-hexagon implants with flat-to-flat implant-abutment interface . Primary end point was peri-implant bone level changes at different time points , failures of implants and /or prosthesis , any complications , implant stability quotient ( ISQ ) values , and periodontal parameters . RESULTS No dropout occurred . Marginal bone changes were statistically significantly different with better results for the internal conical connection . No implants and prosthesis failures have been observed , yielding a cumulative survival rate of 100 % . A high ISQ value was found for both implants , and no statistically significant difference was found for ISQ mean values between interventions at each time point ( p > .05 ) . All implants showed no bleeding on probing and a very slight amount of plaque at the 1-year-in-function visit . CONCLUSIONS Both implant design s investigated performed similarly in terms of failure rates , providing successful results up to 1 year after loading . The back-tapered neck configuration with conical connection and built-in platform shifting showed statistically lower marginal bone loss than straight neck configuration with flat-to-flat implant-abutment interface and external-hexagonal connection PURPOSE To evaluate advantages and disadvantages of identical implants with internal or external connections . MATERIAL S AND METHODS One hundred and twenty patients with any type of edentulism ( single tooth , partial and total edentulism ) , requiring one implant-supported prosthesis were r and omly allocated in two equal groups to receive either implants with an external connection ( EC ) or implants of the same type with an internal connection ( IC ) ( EZ Plus , MegaGen Implant , Gyeongbuk , South Korea ) , at four centres . Due to slight differences in implant design and components , IC implants were platformswitched while EC were not . Patients were followed for 5 years after initial loading . Outcome measures were prosthesis/implant failures , any complication , marginal bone level changes and clinician preference , assessed by blinded outcome assessors . RESULTS Sixty patients received 96 EC implants and 60 patients received 107 IC implants . Three patients dropped out with four EC implants and five patients with ten IC implants , but all remaining patients were followed up to 5-year post-loading . One prosthesis supported by EC implants and two by IC implants failed ( P = 0.615 , difference = -0.02 , 95 % CI : -0.08 to 0.04 ) . One EC implant failed versus three IC implants in two patients ( P = 0.615 , difference = -0.02 , 95 % CI : -0.08 to 0.04 ) . Ten complications occurred in 10 EC patients versus nine complications in 9 IC patients ( P = 1.000 , difference = 0.01 , 95 % CI : -0.13 to 0.15 ) . There were no statistically significant differences for prosthesis and implant failures and complications between the different connection types . Five years after loading , there were no statistically significant differences in marginal bone level estimates between the two groups ( difference = 0.14 mm , 95 % CI : -0.28 to 0.56 , P ( ancova ) = 0.505 ) and both groups lost bone from implant placement in a statistically significant way : 1.13 mm for the EC implants and 1.21 mm for the IC implants . Two operators had no preference and two preferred IC implants . CONCLUSIONS Within the limitations given by the difference in neck design and platform switching between EC and IC implants , 5-year post-loading data did not show any statistically significant differences between the two connection types , therefore clinicians could choose whichever they preferred BACKGROUND Today , implants are placed using both non-submerged and submerged approaches , and in 1- and 2-piece configurations . Previous work has demonstrated that peri-implant crestal bone reactions differ radiographically under such conditions and are dependent on a rough/smooth implant border in 1-piece implants and on the location of the interface ( microgap ) between the implant and abutment/restoration in 2-piece configurations . The purpose of this investigation was to examine histometrically crestal bone changes around unloaded non-submerged and submerged 1- and 2-piece titanium implants in a side-by-side comparison . METHODS A total of 59 titanium implants were r and omly placed in edentulous m and ibular areas of 5 foxhounds , forming 6 different implant subgroups ( types A-F ) . In general , all implants had a relatively smooth , machined coronal portion as well as a rough , s and blasted and acid-etched ( SLA ) apical portion . Implant types A-C were placed in a non-submerged approach , while types D-F were inserted in a submerged fashion . Type A and B implants were 1-piece implants with the rough/smooth border ( r/s ) at the alveolar crest ( type A ) or 1.0 mm below ( type B ) . Type C implants had an abutment placed at the time of surgery with the interface located at the bone crest level . In the submerged group , types D-F , the interface was located either at the bone crest level ( type D ) , 1 mm above ( type E ) , or 1 mm below ( type F ) . Three months after implant placement , abutment connection was performed in the submerged implant groups . At 6 months , all animals were sacrificed . Non-decalcified histology was analyzed by evaluating peri-implant crestal bone levels . RESULTS For types A and B , mean crestal bone levels were located adjacent ( within 0.20 mm ) to the rough/smooth border ( r/s ) . For type C implants , the mean distance ( + /- st and ard deviation ) between the interface and the crestal bone level was 1.68 mm ( + /- 0.19 mm ) with an r/s border to first bone-to-implant contact ( fBIC ) of 0.39 mm ( + /- 0.23 mm ) ; for type D , 1.57 mm ( + /- 0.22 mm ) with an r/s border to fBIC of 0.28 mm ( + /- 0.21 mm ) ; for type E , 2.64 mm ( + /- 0.24 mm ) with an r/s border to fBIC of 0.06 mm ( + /- 0.27 mm ) ; and for type F , 1.25 mm ( + /- 0.40 mm ) with an r/s border to fBIC of 0.89 mm ( + /- 0.41 mm ) . CONCLUSIONS The location of a rough/smooth border on the surface of non-submerged 1-piece implants placed at the bone crest level or 1 mm below , respectively , determines the level of the fBIC . In all 2-piece implants , however , the location of the interface ( microgap ) , when located at or below the alveolar crest , determines the amount of crestal bone resorption . If the same interface is located 1 mm coronal to the alveolar crest , the fBIC is located at the r/s border . These findings , as evaluated by non-decalcified histology under unloaded conditions , demonstrate that crestal bone changes occur during the early phase of healing after implant placement . Furthermore , these changes are dependent on the surface characteristics of the implant and the presence/absence as well as the location of an interface ( microgap ) . Crestal bone changes were not dependent on the surgical technique ( submerged or non-submerged ) PURPOSE The aim of this clinical study was to assess the marginal bone around two different types of implant-abutment junctions-a so-called platform-switched assembly and a conventional external-hexagon connection-after 24 months . MATERIAL S AND METHODS Forty-five patients were included in this prospect i ve study . All selected patients required the extraction of one or two hopeless teeth in maxillary and m and ibular region monoradicular and second premolar teeth , and were r and omly assigned to one of two groups . The first group received 34 implants with an external-hexagon junction with the abutment and the second group received 30 implants with platform-switched abutments . Implants were positioned immediately after tooth extraction and were loaded immediately . RESULTS After 24 months , a cumulative survival rate of 100 % was reported for all implants . The platform-switching group showed a mean bone loss of 0.78 + /- 0.49 mm and the external-hexagon group showed a mean bone loss of 0.73 + /- 0.52 mm ( no statistically significant difference between groups ) . CONCLUSION The results of this study indicate that implants placed immediately in fresh extraction sockets and loaded immediately represent a predictable procedure , with no differences in bone level changes between " platform-switched " and conventional external-hexagon implants after 24 months PURPOSE To evaluate the clinical and radiological performance of an immediately loaded novel implant design over a 3-year period . MATERIAL S AND METHODS This prospect i ve study includes 54 consecutive partially edentulous patients treated between December 2010 and October 2011 . Outcome measures were : implant and prosthetic failures ; biological and mechanical complications ; marginal bone loss ( MBL ) ; sulcus bleeding index ( SBI ) ; and plaque score ( PS ) . RESULTS A total of 118 ( 29 narrow platform , 70 regular platform and 19 wide platform ) NobelReplace Conical Connection implants were placed in both post- extraction sockets and healed sites and immediately loaded . The mean insertion torque was 63.4 ± 7.1 Ncm . One hundred out of 118 implants ( 84.7 % ) were inserted with a torque ranging between 55 and 70 Ncm . Each patient received a single prosthesis . At the 3-year follow-up , no patient dropped out and only two post-extractive implants failed ( 1.7 % ) in two patients ( 3.7 % ) . The only complication ( 1.9 % ) observed was an event of periimplantitis , consisting of a mean mesiodistal peri-implant bone loss of 3.2 mm reported in a healed site of a smoker patient at the 2-year follow-up examination . No prosthesis failures were detected . The cumulative mean MBL between implant placements at the 3-year follow-up was 0.68 mm ( 95 % CI : 0.44 , 0.92 ) . At the 3-year follow-up session , the SBI and PS were 5.7 % and 15.4 % , respectively . CONCLUSIONS The NobelReplace Conical Connection implant can be considered as a valuable treatment option for immediate implant placement and loading in the partially edentulous patients over a 3-year period . Insertion torques ranging between 55 and 70 Ncm are not detrimental to osseointegration PURPOSE To evaluate advantages and disadvantages of identical implants with internal or external connections . MATERIAL S AND METHODS Two hundred patients with any type of edentulism ( single tooth , partial and total edentulism ) requiring one implant-supported prosthesis were r and omly allocated in two equal groups to receive either implants with an external connection ( EC ) or implants of the same type but with an internal connection ( IC ) ( EZ Plus , MegaGen Implant , Gyeongbuk , South Korea ) at seven centres . Due to slight differences in implant design /components , IC implants were platform switched while EC were not . Patients were followed for 1 year after initial loading . Outcome measures were prosthesis/implant failures , any complication , marginal bone level changes and clinician preference assessed by blinded outcome assessors . RESULTS One hundred and two patients received 173 EC implants and 98 patients received 154 IC implants . Six patients dropped out with 11 EC implants and 3 patients with four IC implants , but all remaining patients were followed up to 1-year post-loading . Two centres did not provide any periapical radiographs . Two prostheses supported by EC implants and one supported by IC implants failed ( P = 1.000 , difference = -0.01 , 95 % CI : -0.05 to 0.04 ) . Three EC implants failed in 3 patients versus two IC implants in 1 patient ( P = 0.6227 , difference = -0.02 , 95 % CI : -0.07 to 0.03 ) . EC implants were affected by nine complications in 9 patients versus six complications of IC implants in 6 patients ( P = 0.5988 , difference = -0.02 , 95 % CI : -0.10 to 0.06 ) . There were no statistically significant differences for prosthesis/implant failures and complications between the implant systems . One year after loading , there were no statistically significant differences in marginal bone level changes between the two groups ( difference = 0.24 , 95 % CI : -0.01 to 0.50 , P = 0.0629 ) and both groups lost bone from implant placement in a statistically significant manner : 0.98 mm for the EC implants and 0.85 mm for the IC implants . Five operators had no preference and two preferred IC implants . CONCLUSIONS Within the limitations given by the difference in neck design and platform switching between EC and IC implants , preliminary short-term data ( 1-year post-loading ) did not show any statistically significant differences between the two connection types , therefore clinicians could choose whichever one they preferred PURPOSE This prospect i ve clinical study evaluated the incidence of abutment loosening of Morse taper-connection implants used for single-tooth replacement . In addition , the cumulative survival rate and the implant/crown success were evaluated . MATERIAL S AND METHODS Implants were evaluated 12 , 24 , 36 , and 48 months after insertion . The incidence of abutment loosening , modified Plaque Index , modified Sulcus Bleeding Index , probing depth , distance from the implant-crown margin to the coronal border of the peri-implant mucosa , width of keratinized mucosa , and the distance between implant shoulder and first bone-implant contact ( DIB ) were assessed . The cumulative survival rates were calculated with Kaplan-Meier estimates . Implant/crown success criteria included absence of abutment loosening , absence of suppuration and mobility , probing depth < 5.0 mm , and DIB < 1.5 mm after 12 months and not exceeding 0.2 mm for each following year . RESULTS Over a 4-year period ( 2003 - 2007 ; mean follow-up per implant : 30.79 months ) , 307 implants ( 162 maxillary , 145 m and ibular ) were inserted in 295 patients ( 125 men and 170 women aged between 24 and 79 years ) at six different clinical centers . The sites included anterior ( n = 115 ) and posterior ( n = 192 ) teeth . At the end of the study , a very low percentage of implant-abutment loosening ( 0.66 % ) was found , with only two loosened abutments . The cumulative implant survival rate was 98.4 % . Mean DIB was 1.14 mm ( 48 months ) . Only four surviving implants did not meet the criteria for success , and the implant/crown success rate was 97.07 % . CONCLUSION Based upon this study of 307 implants observed during a 4-year period , Morse taper-connection implants represent a good solution for single-tooth restorations , with a very low incidence of abutment loosening ( 0.66 % ) PURPOSE The purpose of the present study was to compare the clinical and radiographic outcomes of single implants immediately placed and restored with two different implant-abutment connections . MATERIAL S AND METHODS Forty subjects requiring single maxillary premolar replacement were consecutively included in this study and prospect ively followed for 12 months . One implant was placed at the time of tooth extraction and immediately restored in each patient . Subjects were r and omly selected to receive either prosthetic abutments with a Morse taper connection and a platform switch ( test group ) or conventional abutments with an internal connection and a matching diameter ( control group ) . A provisional screw-retained crown was positioned and adjusted for nonfunctional loading within 24 hours . Four months later , the definitive crowns were delivered . Periodontal parameters and clinical and radiographic measurements of soft and hard tissue levels were recorded at the moment of prosthesis placement and at 4 and 12 months afterward . Means of the two groups were compared using paired and independent- sample t tests ( P = .05 ) . RESULTS Of the 40 patients recruited , 38 ( 24 women and 14 men ) completed the study . No implants were lost in the control group , whereas one implant failed in the test group . At the 12-month examination , no statistically significant differences were seen between the two groups for periodontal parameters , marginal soft tissue level change , or papilla height ( P > .05 ) , but greater marginal bone loss was observed at the control sites ( 0.51 ± 0.24 mm ) compared to the test sites ( 0.2 ± 0.17 mm ) ( P = .0004 ) . CONCLUSION Although the control group demonstrated a slight increase in marginal bone loss compared to the test group , the peri-implant soft tissues were very stable with both types of implant-abutment connection after 12 months of loading STATEMENT OF PROBLEM A tapered implant with continuously changing threads purported to provide stable tissue support and allow immediate function has been developed . Treatment success and stabilization of supporting tissues over time require documentation . PURPOSE The purpose of this prospect i ve , r and omized , controlled , multicenter study was to evaluate changes in bone level and soft tissue behavior between the novel implant ( NobelActive/NA ) and a st and ard tapered implant ( NobelReplace Tapered Groovy/NR ) with regard to immediate function . MATERIAL AND METHODS A total of 177 patients r and omly allocated to 3 treatment groups ( 2 different test implant groups : NA Internal ( n=117 ; internal connection ) and External ( n=82 ) , and 1 st and ard treatment group , NR ( n=126 ) ) received 325 implants . Implants were placed into healed sites , and all but 6 implants were immediately nonocclusally loaded . Clinical and radiographic evaluations of treatment success , crestal bone levels , and soft tissue changes were performed at the time of placement and after 3 , 6 , and 12 months . Log-Rank test was used to analyze the differences in survival rate . Marginal bone level was compared using the Kruskal-Wallis test and Mann-Whitney U-test ( alpha=.05 ) . RESULTS One-year cumulative survival rates were comparable ( 96.6 % for NA Internal ; 96.3 % for NA External ; 97.6 % for NR ; P=.852 ; Log-Rank ) . Mean ( SD ) change in bone level was -0.95 mm ( 1.37 ) for NA Internal , -0.64 mm ( 0.97 ) for NA External , and -0.63 mm ( 1.18 ) for NR ( P=.589 ; Kruskal-Wallis ) . Stable soft tissues and significantly increased papilla scores ( P<.001 ; Wilcoxon signed-rank ) were observed for all implant types . CONCLUSIONS The novel implants showed high survival rates as well as stable bone and soft tissue levels after 1 year , and may be recommended for clinical use , even under immediate function PURPOSE The aim of this prospect i ve clinical trial was to compare the three-dimensional marginal bone level , implant stability , and peri-implant health of two types of submerged dental implants that were restored with matching or platform-switched abutments . MATERIAL S AND METHODS Twenty-five subjects were recruited ( test group : 43 implants with internal conical connection and back-tapered collar carrying a platform-switched abutment ; control group : 50 implants carrying a matched-platform abutment ) . Implant uncovering and conventional loading were performed after 3 months of healing , and the total observation time was 15 months . Marginal bone levels , resonance frequency analysis , insertion torque , and peri-implant health indices were recorded and analyzed statistically . RESULTS The cumulative implant survival rate was 100 % . At the second-stage surgery , bone levels were similar between groups . One year after loading , mean crestal bone loss was 0.35 ± 0.13 mm for test implants and 0.83 ± 0.16 mm for control implants , a significant difference . Primary stability was significantly higher in the test group than in the control group , but this difference disappeared after 3 months of healing prior to loading . Between-group differences for peri-implant health indices were negligible . CONCLUSIONS Both implant systems had the same survival rates . Implants with a built-in platform switch and conical connection with back-tapered collar design achieved higher primary stability at insertion and less bone resorption after 15 months PURPOSE The aim of this study was to evaluate and compare the clinical and radiographic outcomes of single implants with a platform-switched rough collar ( PSRC ) and a platform-matched smooth collar ( PMSC ) . MATERIAL S AND METHODS Twenty-six patients missing a tooth in the anterior maxilla ( through the premolars ) were r and omly assigned to the PSRC or the PMSC group . All implants were placed in a flapless approach and restored with an early loading protocol . Clinical measurements were performed at surgery , loading , and at 3 , 6 , and 12 months after loading . In addition , radiographic evaluations were carried out using st and ardized periapical radiographs and cone beam computed tomography . Patient satisfaction surveys were completed , and microbial analysis with DNA probes was performed . RESULTS The implant survival rate was 100 % for both groups . The mean marginal bone level ( MBL ) was significantly higher in the PSRC group compared to the PMSC group at all time points . From the 2-week postoperative visit to 1 year postloading , the mean MBL change in the PSRC group was 0.21 ± 0.56 mm and in the PMSC group it was 0.74 ± 0.47 mm . Soft tissue profiles were stable over time , with no significant differences between groups . There were no significant differences between groups in the number of microbial species seen . Patients in both groups were highly satisfied with postoperative and postprosthetic experiences . CONCLUSION In this study , the PSRC method preserved marginal bone by a mean of 0.53 mm more than the st and ard PMSC protocol . Within the limitations of the present study , it can be concluded that the PSRC protocol may be beneficial in marginal bone preservation . Longitudinal studies are needed to verify the long-term effects of this approach |
13,783 | 29,907,124 | Conclusions Current available data do not show evidence that exon-skipping drugs are effective in DMD .
Despite potential effectiveness when used at a specific dose , significant side effects were reported with drisapersen . | Background Exon skipping has been considered a promising therapeutic approach for Duchenne muscular dystrophy ( DMD ) .
Eteplirsen received conditional approval in the United States in 2016 .
To date , no systematic review s or meta-analyses of r and omized controlled trials ( RCTs ) of exon skipping drugs have been published to determine the pooled estimates for the effect of exon skipping in treating DMD . | This 48-week , r and omized , placebo-controlled phase 3 study ( DMD114044 ; NCT01254019 ) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years , with Duchenne muscular dystrophy ( DMD ) result ing from an exon 51 skipping amenable mutation . Drisapersen was generally well tolerated , with injection-site reactions and renal events as most commonly reported adverse events . A nonsignificant treatment difference ( P = 0.415 ) in the change from baseline in six-minute walk distance ( 6MWD ; primary efficacy endpoint ) of 10.3 meters in favor of drisapersen was observed at week 48 . Key secondary efficacy endpoints ( North Star Ambulatory Assessment , 4-stair climb ascent velocity , and 10-meter walk/run velocity ) gave consistent findings . Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity . The increased st and ard deviation alone , due to less stringent inclusion /exclusion criteria , reduced the statistical power from pre-specified 90 % to actual 53 % . Therefore , a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300 - 400 meters and ability to rise from floor . A statistically significant improvement in 6MWD of 35.4 meters ( P = 0.039 ) in favor of drisapersen was observed in this sub population . Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects Summary Background We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiami date morpholino oligomer ( PMO ) in patients with Duchenne muscular dystrophy . Method We undertook an open-label , phase 2 , dose-escalation study ( 0·5 , 1·0 , 2·0 , 4·0 , 10·0 , and 20·0 mg/kg bodyweight ) in ambulant patients with Duchenne muscular dystrophy aged 5–15 years with amenable deletions in DMD . Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658 . The primary study objective was to assess safety and tolerability of AVI-4658 . The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR , immunohistochemistry , and immunoblotting . The study is registered , number NCT00844597 . Findings 19 patients took part in the study . AVI-4658 was well tolerated with no drug-related serious adverse events . AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent ( p=0·0203 ) , but variable , manner in boys from cohort 3 ( dose 2 mg/kg ) onwards . Seven patients responded to treatment , in whom mean dystrophin fluorescence intensity increased from 8·9 % ( 95 % CI 7·1–10·6 ) to 16·4 % ( 10·8–22·0 ) of normal control after treatment ( p=0·0287 ) . The three patients with the greatest responses to treatment had 21 % , 15 % , and 55 % dystrophin-positive fibres after treatment and these findings were confirmed with western blot , which showed an increase after treatment of protein levels from 2 % to 18 % , from 0·9 % to 17 % , and from 0 % to 7·7 % of normal muscle , respectively . The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma . Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts . Interpretation The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy . Funding UK Medical Research Council ; AVI BioPharma BACKGROUND Cardiorespiratory failure is the leading cause of death in Duchenne muscular dystrophy . Based on pre clinical and phase 2 evidence , we assessed the efficacy and safety of idebenone in young patients with Duchenne muscular dystrophy who were not taking concomitant glucocorticoids . METHODS In a multicentre phase 3 trial in Belgium , Germany , the Netherl and s , Switzerl and , France , Sweden , Austria , Italy , Spain , and the USA , patients ( age 10 - 18 years old ) with Duchenne muscular dystrophy were r and omly assigned in a one-to-one ratio with a central interactive web response system with a permuted block design with four patients per block to receive idebenone ( 300 mg three times a day ) or matching placebo orally for 52 weeks . Study personnel and patients were masked to treatment assignment . The primary endpoint was change in peak expiratory flow ( PEF ) as percentage predicted ( PEF%p ) from baseline to week 52 , measured with spirometry . Analysis was by intention to treat ( ITT ) and a modified ITT ( mITT ) , which was prospect ively defined to exclude patients with at least 20 % difference in the yearly change in PEF%p , measured with hospital-based and weekly home-based spirometry . This study is registered with Clinical Trials.gov , number NCT01027884 . FINDINGS 31 patients in the idebenone group and 33 in the placebo group comprised the ITT population , and 30 and 27 comprised the mITT population . Idebenone significantly attenuated the fall in PEF%p from baseline to week 52 in the mITT ( -3·05%p [ 95 % CI -7·08 to 0·97 ] , p=0·134 , vs placebo -9·01%p [ -13·18 to -4·84 ] , p=0·0001 ; difference 5·96%p [ 0·16 to 11·76 ] , p=0·044 ) and ITT population s ( -2·57%p [ -6·68 to 1·54 ] , p=0·215 , vs -8·84%p [ -12·73 to -4·95 ] , p<0·0001 ; difference 6·27%p [ 0·61 to 11·93 ] , p=0·031 ) . Idebenone also had a significant effect on PEF ( L/min ) , weekly home-based PEF , FVC , and FEV1 . The effect of idebenone on respiratory function outcomes was similar between patients with previous corticosteroid use and steroid-naive patients . Treatment with idebenone was safe and well tolerated with adverse event rates were similar in both groups . Nasopharyngitis and headache were the most common adverse events ( idebenone , eight [ 25 % ] and six [ 19 % ] of 32 patients ; placebo , nine [ 26 % ] and seven [ 21 % ] of 34 patients ) . Transient and mild diarrhoea was more common in the idebenone group than in the placebo group ( eight [ 25 % ] vs four [ 12 % ] patients ) . INTERPRETATION Idebenone reduced the loss of respiratory function and represents a new treatment option for patients with Duchenne muscular dystrophy . FUNDING Santhera Pharmaceuticals BACKGROUND Local intramuscular administration of the antisense oligonucleotide PRO051 in patients with Duchenne 's muscular dystrophy with relevant mutations was previously reported to induce the skipping of exon 51 during pre-messenger RNA splicing of the dystrophin gene and to facilitate new dystrophin expression in muscle-fiber membranes . The present phase 1 - 2a study aim ed to assess the safety , pharmacokinetics , and molecular and clinical effects of systemically administered PRO051 . METHODS We administered weekly abdominal subcutaneous injections of PRO051 for 5 weeks in 12 patients , with each of four possible doses ( 0.5 , 2.0 , 4.0 , and 6.0 mg per kilogram of body weight ) given to 3 patients . Changes in RNA splicing and protein levels in the tibialis anterior muscle were assessed at two time points . All patients subsequently entered a 12-week open-label extension phase , during which they all received PRO051 at a dose of 6.0 mg per kilogram per week . Safety , pharmacokinetics , serum creatine kinase levels , and muscle strength and function were assessed . RESULTS The most common adverse events were irritation at the administration site and , during the extension phase , mild and variable proteinuria and increased urinary α(1)-microglobulin levels ; there were no serious adverse events . The mean terminal half-life of PRO051 in the circulation was 29 days . PRO051 induced detectable , specific exon-51 skipping at doses of 2.0 mg or more per kilogram . New dystrophin expression was observed between approximately 60 % and 100 % of muscle fibers in 10 of the 12 patients , as measured on post-treatment biopsy , which increased in a dose-dependent manner to up to 15.6 % of the expression in healthy muscle . After the 12-week extension phase , there was a mean ( ±SD ) improvement of 35.2±28.7 m ( from the baseline of 384±121 m ) on the 6-minute walk test . CONCLUSIONS Systemically administered PRO051 showed dose-dependent molecular efficacy in patients with Duchenne 's muscular dystrophy , with a modest improvement in the 6-minute walk test after 12 weeks of extended treatment . ( Funded by Prosensa Therapeutics ; Netherl and s National Trial Register number , NTR1241 . ) Despite long-st and ing critiques of the conduct of underpowered clinical trials , the practice not only remains widespread , but also has garnered increasing support . Patients and healthy volunteers continue to participate in research that may be of limited clinical value , and authors recently have offered 2 related arguments to support the validity and value of underpowered clinical trials : that meta- analysis may " save " small studies by providing a means to combine the results with those of other similar studies to enable estimates of an intervention 's efficacy , and that although small studies may not provide a good basis for testing hypotheses , they may provide valuable estimates of treatment effects using confidence intervals . In this article , we examine these arguments in light of the distinctive moral issues associated with the conduct of underpowered trials , the disclosures that are owed to potential participants in underpowered trials so they may make autonomous enrollment decisions , and the circumstances in which the prospect s for future meta-analyses may justify individually underpowered trials . We conclude that underpowered trials are ethical in only 2 situations : small trials of interventions for rare diseases in which investigators document explicit plans for including their results with those of similar trials in a prospect i ve meta- analysis , and early-phase trials in the development of drugs or devices , provided they are adequately powered for defined purpose s other than r and omized treatment comparisons . In both cases , investigators must inform prospect i ve subjects that their participation may only indirectly contribute to future health care benefits Objective : We aim ed to perform an observational study of age at loss of independent ambulation ( LoA ) and side-effect profiles associated with different glucocorticoid corticosteroid ( GC ) regimens in Duchenne muscular dystrophy ( DMD ) . Methods : We studied 340 participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study ( CINRG-DNHS ) . LoA was defined as continuous wheelchair use . Effects of prednisone or prednisolone (PRED)/deflazacort ( DFZ ) , administration frequency , and dose were analyzed by time-varying Cox regression . Side-effect frequencies were compared using χ2 test . Results : Participants treated ≥1 year while ambulatory ( n = 252/340 ) showed a 3-year median delay in LoA ( p < 0.001 ) . Fourteen different regimens were observed . Nondaily treatment was common for PRED ( 37 % ) and rare for DFZ ( 3 % ) . DFZ was associated with later LoA than PRED ( hazard ratio 0.294 ± 0.053 vs 0.490 ± 0.08 , p = 0.003 ; 2-year difference in median LoA with daily administration , p < 0.001 ) . Average dose was lower for daily PRED ( 0.56 mg/kg/d , 75 % of recommended ) than daily DFZ ( 0.75 mg/kg/d , 83 % of recommended , p < 0.001 ) . DFZ showed higher frequencies of growth delay ( p < 0.001 ) , cushingoid appearance ( p = 0.002 ) , and cataracts ( p < 0.001 ) , but not weight gain . Conclusions : Use of DFZ was associated with later LoA and increased frequency of side effects . Differences in st and ards of care and dosing complicate interpretation of this finding , but stratification by PRED/DFZ might be considered in clinical trials . This study emphasizes the necessity of a r and omized , blinded trial of GC regimens in DMD . Classification of evidence : This study provides Class IV evidence that GCs are effective in delaying LoA in patients with DMD Therapeutic trials in muscular dystrophy have often been inconclusive . A protocol has been design ed which selects patients with Duchenne muscular dystrophy and permits accurate measurement of their status . An integral part of the protocol is a system for checking on the consistency of the data obtained using a computer program BACKGROUND Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy . Nusinersen is specifically design ed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron ( SMN ) protein that is deficient in patients with spinal muscular atrophy . METHODS This open-label , phase 2 , escalating dose clinical study assessed the safety and tolerability , pharmacokinetics , and clinical efficacy of multiple intrathecal doses of nusinersen ( 6 mg and 12 mg dose equivalents ) in patients with infantile-onset spinal muscular atrophy . Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months , who had SMN1 homozygous gene deletion or mutation . Safety assessment s included adverse events , physical and neurological examinations , vital signs , clinical laboratory tests , cerebrospinal fluid laboratory tests , and electrocardiographs . Clinical efficacy assessment s included event free survival , and change from baseline of two assessment s of motor function : the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 ( HINE-2 ) and the Children 's Hospital of Philadelphia Infant Test of Neuromuscular Disorders ( CHOP-INTEND ) motor function test , and compound motor action potentials . Autopsy tissue was analysed for target engagement , drug concentrations , and pharmacological activity . HINE-2 , CHOP-INTEND , and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test . Age at death or permanent ventilation was compared with natural history using the log-rank test . The study is registered at Clinical Trials.gov , number NCT01839656 . FINDINGS 20 participants were enrolled between May 3 , 2013 , and July 9 , 2014 , and assessed through to an interim analysis done on Jan 26 , 2016 . All participants experienced adverse events , with 77 serious adverse events reported in 16 participants , all considered by study investigators not related or unlikely related to the study drug . In the 12 mg dose group , incremental achievements of motor milestones ( p<0·0001 ) , improvements in CHOP-INTEND motor function scores ( p=0·0013 ) , and increased compound muscle action potential amplitude of the ulnar nerve ( p=0·0103 ) and peroneal nerve ( p<0·0001 ) , compared with baseline , were observed . Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series ( p=0·0014 ) . Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions , exposure at therapeutic concentrations , and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord . INTERPRETATION Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability , pharmacology consistent with its intended mechanism of action , and encouraging clinical efficacy . Results informed the design of an ongoing , sham-controlled , phase 3 clinical study of nusinersen in infantile-onset spinal muscular atrophy . FUNDING Ionis Pharmaceuticals , Inc and Biogen BACKGROUND Duchenne muscular dystrophy is caused by dystrophin deficiency and muscle deterioration and preferentially affects boys . Antisense-oligonucleotide-induced exon skipping allows synthesis of partially functional dystrophin . We investigated the efficacy and safety of drisapersen , a 2'-O-methyl-phosphorothioate antisense oligonucleotide , given for 48 weeks . METHODS In this exploratory , double-blind , placebo-controlled study we recruited male patients ( ≥5 years of age ; time to rise from floor ≤7 s ) with Duchenne muscular dystrophy from 13 specialist centres in nine countries between Sept 1 , 2010 , and Sept 12 , 2012 . By use of a computer-generated r and omisation sequence , we r and omly allocated patients ( 2:2:1:1 ; block size of six ; no stratification ) to drisapersen 6 mg/kg or placebo , each given subcutaneously and either continuously ( once weekly ) or intermittently ( nine doses over 10 weeks ) . The primary endpoint was change in 6-min walk distance ( 6MWD ) at week 25 in patients in the intention-to-treat population for whom data were available . Safety assessment s included renal , hepatic , and haematological monitoring and recording of adverse events . This trial is registered with Clinical Trials.gov , number NCT01153932 . FINDINGS We recruited 53 patients : 18 were given continuous drisapersen , 17 were given intermittent drisapersen , and 18 were given placebo ( continuous and intermittent groups combined ) . At week 25 , mean 6MWD had increased by 31·5 m ( SE 9·8 ) from baseline for continuous drisapersen , with a mean difference in change from baseline of 35·09 m ( 95 % CI 7·59 to 62·60 ; p=0·014 ) versus placebo . We recorded no difference in 6MWD changes from baseline between intermittent drisapersen ( mean change -0·1 [ SE 10·3 ] ) and placebo ( mean difference 3·51 m [ -24·34 to 31·35 ] ) at week 25 . The most common adverse events in drisapersen-treated patients were injection-site reactions ( 14 patients given continuous drisapersen , 15 patients given intermittent drisapersen , and six given placebo ) and renal events ( 13 for continuous drisapersen , 12 for intermittent drisapersen , and seven for placebo ) , most of which were sub clinical proteinuria . None of the serious adverse events reported ( one for continuous , two for intermittent , and two for placebo ) result ed in withdrawal from the study . INTERPRETATION Continuous drisapersen result ed in some benefit in 6MWD versus placebo at week 25 . The safety findings are similar to those from previous studies . Ambulation improvements in this young population with early-stage Duchenne muscular dystrophy are encouraging but need to be confirmed in larger studies . FUNDING GlaxoSmithKline , Prosensa Therapeutics BV ( a subsidiary of Prosensa Holding NV ) In September 2016,theUSFood and DrugAdministration ( FDA ) approved eteplirsen ( Exondys 51 ) , a new drug for Duchenne muscular dystrophy ( DMD ) , overruling the recommendations of both its scientific staff and its external advisory committee . Duchenne muscular dystrophy is a progressive X-linked genetic disease caused by mutations in a gene that produces the protein dystrophin that helps stabilize muscle fibers . It is usually fatal by the third decade of life . No disease-modifying treatments are available . Eteplirsen offered a promising new therapeutic approach that would correct a mutation in a gene coding for dystrophin , allowing production of a truncated but functional version of the protein . In particular , eteplirsen was design ed to skip exon 51 , which would address the mutations in about 10 % to 15 % of patients with DMD ( an estimated 2000 - 2500 cases in the United States ) . Despite this innovative mechanism , the development of eteplirsen was controversial , starting with its manufacturer-supported pivotal double-blind study , which involved only 12 patients : 8 were r and omized to 2 different eteplirsen doses and 4 were r and omized to placebo for 24 weeks . The latter were then switched to eteplirsen and all were to be followed for an additional 24 weeks . The sample size was substantially smaller than the study sample size in which a similar DMD drug , drisapersen , had been tested in 3 r and omized trials that together enrolled 290 patients . The FDA declined to approve drisapersen in 2015 after these studies showed no clear benefit after 24 weeks in prespecified clinical end points , such as changes in a 6-minute walk test . Those trials also suggested the possibility of safety problems , including renal toxic effects and thrombocytopenia . In the eteplirsen study , by contrast , the primary trial end point was a surrogate measure : an increase in the presence of dystrophin in muscle biopsy specimens . Serial biopsies were performed at 12 , 24 , and 48 weeks , although biopsies were performed on only half the treated patients at each of the 12 and 24-week periods ; all 12 patients were receiving drug treatment by week 48 . The biopsy specimens were analyzed by scientists blinded to the patients ’ group assignments but not blinded to the time receiving treatment.1 In a 2013 publication , the authors reported increases to about 50 % of normal in dystrophincontaining fibers in the biopsy specimens,2 results that were met with enthusiasm by the DMD community . However , these results were based on an immunohistochemical assay that assessed only an increase of newly produced dystrophin compared with baseline values . Quantitative Western blot analysis of a fourth biopsy performed in 11 of the study patients after 3 to 3.5 years of continued open-label extension showed an actual increase to only a mean ( SD ) of 0.9 % ( 0.8 % ) of normal dystrophin levels , far less than what might be expected to provide clinical benefit . A more rigorous , fully blinded re analysis of the immunohistochemical assay organized by the FDA cast further doubt on the initial results .3 The trial also assessed clinical progression . At 24 and 48 weeks , there was no consistent advantage in the 6-minute walk test capacity of patients who received eteplirsen compared with those initially given placebo . However , new post hoc calculations excluded 2 eteplirsentreated patients who deteriorated quickly while receiving therapy ; these analyses suggested a statistically significant advantage for the remaining treated patients . These more selective post hoc analyses were highlighted in the figure displaying this finding in the 2013 article2 and in the manufacturer ’s press release announcing the success of the trial.4 Subsequent evaluation of 6-minute walk test data over 3 to 3.5 years of open-label therapy appeared to be associated with slower rates of decline when compared with a historical cohort , but the problematic nature of historical controls complicated the interpretation . Controversy over eteplirsen came into broader public view when the FDA convened an advisory committee in April 2016 to review these data . That hearing included more than a thous and public attendees and more than 4 hours of comments from patients , families , advocates , scientists , and legislators . The public presentations were frequently emotional , and nearly all of the presenters ( 51 of 52 ) favored drug approval . The advisory committee was generally unimpressed with the efficacy data , although the committee split its vote : 7 members found no evidence that eteplirsen was clinical ly effective in treating DMD ( vs 3 in favor and 3 abstentions ) , and 7 members found that the drug did not produce dystrophin at a level likely to result in clinical benefit ( vs 6 in favor ) . After the meeting , the FDA delayed its decision and requested additional data , including Western blot assays from biopsy specimens in 13 patients from another ongoing study at week 48 . These data showed a mean increase in dystrophin to just 0.2 % to 0.3 % of normal . In September 2016 , another reason for the delay was revealed — disagreement within the FDA about the approval decision . The main FDA scientific review ers all opposed approval , but Janet Woodcock , MD , director of the FDA ’s Center for Drug Evaluation and Research , overruled them , suggesting that the extremely small increase in dystrophin might conceivably translate to clinical benefit.1 She indicated that considering the life-threatening nature of the disease and the lack of reasonable alternative treatments , the FDA should exercise “ the greatest flexibility possible ” under its statutory authority in considering eteplirsen ’s efficacy.1 The internal FDA review staff took the unusual step of appealing to Commissioner Robert Califf , MD , who upheld Woodcock ’s decision.1 Aaron S. Kesselheim , MD , JD , MPH Program on Regulation , Therapeutics , and Law ( PORTAL ) , Division of Pharmacoepidemiology and Pharmacoeconomics , Department of Medicine , Brigham and Women ’s Hospital and Harvard Medical School , Boston , Massachusetts |
13,784 | 29,916,111 | Results demonstrated that probiotics used during pregnancy in women with GDM may improve glycaemic control and reduce VDL cholesterol , triglycerides , and inflammatory markers .
Conclusions The present systematic review highlights the importance of probiotics for glycemic control and decrease of inflammatory markers in GDM . | Background Gestational diabetes mellitus ( GDM ) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy .
The aim of this work was to systematic ally review all studies in which probiotic supplements were used during pregnancy and analyse the effects on GDM . | Background Although several studies have found probiotics encouraging in prevention of gestational diabetes mellitus ( GDM ) , the evidence for the use of probiotics in diagnosed GDM is largely limited . The aim of this study was to assess the effect of a probiotic supplement capsule containing four bacterial strains on glucose metabolism indices and weight changes in women with newly diagnosed GDM . Methods Sixty-four pregnant women with GDM were enrolled into a double-blind placebo-controlled r and omized clinical trial . They were r and omly assigned to receive either a probiotic or placebo capsule along with dietary advice for eight consecutive weeks . The trend of weight gain along with glucose metabolism indices was assayed . Results During the first 6 weeks of the study , the weight gain trend was similar between the groups . However , in the last 2 weeks of the study , the weight gain in the probiotic group was significantly lower than in the placebo group ( p < 0.05 ) . Fasting blood sugar ( FBS ) decreased in both intervention ( from 103.7 to 88.4 mg/dl ) and control ( from 100.9 to 93.6 mg/dl ) groups significantly , and the decrease in the probiotic group was significantly higher than in the placebo group ( p < 0.05 ) . Insulin resistance index in the probiotic group had 6.74 % reduction over the study period ( p < 0.05 ) . In the placebo group , however , there was an increase in insulin resistance index ( 6.45 % ) , but the observed change in insulin resistance was not statistically significant . Insulin sensitivity index was increased in both groups . The post-intervention insulin sensitivity index in the probiotic group was not significantly different from placebo when adjusted for the baseline levels . Conclusions The probiotic supplement appeared to affect glucose metabolism and weight gain among pregnant women with GDM . This needs to be confirmed in other setting s before a therapeutic value could be approved The study aims to assess whether supplementation with the probiotic Lactobacillus rhamnosus HN001 ( HN001 ) can reduce the prevalence of gestational diabetes mellitus ( GDM ) . A double-blind , r and omised , placebo-controlled parallel trial was conducted in New Zeal and ( NZ ) ( Wellington and Auckl and ) . Pregnant women with a personal or partner history of atopic disease were r and omised at 14–16 weeks ’ gestation to receive HN001 ( 6 × 109 colony-forming units ) ( n 212 ) or placebo ( n 211 ) daily . GDM at 24–30 weeks was assessed using the definition of the International Association of Diabetes and Pregnancy Study Groups ( IADPSG ) ( fasting plasma glucose ≥5·1 mmol/l , or 1 h post 75 g glucose level at ≥10 mmol/l or at 2 h ≥8·5 mmol/l ) and NZ definition ( fasting plasma glucose ≥5·5 mmol/l or 2 h post 75 g glucose at ≥9 mmol/l ) . All analyses were intention-to-treat . A total of 184 ( 87 % ) women took HN001 and 189 ( 90 % ) women took placebo . There was a trend towards lower relative rates ( RR ) of GDM ( IADPSG definition ) in the HN001 group , 0·59 ( 95 % CI 0·32 , 1·08 ) ( P=0·08 ) . HN001 was associated with lower rates of GDM in women aged ≥35 years ( RR 0·31 ; 95 % CI 0·12 , 0·81 , P=0·009 ) and women with a history of GDM ( RR 0·00 ; 95 % CI 0·00 , 0·66 , P=0·004 ) . These rates did not differ significantly from those of women without these characteristics . Using the NZ definition , GDM prevalence was significantly lower in the HN001 group , 2·1 % ( 95 % CI 0·6 , 5·2 ) , v. 6·5 % ( 95 % CI 3·5 , 10·9 ) in the placebo group ( P=0·03 ) . HN001 supplementation from 14 to 16 weeks ’ gestation may reduce GDM prevalence , particularly among older women and those with previous GDM Objective . This trial aims to examine the effects of a Probiotic Mixture ( VSL#3 ) on glycemic status and inflammatory markers , in women with GDM . Material s and Methods . Over a period of 8 weeks , 82 women with gestational diabetes were r and omly assigned to either an intervention group ( n = 41 ) which were given VSL#3 capsule or to a control group which were given placebo capsule ( n = 41 ) . Fasting plasma glucose , homeostatic model assessment of insulin resistance , glycosylated hemoglobin , high-sensitivity C-reactive protein , tumor necrosis factor-α , interleukin-6 , Interferon gamma , and interleukin-10 were measured before and after the intervention . Results . After 8 wk of supplementation FPG , HbA1c , HOMA-IR , and insulin levels remained unchanged in the probiotic and placebo groups . The comparison between the two groups showed no significant differences with FPG and HbA1c , but there were significant differences in insulin levels and HOMA-IR ( 16.6 ± 5.9 ; 3.7 ± 1.5 , resp . ) . Unlike the levels of IFN-g ( 19.21 ± 16.6 ) , there was a significant decrease in levels of IL-6 ( 3.81 ± 0.7 ) , TNF-α ( 3.10 ± 1.1 ) , and hs-CRP ( 4927.4 ± 924.6 ) . No significant increase was observed in IL-10 ( 3.11 ± 5.7 ) in the intervention group as compared with the control group . Conclusions . In women with GDM , supplementation with probiotics ( VSL#3 ) may help to modulate some inflammatory markers and may have benefits on glycemic control Background / objectives : Owing to excess body weight and increased secretion of inflammatory cytokines primarily during the third trimester , pregnancy is associated with elevated insulin resistance . To our knowledge , no report is available indicating the effects of probiotic yoghurt consumption on serum insulin levels in pregnant women . This study was design ed to determine the effects of daily consumption of probiotic yoghurt on insulin resistance and serum insulin levels of Iranian pregnant women . Subjects/ methods : In this r and omized controlled clinical trial , 70 primigravida pregnant women with singleton pregnancy at their third trimester were participated . We r and omly assigned participants to consume 200 g per day of conventional ( n=33 ) or the probiotic group ( n=37 ) for 9 weeks . The probiotic yoghurt was a commercially available product prepared with the starter cultures of Streptococcus thermophilus and Lactobacillus bulgaricus , enriched with probiotic culture of two strains of lactobacilli ( Lactobacillus acidophilus LA5 ) and bifidobacteria ( Bifidobacterium animalis BB12 ) with a total of min 1 × 107 colony-forming units . Fasting blood sample s were taken at baseline and after 9-week intervention to measure fasting plasma glucose and serum insulin levels . Homeostatic model assessment of insulin resistance ( HOMA-IR ) was used to calculate insulin resistance score . Results : Although consumption of probiotic yogurt for 9 weeks did not affect serum insulin levels and HOMA-IR score , significant differences were found comparing changes in these variables between probiotic and conventional yogurts ( changes from baseline in serum insulin levels : + 1.2±1.2 vs + 5.0±1.1 μIU/ml , respectively , P=0.02 ; and in HOMA-IR score : −0.2±0.3 vs 0.7±0.2 , respectively , P=0.01 ) . Conclusions : It is concluded that in contrast to conventional yogurt , daily consumption of probiotic yogurt for 9 weeks maintains serum insulin levels and might help pregnant women prevent developing insulin resistance Objectives To explore the predictive power of measuring the abdominal fetal fat layer ( FFL ) as a soft tissue marker at 31 , 34 , and 37 weeks ’ gestation to improve the detection of fetal macrosomia in pregnant women with GDM , in addition to the biometric values with close monitoring of maternal blood sugar level and BMI changes . Methods We conducted a prospect i ve observational study at the Department of Obstetrics , University Hospitals , Campus Kiel , Germany , in collaboration with diabetic clinic staff . Participants underwent a third-trimester scan and extra FFL measurements were performed at 31 , 34 , and 37 weeks of gestation . The clinical outcomes of pregnancy and birth weight were collected from the obstetric record . All of the enrolled women had an early pregnancy ultrasound scan to confirm gestational age . Results The FFL at 34 and 37 weeks , with respective cutoff values of > 0.48 cm and > 0.59 cm , showed a very good sensitivity of 60 % for both gestational points , and specificity of 89.3 and 90.6 % , respectively . The probability of fetal macrosomia could be more than doubled if the FFL at 34 weeks was more than 0.48 cm . However , the probability of macrosomia dropped to 16 % if the FFL was ≤0.48 cm . The median FFLs of macrosomic fetuses at 34 and 37 weeks were 0.50 ( IQR 0.10 ) and 0.60 ( IQR 0.25 ) cm , respectively . The mean age of the study population ( n = 80 ) was 32.26 ( SD = 5.06 ) years . In our study population , ten newborns were born with birth weight > 4000 g. The body mass index ( BMI ) for the mothers of later-onset macrosomic newborns showed higher median values of 30 ( IQR 8) , 32 ( IQR 5 ) , and 33 ( IQR 9 ) at 31 , 34 , and 37 weeks , respectively , in comparison to mothers of non-macrosomic newborn . However , the BMI did not show any statistically significant difference from those with normal-weight newborn and did not show any specific sensitivity for predicting macrosomia . Conclusion Measuring the FFL at 34 and 37 weeks of gestation , in addition to the st and ard measurement , might be useful for predicting macrosomia and is worth further evaluation Abstract The human gut microbiome can modulate metabolic health and affect insulin resistance , and it may play an important role in the etiology of gestational diabetes mellitus ( GDM ) . Here , we compared the gut microbial composition of 43 GDM patients and 81 healthy pregnant women via whole-metagenome shotgun sequencing of their fecal sample s , collected at 21–29 weeks , to explore associations between GDM and the composition of microbial taxonomic units and functional genes . A metagenome-wide association study identified 154 837 genes , which clustered into 129 metagenome linkage groups ( MLGs ) for species description , with significant relative abundance differences between the 2 cohorts . Parabacteroides distasonis , Klebsiella variicola , etc . , were enriched in GDM patients , whereas Methanobrevibacter smithii , Alistipes spp . , Bifidobacterium spp . , and Eubacterium spp . were enriched in controls . The ratios of the gross abundances of GDM-enriched MLGs to control-enriched MLGs were positively correlated with blood glucose levels . A r and om forest model shows that fecal MLGs have excellent discriminatory power to predict GDM status . Our study discovered novel relationships between the gut microbiome and GDM status and suggests that changes in microbial composition may potentially be used to identify individuals at risk for GDM BACKGROUND Recent studies have reported beneficial effects of probiotics on maternal glycemia in healthy pregnant women . Obesity significantly increases risk of impaired glucose tolerance in pregnancy , but glycemic effects of probiotics in this specific obstetric group require additional investigation . OBJECTIVE The aim of the Probiotics in Pregnancy Study was to investigate the effect of a probiotic capsule on maternal fasting glucose in obese pregnant women . DESIGN In this placebo-controlled , double-blind , r and omized trial , 175 pregnant women with an early pregnancy body mass index ( BMI ; in kg/m² ) from 30.0 to 39.9 were recruited from antenatal clinics at the National Maternity Hospital , Dublin , Irel and . Exclusion criteria were BMI < 30.0 or > 39.9 , prepregnancy or gestational diabetes , age < 18 y , multiple pregnancy , and fetal anomaly . Women were r and omly assigned to receive either a daily probiotic or a placebo capsule from 24 to 28 wk of gestation in addition to routine antenatal care . The primary outcome was the change in fasting glucose between groups from preintervention to postintervention . Secondary outcomes were the incidence of gestational diabetes and neonatal anthropometric measures . RESULTS In 138 women who completed the study ( 63 women in the probiotic group ; 75 women in the placebo group ) , mean ( ±SD ) early pregnancy BMI was 33.6 ± 2.6 , which differed significantly between probiotic ( 32.9 ± 2.4 ) and placebo ( 34.1 ± 2.7 ) groups . With adjustment for BMI , the change in maternal fasting glucose did not differ significantly between treated and control groups [ -0.09 ± 0.27 compared with -0.07 ± 0.39 mmol/L ; P = 0.391 ; B = -0.05 ( 95 % CI : -0.17 , 0.07 ) ] . There were also no differences in the incidence of impaired glycemia ( 16 % in the probiotic group compared with 15 % in the placebo group ; P = 0.561 ) , birth weight ( 3.70 kg in the probiotic group compared with 3.68 kg in the placebo group ; P = 0.723 ) , or other metabolic variables or pregnancy outcomes . A secondary analysis of 110 women , excluding antibiotic users and poor compliers , also revealed no differences in maternal glucose or other outcomes between groups . CONCLUSION Probiotic treatment of 4 wk during pregnancy did not influence maternal fasting glucose , the metabolic profile , or pregnancy outcomes in obese women BACKGROUND To our knowledge , data on the effects of probiotic supplementation on glycaemic control and lipid concentrations in patients with gestational diabetes mellitus ( GDM ) are scarce . AIM The aim of the present study was to determine the effects of probiotic supplementation on glycaemic control and lipid profiles in GDM patients . METHODS Sixty pregnant women with GDM , primigravida and aged 18 - 40years , were divided into two groups to receive either probiotic capsules ( n=30 ) or a matching placebo ( n=30 ) in this r and omized double-blind , placebo-controlled trial . The patients in the probiotic group took a daily capsule that contained three viable freeze-dried strains : Lactobacillus acidophilus ( 2 × 10(9)CFU/g ) , L. casei ( 2 × 10(9)CFU/g ) and Bifidobacterium bifidum ( 2 × 10(9)CFU/g ) for 6weeks . The placebo group took capsules filled with cellulose for the same time period . Fasting blood sample s were taken at the beginning and end of the study to quantify the relevant markers . RESULTS After 6weeks of intervention , probiotic supplementation vs a placebo result ed in significant decreases in fasting plasma glucose ( -9.2±9.2mg/dL vs + 1.1±12.2mg/dL , P<0.001 ) , serum insulin levels ( -0.8±3.1μIU/mL vs + 4.5±10.6μIU/mL , P=0.01 ) , homoeostasis model assessment ( HOMA ) for insulin resistance ( -0.4±0.9 vs + 1.1±2.5 , P=0.003 ) and HOMA for β-cell function ( + 1.1±9.8 vs + 18.0±42.5 , P=0.03 ) , and a significant increase in the quantitative insulin sensitivity check index ( + 0.007±0.01 vs -0.01±0.02 , P=0.007 ) . In addition , significant decreases in serum triglycerides ( -1.6±59.4mg/dL vs + 27.1±37.9mg/dL , P=0.03 ) and VLDL cholesterol concentrations ( -0.3±11.9mg/dL vs + 5.4±7.6mg/dL , P=0.03 ) were seen following supplementation with the probiotics compared with the placebo . However , no significant changes in other lipid profiles were seen with the intervention . CONCLUSION Overall , the results of our study have demonstrated that taking probiotic supplements for 6weeks in patients with GDM had beneficial effects on glycaemic control , triglycerides and VLDL cholesterol concentrations , although there was no effect on other lipid profiles BACKGROUND Hypoglycemia is common in neonates and may cause adverse neurological outcomes . Guidelines should aim to prevent repeated hypoglycemic episodes in risk groups , but they are not usually stratified according to the severity of hypoglycemia risk , which may lead to inappropriate and redundant interventions . We evaluated the effect of a national prevention guideline stratified according to mild , moderate , and severe risks of hypoglycemia . METHODS From national registers , a population cohort of 22,725 neonates was identified retrospectively before and after implementation of a national guideline . Of these , 1900 had World Health Organization International Classification of Diseases 10 discharge diagnoses of hypoglycemia . Diagnoses indicating hypoglycemia risk [ small/large for gestational age ( SGA/LGA ) , asphyxia , prematurity , maternal insulin-treated diabetes mellitus ] were recorded . Neonatal ward files were evaluated to vali date hypoglycemia diagnoses . Adjusted odds ratios ( aORs ) were calculated , adjusting for sex , parity , SGA , LGA , preterm birth , and asphyxia , where relevant . RESULTS Primiparity and male sex were associated independently with hypoglycemia diagnosis [ aORs , 1.29 ( 1.17 - 1.42 ) and 1.14 ( 1.03 - 1.26 ) , respectively ] . Overall incidence of hypoglycemia at discharge decreased from 9.4 % to 5.5 % after guideline implementation [ aORchange , 0.57 ( 0.50 - 0.64 ) ] . Overall incidence of vali date d hypoglycemia decreased from 2.1 % to 1.2 % [ aOR 0.59 ( 0.46 - 0.77 ) , p<0.001 ] . By risk group , the hypoglycemia incidence decreased from 30.5 % to 18.6 % [ aOR 0.52 ( 0.36 - 0.75 ) ] among SGA neonates , from 25.8 % to 16.4 % [ aOR 0.57 ( 0.42 - 0.76 ) ] among preterm infants , and from 27.4 % to 16.6 % [ aOR 0.63 ( 0.34 - 0.83 ) ] among those with asphyxia . LGA neonates showed a decreased incidence in obstetric wards only . No significant change was observed for the diabetes group . CONCLUSION Stratification of hypoglycemia risk in a hypoglycemia prevention guideline was followed by decreased estimated hypoglycemia incidence , but no causative conclusion could be drawn . Prospect i ve studies with risk stratification for hypoglycemia prevention are encouraged |
13,785 | 30,119,943 | Conclusion : Transtracheal sonography is rapid to perform , with an acceptable degree of sensitivity and specificity for the confirmation of endotracheal intubation . | Study objective : Intubation is routinely performed in the emergency department , and rapid , accurate confirmation is essential to avoid potentially serious adverse outcomes .
The number of studies assessing ultrasonography for the verification of endotracheal tube placement has exp and ed rapidly in recent years .
We performed this systematic review and meta‐ analysis to determine the sensitivity and specificity of transtracheal ultrasonography for the verification of endotracheal tube location . | Introduction In the emergency department setting , it is essential to rapidly and accurately confirm correct endotracheal tube ( ETT ) placement . Ultrasound is an increasingly studied modality for identifying ETT location . However , there has been significant variation in techniques between studies , with some using the dynamic technique , while others use a static approach . This study compared the static and dynamic techniques to determine which was more accurate for ETT identification . Methods We performed this study in a cadaver lab using three different cadavers to represent variations in neck circumference . Cadavers were r and omized to either tracheal or esophageal intubation in equal proportions . Blinded sonographers then assessed the location of the ETT using either static or dynamic sonography . We assessed accuracy of sonographer identification of ETT location , time to identification , and operator confidence . Results A total of 120 intubations were performed : 62 tracheal intubations and 58 esophageal intubations . The static technique was 93.6 % ( 95 % confidence interval [ CI ] [ 84.3 % to 98.2 % ] ) sensitive and 98.3 % specific ( 95 % CI [ 90.8 % to 99.9 % ] ) . The dynamic technique was 92.1 % ( 95 % CI [ 82.4 % to 97.4 % ] ) sensitive and 91.2 % specific ( 95 % CI [ 80.7 % to 97.1 % ] ) . The mean time to identification was 6.72 seconds ( 95 % CI [ 5.53 to 7.9 ] seconds ) in the static technique and 6.4 seconds ( 95 % CI [ 5.65 to 7.16 ] seconds ) in the dynamic technique . Operator confidence was 4.9/5.0 ( 95 % CI [ 4.83 to 4.97 ] ) in the static technique and 4.86/5.0 ( 95 % CI [ 4.78 to 4.94 ] ) in the dynamic technique . There was no statistically significant difference between groups for any of the outcomes . Conclusion This study demonstrated that both the static and dynamic sonography approaches were rapid and accurate for confirming ETT location with no statistically significant difference between modalities . Further studies are recommended to compare these techniques in ED patients and with more novice sonographers Introduction : Confirmation of proper endotracheal tube placement is one of the most important and lifesaving issues of tracheal intubation . The present study was aim ed to evaluate the accuracy of tracheal ultrasonography by emergency residents in this regard . Method : This was a prospect i ve , cross sectional study for evaluating the diagnostic accuracy of ultrasonography in endotracheal tube placement confirmation compared to a combination of 4 clinical confirmation methods of chest and epigastric auscultation , direct laryngoscopy , aspiration of the tube , and pulse oximetry ( as reference test ) . Results : 150 patients with the mean age of 58.52 ± 1.73 years were included ( 56.6 % male ) . Sensitivity , specificity , positive predictive value , negative predictive value , and positive and negative likelihood ratio of tracheal ultrasonography in endotracheal tube confirmation were 96 ( 95 % CI : 92 - 99 ) , 88 ( 95 % CI : 62 - 97 ) , 98 ( 95 % CI : 94 - 99 ) , 78 ( 95 % CI : 53 - 93 ) , 64 ( 95 % CI : 16 - 255 ) , and 0.2 ( 95 % CI : 0.1 - 0.6 ) , respectively . Conclusion : The present study showed that tracheal ultrasonography by trained emergency medicine residents had excellent sensitivity ( > 90 % ) and good specificity ( 80 - 90 ) for confirming endotracheal tube placement . Therefore , it seems that ultrasonography is a proper screening tool in determining endotracheal tube placement Background In emergency setting s , verification of endotracheal tube ( ETT ) location is important for critically ill patients . Ignorance of oesophageal intubation can be disastrous . Many methods are used for verification of the endotracheal tube location ; none are ideal . Quantitative waveform capnography is considered the st and ard of care for this purpose but is not always available and is expensive . Therefore , this feasibility study is conducted to compare a cheaper alternative , bedside upper airway ultrasonography to waveform capnography , for verification of endotracheal tube location after intubation . Methods This was a prospect i ve , single-centre , observational study , conducted at the HRPB , Ipoh . It included patients who were intubated in the emergency department from 28 March 2012 to 17 August 2012 . A waiver of consent had been obtained from the Medical Research Ethics Committee . Bedside upper airway ultrasonography was performed after intubation and compared to waveform capnography . Specificity , sensitivity , positive and negative predictive value and likelihood ratio are calculated . Results A sample of 107 patients were analysed , and 6 ( 5.6 % ) had oesophageal intubations . The overall accuracy of bedside upper airway ultrasonography was 98.1 % ( 95 % confidence interval ( CI ) 93.0 % to 100.0 % ) . The kappa value ( Κ ) was 0.85 , indicating a very good agreement between the bedside upper airway ultrasonography and waveform capnography . Thus , bedside upper airway ultrasonography is in concordance with waveform capnography . The sensitivity , specificity , positive predictive value and negative predictive value of bedside upper airway ultrasonography were 98.0 % ( 95 % CI 93.0 % to 99.8 % ) , 100 % ( 95 % CI 54.1 % to 100.0 % ) , 100 % ( 95 % CI 96.3 % to 100.0 % ) and 75.0 % ( 95 % CI 34.9 % to 96.8 % ) . The likelihood ratio of a positive test is infinite and the likelihood ratio of a negative test is 0.0198 ( 95 % CI 0.005 to 0.0781 ) . The mean confirmation time by ultrasound is 16.4 s. No adverse effects were recorded . Conclusions Our study shows that ultrasonography can replace waveform capnography in confirming ETT placement in centres without capnography . This can reduce incidence of unrecognised oesophageal intubation and prevent morbidity and mortality . Trial registration National Medical Research Register NMRR11100810230 Introduction Recent research has investigated the use of ultrasound ( US ) for confirming endotracheal tube ( ETT ) placement with varying techniques , accuracies , and challenges . Our objective was to evaluate the accuracy of a novel , simplified , four-step ( 4S ) technique . Methods We conducted a blinded , r and omized trial of the 4S technique utilizing an adult human cadaver model . ETT placement was r and omized to tracheal or esophageal location . Three US experts and 45 emergency medicine residents ( EMR ) performed a total of 150 scans . The primary outcome was the overall sensitivity and specificity of both experts and EMRs to detect location of ETT placement . Secondary outcomes included a priori subgroup comparison of experts and EMRs for thin and obese cadavers , time to detection , and level of operator confidence . Results Experts had a sensitivity of 100 % ( 95 % CI = 72 % to 100 % ) and specificity of 100 % ( 95 % CI = 77 % to 100 % ) on thin , and a sensitivity of 93 % ( 95 % CI = 66 % to 100 % ) and specificity of 100 % ( 95 % CI = 75 % to 100 % ) on obese cadavers . EMRs had a sensitivity of 91 % ( 95 % CI = 69 % to 98 % ) and of specificity 96 % ( 95 % CI = 76 % to 100 % ) on thin , and a sensitivity of 100 % ( 95 % CI = 82 % to 100 % ) specificity of 48 % ( 95 % CI = 27 % to 69 % ) on obese cadavers . The overall mean time to detection was 17 seconds ( 95 % CI = 13 seconds to 20 seconds , range : 2 to 63 seconds ) for US experts and 29 seconds ( 95 % CI = 25 seconds to 33 seconds ; range : 6 to 120 seconds ) for EMRs . There was a statistically significant decrease in the specificity of this technique on obese cadavers when comparing the EMRs and experts , as well as an increased overall time to detection among the EMRs . Conclusion The simplified 4S technique was accurate and rapid for US experts . Among novices , the 4S technique was accurate in thin , but appears less accurate in obese cadavers . Further studies will determine optimal teaching time and accuracy in emergency department patients OBJECTIVES This study aim ed to assess the diagnostic accuracy and timeliness of using tracheal ultrasound to examine endotracheal tube placement during emergency intubation . METHODS This was a prospect i ve , observational study , conducted at the emergency department of a national university teaching hospital . Patients received emergency intubation because of impending respiratory failure , cardiac arrest , or severe trauma . The tracheal rapid ultrasound exam ( T.R.U.E. ) was performed during emergency intubation with the transducer placed transversely at the trachea over the suprasternal notch . Quantitative waveform capnography was used as the criterion st and ard for confirmation of tracheal intubation . The main outcome was the concordance between the T.R.U.E. and the capnography . RESULTS A total of 112 patients were included in the analysis , and 17 ( 15.2 % ) had esophageal intubations . The overall accuracy of the T.R.U.E. was 98.2 % ( 95 % confidence interval [ CI ] : 93.7 - 99.5 % ) . The kappa ( κ ) value was 0.93 ( 95 % CI : 0.84 - 1.00 ) , indicating a high degree of agreement between the T.R.U.E. and capnography . The sensitivity , specificity , positive predictive value , and negative predictive value of the T.R.U.E. were 98.9 % ( 95 % CI : 94.3 - 99.8 % ) , 94.1 % ( 95 % CI : 73.0 - 99.0 % ) , 98.9 % ( 95 % CI : 94.3 - 99.8 % ) and 94.1 % ( 95 % CI : 73.0 - 99.0 % ) . The median operating time of the T.R.U.E. was 9.0s ( interquartile range [ IQR ] : 6.0 , 14.0 ) . CONCLUSIONS The application of the T.R.U.E. to examine endotracheal tube placement during emergency intubation is feasible , and can be rapidly performed Background Unrecognized esophageal intubations are associated with significant patient morbidity and mortality . No single confirmatory device has been shown to be 100 % accurate at ruling out esophageal intubations in the emergency department . Recent studies have demonstrated that point-of-care ultrasound ( POCUS ) may be a useful adjunct for confirming endotracheal tube placement ; however , the amount of practice required to become proficient at this technique is unclear . The purpose of this study is to determine the amount of practice required by emergency physicians to become proficient at interpreting ultrasound video clips of esophageal and endotracheal intubations . Methods Emergency physicians and emergency medicine residents completed a baseline interpretation test followed by a 10 min online tutorial . They then interpreted POCUS clips of esophageal and endotracheal intubations in a r and omly selected order . If an incorrect response was provided , the participant completed another practice session with feedback . This process continued until they correctly interpreted ten consecutive ultrasound clips . Descriptive statistics were used to summarize the data . Results Of the 87 eligible physicians , 66 ( 75.9 % ) completed the study . The mean score on the baseline test was 42.9 % ( SD 32.7 % ) . After the tutorial , 90.9 % ( 60/66 ) of the participants achieved proficiency after one practice attempt and 100 % achieved proficiency after two practice attempts . Six intubation ultrasound clips were misinterpreted , for a total error rate of 0.9 % ( 6/684 ) . Overall , the participants had a sensitivity of 98.3 % ( 95 % CI 96.3–99.4 % ) and specificity of 100 % ( 95 % CI 98.9–100 % ) for detecting correct tube location . Scans were interpreted within an average of 4 s ( SD 2.9 s ) of the intubation . Conclusions After a brief online tutorial and only two practice attempts , emergency physicians were able to quickly and accurately interpret ultrasound intubation clips of esophageal and endotracheal intubations STUDY OBJECTIVE Visualization of the vocal cords and end-tidal capnography are the usual st and ards in confirming endotracheal tube placement . Vocal cord visualization is , however , not always possible , and capnography is not 100 % reliable and requires ventilation of the lungs to confirm placement . The goal of this study is to determine the accuracy of ultrasonography for detecting endotracheal tube placement into the trachea and esophagus in real time . METHODS This was a prospect i ve , r and omized , controlled study . Eligible patients were adults undergoing elective surgery requiring intubation . Exclusion criteria were a history of difficult intubation , abnormal airway anatomy , aspiration risk factors , and esophageal disease . Thirty-three patients were enrolled . After induction of anesthesia and neuromuscular blockade , the anesthesiologist placed the endotracheal tube in the trachea and esophagus in r and om order with direct laryngoscopy . During the intubations , a high-frequency , linear transducer was placed transversely on the neck at the suprasternal notch . Two emergency physicians , blinded to the order and performance of the intubations , independently recorded the location of the endotracheal tube according to the real-time ultrasonographic image . A 2-by-2 table was used to calculate sensitivity and specificity of the emergency physicians ' ability to detect placement of the endotracheal tube . RESULTS For each physician , the sensitivity for identifying the first intubation as tracheal was 100 % ( 95 % confidence interval [ CI ] 77 % to 100 % ) with a specificity of 100 % ( 95 % CI 82 % to 100 % ) . One endotracheal tube was unintentionally placed twice in the esophagus , but both tube placements were identified as esophageal by the emergency physicians . CONCLUSION In this pilot study , 2 emergency physicians experienced in ultrasonography accurately detected placement of endotracheal tubes during intubation with ultrasonography in select patients in the controlled environment of the operating room . Future studies should examine the use of ultrasonography to visualize endotracheal tube placement in real time by emergency physicians with less ultrasonographic training ; use of the technique in the emergency department on a wider range of patients , including patients with difficult airways ; and assessment of the utility of ultrasonography in confirmation of endotracheal tube position in already intubated patients STUDY OBJECTIVE To determine the ability of a disposable colorimetric CO2 detector to accurately confirm or refute endotracheal tube placement . DESIGN Two hundred fifty prospect i ve emergency intubations . SETTING Emergency intubations performed in the emergency department , helicopter , and prehospital ground environment . TYPE OF PARTICIPANTS Intubations were performed by emergency medicine residents , paramedics , and flight nurses . INTERVENTIONS The FEF CO2 detector was applied after 250 emergency intubations . Notation of color change indicating intratracheal placement was recorded in each case . Confirmation of refutation of the detector 's results was determined subsequently through traditional methods . RESULTS The sensitivity for confirmation of endotracheal intubation in the 137 patients with a palpable pulse was 100 % . However , only 76 of 103 patients ( sensitivity , 72 % ) in cardiac arrest had endotracheal intubation confirmed by color change . The device was uniformly specific for tracheal intubation in 73 arrested patients in whom a color change was noted ( 100 % ) . There was one instance ( of a total of seven misintubations ) in which a positive color change was noted , but the tube was not intratracheal ( specificity , 86 % ) . Overall sensitivity for tracheal intubation was 88 % ( 95 % confidence limits ; range , 0.83 to 0.92 ) , and specificity for tracheal intubation was 92 % ( 95 % confidence limits ; range , 0.62 to 0.99 ) . CONCLUSION The FEF colorimetric detector reliably detects intratracheal placement in the nonarrested patient . Its use in prolonged cardiac arrest merits further study OBJECTIVES The objective of the present study was to investigate whether the combined use of transcricothyroid membrane ultrasonography and ultrasonographic evaluation for pleural sliding is useful for verifying endotracheal intubation in the ED . METHODS We performed a prospect i ve clinical trial in the ED from January to July 2008 . All patients enrolled in the present study had been admitted to the ED owing to severe airway problems . A linear probe was placed horizontally over the cricothyroid membrane ( dynamic phase ) during the intubation process . Endotracheal intubation was confirmed by ultrasonographic lung sliding . Sensitivity , specificity , positive predictive value ( PPV ) and negative predictive value ( NPV ) were calculated . RESULTS Thirty patients ( 17 men , 13 women ; mean age 59.6 + /- 16.7 [ SD ] years ) were enrolled in the study . Of the 30 , 7 had a history of trauma . Four trauma patients were diagnosed with haemopneumothorax . The ratio of initial oesophageal-to-endotracheal intubation was 3:27 . Sensitivity , specificity , PPV and NPV for endotracheal intubation were 96.3 % , 100 % , 100 % and 75 % , respectively . After verification by ultrasonographic lung sliding , sensitivity , specificity , PPV and NPV were each 100 % . CONCLUSIONS The combination of transcricothyroid membrane ultrasonography and ultrasonographic lung-sliding evaluation could be useful in confirming endotracheal intubation in the ED This prospect i ve , blinded , observational , efficacy study is one of the first to evaluate ultrasound in detecting esophageal intubation , a significant source of morbidity and mortality . We utilized a convenience sample of patients undergoing elective surgery during July 2004 in an urban teaching hospital . Trained Emergency Physician sonographers performed transtracheal ultrasounds of intubations to identify esophageal intubation . In 35 of the 40 patients enrolled , there was intubation of the trachea , whereas esophageal intubation occurred in five patients . Sonographers correctly identified all five esophageal intubations , for a sensitivity of 100 % ( 95 % confidence interval [ CI ] 48 - 100 ) . Ultrasound correctly identified 34 of 35 tracheal intubations and misidentified one result ing in a specificity of 97 % ( 95 % CI 90 - 100 ) . It seems that transtracheal ultrasound may be an efficacious adjunct for detecting esophageal intubation STUDY OBJECTIVE We describe the operators , techniques , success , and adverse event rates of adult emergency department ( ED ) intubation through multicenter prospect i ve surveillance . METHODS Eighteen EDs in the United States , Canada , and Australia recorded intubation data onto a Web-based data collection tool , with a greater than or equal to 90 % reporting compliance requirement . We report proportions with binomial 95 % confidence intervals ( CIs ) and regression , with year as the dependent variable , to model change over time . RESULTS Of 18 participating centers , 5 were excluded for failing to meet compliance st and ards . From the remaining 13 centers , we report data on 17,583 emergency intubations of patients aged 15 years or older from 2002 to 2012 . Indications were medical in 65 % of patients and trauma in 31 % . Rapid sequence intubation was the first method attempted in 85 % of encounters . Emergency physicians managed 95 % of intubations and most ( 79 % ) were physician trainees . Direct laryngoscopy was used in 84 % of first attempts . Video laryngoscopy use increased from less than 1 % in the first 3 years to 27 % in the last 3 years ( risk difference 27 % ; 95 % CI 25 % to 28 % ; mean odds ratio increase per year [ ie , slope ] 1.7 ; 95 % CI 1.6 to 1.8 ) . Etomi date was used in 91 % and succinylcholine in 75 % of rapid sequence intubations . Among rapid sequence intubations , rocuronium use increased from 8.2 % in the first 3 years to 42 % in the last 3 years ( mean odds ratio increase per year 1.3 ; 95 % CI 1.3 to 1.3 ) . The first-attempt intubation success rate was 83 % ( 95 % CI 83 % to 84 % ) and was higher in the last 3 years than in the first 3 ( 86 % versus 80 % ; risk difference 6.2 % ; 95 % CI 4.2 % to 7.8 % ) . The airway was successfully secured in 99.4 % of encounters ( 95 % CI 99.3 % to 99.6 % ) . CONCLUSION In the EDs we studied , emergency intubation has a high and increasing success rate . Both drug and device selection evolved significantly during the study period We studied prospect ively the reliability of clinical methods , end-tidal carbon dioxide ( ETCO(2 ) ) detection , and the esophageal detector device ( EDD ) for verifying tracheal intubation in 137 adult patients in the emergency department . Immediately after intubation , the tracheal tube position was tested by the EDD and ETCO(2 ) monitor , followed by auscultation of the chest . The views obtained at laryngoscopy were classified according to the Cormack grade . Of the 13 esophageal intubations that occurred , one false-positive result occurred in the EDD test and auscultation . In the non-cardiac arrest patients ( n=56 ) , auscultation , the ETCO(2 ) , and EDD test correctly identified 89.3 , 98.2 * , and 94.6 % * of tracheal intubations , respectively ( * , P<0.05 vs. the cardiac arrest patients ) . In the cardiac arrest patients ( n=81 ) , auscultation , the ETCO(2 ) , and the EDD tests correctly identified 92.6 * * , 67.9 , and 75.3 % of tracheal intubations , respectively ( * * , P<0.05 vs. EDD and ETCO(2 ) ) . The frequencies of Cormack grade 1 or 2 were 83.9 % in the non-cardiac arrest , and 95.1 % in the cardiac arrest patients . In conclusion , the ETCO(2 ) monitor is the most reliable method for verifying tracheal intubation in non-cardiac arrest patients . During cardiac arrest and cardiopulmonary resuscitation , however , negative results by the ETCO(2 ) or the EDD are not uncommon , and clinical methods are superior to the use of these devices Background and Objectives : Over the past few years , ultrasonography is increasingly being used to confirm the correct placement of endotracheal tube ( ETT ) . In our study , we aim ed to compare it with the traditional clinical methods and the gold st and ard quantitative waveform capnography . Two primary outcomes were measured in our study . First was the sensitivity and specificity of ultrasonography against the other two methods to confirm endotracheal intubation . The second primary outcome assessed was the time taken for each method to confirm tube placement in an emergency setting . Methods : This is a single-centered , prospect i ve cohort study conducted in an emergency department of a tertiary care hospital . We included 100 patients with indication of emergency intubation by convenient sampling . The intubation was performed as per st and ard hospital protocol . As part of the study protocol , ultrasonography was used to identify ETT placement simultaneously with the intubation procedure along with quantitative waveform capnography ( end-tidal carbon dioxide ) and clinical methods . Confirmation of tube placement and time taken for the same were noted by three separate health-care staffs . Results and Discussion : Out of the 100 intubation attempts , five ( 5 % ) had esophageal intubations . The sensitivity and specificity of diagnosis using ultrasonography were 97.89 % and 100 % , respectively . This was statistically comparable with the other two modalities . The time taken to confirm tube placement with ultrasonography was 8.27 ± 1.54 s compared to waveform capnography and clinical methods which were 18.06 ± 2.58 and 20.72 ± 3.21 s , respectively . The time taken by ultrasonography was significantly less . Conclusions : Ultrasonography confirmed tube placement with comparable sensitivity and specificity to quantitative waveform capnography and clinical methods . But then , it yielded results considerably faster than the other two modalities BACKGROUND : Verification of the correct placement of the endotracheal tube ( ETT ) has been one of the most challenging issues of airway management in the field of emergency medicine . Early detection of oesophagal intubation through a reliable method is important for emergency physicians . AIM : The aim of this study was to assess the diagnostic accuracy of tracheal rapid ultrasound exam ( TRUE ) to assess endotracheal tube misplacement during emergency intubation . METHODS : This was an observational prospect i ve study performed in the emergency department of the major tertiary referral hospital in the city . We included a consecutive selection of 100 patients . TRUE was performed for all these patients , and subsequently , quantitative waveform capnography was done . The later test is considered as the gold st and ard . RESULTS : From our total 100 eligible patients , 93 ( 93 % ) participants had positive TRUE results ( tracheal intubation ) and 7 ( 7 % ) patients have negative TRUE results ( esophageal intubation ) . Quantitative waveform capnography report of all 93 ( 100 % ) patients who had positive TRUE was positive ( appropriate tracheal placement ) . Sensitivity , specificity , positive predictive value ( PPV ) and negative predictive value ( NPV ) of TRUE for detecting appropriate tracheal placement of ETT were 98.9 % ( 95 % CI , 93.3 % to 99.8 % ) , 100 % ( 95 % CI , 51.6 % to 100 % ) , 100 % ( 95 % CI , 95.1 % to 100 % ) and 85.7 % ( 95 % CI , 42 % to 99.2 % ) respectively . CONCLUSIONS : Performing TRUE is convenient and feasible in many emergency departments and pre-hospital setting s. We would recommend emergency units explore the possibility of using TRUE as a method in the assessment of proper ETT placement Background and objective Early confirmation of incorrect endotracheal tube ( ETT ) placement is of vital importance when performing emergency airway management . No ideal confirmation technique has been proposed under all circumstances . Recently , ultrasonography was suggested as a useful tool for confirmation of correct positioning of the ETT . The aim of this study is to assess the diagnostic accuracy of ultrasonography for detection of proper ETT placement . Material s and methods This prospect i ve study was carried out in the emergency department from February to October 2012 . The ultrasonography was performed by a trained senior resident in two phases : ( a ) as the intubation was being performed ( dynamic phase ) and ( b ) after the intubation had been completed ( static phase ) . A linear probe was placed transversely over the cricothyroid membrane during the intubation process ( dynamic phase ) and on the anterior neck just superior to the suprasternal notch in the static method . Operating characteristics were calculated for both dynamic and static determination of ETT placement . Results Sixty patients were enrolled in each study group . The sensitivity , specificity , positive predictive value , and negative predictive value of the dynamic technique for determining correct endotracheal intubation were 98.1 % [ 95 % confidence interval ( CI ) , 88.8–99.9 % ] , 100 % ( 95 % CI , 51.6–100 % ) , 100 % ( 95 % CI , 91.5–100 % ) , and 85.7 % ( 95 % CI , 42–99.2 % ) , respectively . Using the static technique , all testing characteristics listed previously were 100 % . Conclusion In this study , we found acceptable sensitivity , specificity , positive predictive value , and negative predictive value for prediction of tracheal ETT placement with the use of dynamic and static ultrasonography 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 Background and Aims : Confirmation of correct endotracheal tube placement is essential immediately after intubation for general anaesthesia . In this study , we have compared upper airway ultrasonography ( USG ) with reference to capnography for rapid confirmation of endotracheal tube placement after general anaesthesia . Methods : A prospect i ve , single centre , observational study was conducted on 100 patients requiring tracheal intubation for general anaesthesia . Both capnography and upper airway USG were performed immediately after intubation to confirm the endotracheal tube ( ETT ) placement . Sensitivity , specificity , and positive and negative predictive values of upper airway USG were determined against capnography as the reference method . Agreement between the methods and time required to determine ETT placement by the two methods were assessed with kappa statistics and Student 's t-test . Results : Upper airway USG detected all five cases of oesophageal intubation , but could not detect five patients with correct tracheal intubation . Upper airway USG had a sensitivity of 96.84 % ( 95 % confidence interval [ CI ] : 94.25%–96.84 % ) , specificity of 100 % ( 95 % CI : 50.6%–100 % ) , positive predictive value of 100 % ( 95 % CI : 97.3%–100 % ) and negative predictive value of 62.5 % ( 95 % CI : 31.6%–62.5 % ) . Kappa value was found to be 0.76 , indicating a good agreement between upper airway USG and capnography for confirmation of ETT placement . Time taken for confirmation of ETT by capnography was 8.989 ± 1.043 s vs. 12.0 ± 1.318 s for upper airway USG ( P < 0.001 ) . Conclusion : Both capnography and upper airway USG may be used as primary procedures for the confirmation of ETT placement We performed this prospect i ve study to evaluate the efficacy of esophageal detector devices ( EDDs ) , both the bulb and the syringe-type , to indicate positioning of endotracheal tubes ( ETTs ) in out-of-hospital cardiac arrest patients . Forty-eight adult patients with out-of-hospital cardiac arrest were enrolled . Immediately after tracheal intubation and ETT cuff inflation in the emergency department , the patients were allocated r and omly to two cross-over groups . In Group 1 ( n = 24 ) , patients underwent a bulb test and a syringe test in sequence . In Group 2 ( n = 24 ) , patients underwent a syringe test and a bulb test in sequence . End-tidal carbon dioxide ( ETCO2 ) was also monitored . In 56 attempts at tracheal intubation , the bulb , the syringe , and ETCO2 indicated all eight esophageal intubations . In 48 tracheal intubations , the bulb test correctly indicated 34 tracheal intubations ( sensitivity , 70.8 % ) . The syringe test identified 35 tracheal intubations ( sensitivity , 72.9 % ) . The results of both tests agreed in 33 tracheal intubations . ETCO2 was detected in 31 tracheal intubations ( sensitivity , 64.6 % ) . No statistical difference was found among the tests . EDDs were less sensitive in detecting tracheal intubation for out-of-hospital cardiac arrest patients . Therefore , proper clinical judgment in conjunction with these devices should be used to confirm ETT placement in these difficult situations . Implication s The esophageal detector device ( EDD ) failed to confirm endotracheal tube ( ETT ) placement in more than 25 % of tracheal intubations in this study . One must not rely too heavily on the results of the EDD alone , and proper clinical judgment in conjunction with all available modalities should be used to confirm ETT placement in out-of-hospital cardiac arrest patients Introduction : Intubation is a frequently performed procedure in emergency medicine that is associated with significant morbidity and mortality when unrecognized esophageal intubation occurs . However , it may be difficult to visualize the endotracheal tube ( ETT ) in some patients . This study assessed whether the addition of color Doppler was able to improve the ability to visualize the ETT location . Methods : This study was performed in a cadaver lab using three different cadavers chosen to represent varying neck circumference . Cadavers were r and omized to tracheal or esophageal intubation . Blinded sonographers then assessed the location of the ETT using either grayscale or color Doppler imaging . Accuracy of sonographer identification of ETT location , time to identification , and operator confidence were assessed . Results : One hundred and fifty intubations were performed and each was assessed by both st and ard and color Doppler techniques . There were 78 tracheal intubations and 72 esophageal intubations . The st and ard technique was 99.3 % ( 95 % CI 96.3 to 99.9 % ) accurate . The color flow technique was also 99.3 % ( 95 % CI 96.3 to 99.9 % ) accurate . The mean operator time to identification was 3.24 s ( 95 % CI 2.97 to 3.51 s ) in the st and ard approach and 5.75 s ( 95 % CI 5.16 to 6.33 s ) in the color flow technique . The mean operator confidence was 4.99/5.00 ( 95 % CI 4.98 to 5.00 ) in the st and ard approach and 4.94/5.00 ( 95 % CI 4.90 to 4.98 ) in the color flow technique . Conclusion : When added to st and ard ultrasound imaging , color flow did not improve accuracy or operator confidence for identifying ETT location and result ed in a longer examination time OBJECTIVES Establishing a definitive airway is often the first step in emergency department treatment of critically ill patients . Currently , there is no agreed upon consensus as to the most efficacious method of airway confirmation . Our objective was to determine the diagnostic accuracy of real-time sonography performed by resident physicians to confirm placement of the endotracheal tube during emergent intubation . METHODS We performed a prospect i ve cohort study of adult patients in the emergency department undergoing emergent endotracheal intubation . Thirty emergency medicine residents , who were blinded to end-tidal carbon dioxide detection results , performed real-time transverse tracheal sonography during intubation to evaluate correct endotracheal tube placement . RESULTS Seventy-two patients were enrolled in the study . Sixty-eight instances ( 94.4 % ) were interpreted as correct placement in the trachea ; 4 ( 5.6 % ) were interpreted as esophageal , of which 1 was a false-negative finding , therefore conferring sensitivity of 98.5 % ( 95 % confidence interval , 92.1%-99.9 % ) and specificity of 75.0 % ( 95 % confidence interval , 19.4%-99.4 % ) for correct placement . There was no significant difference in accuracy among resident sonographers with different levels of residency training . CONCLUSIONS A simple transverse tracheal sonographic examination performed by emergency medicine resident physicians can be used as an adjunct to help confirm correct endotracheal tube placement during intubation . In our cohort , the level of training did not appear to affect the ability of residents to correctly identify the endotracheal tube position OBJECTIVES The aim of this study was to investigate the usefulness of sonography for verifying tracheal tube placement within 3 seconds in adult surgical patients . METHODS This was a blinded prospect i ve r and omized study . The anesthesiologist placed the tracheal tube r and omly in the trachea ( n = 75 ) or in the esophagus ( n = 75 ) with direct laryngoscopy . A sonographer identified all tracheal and esophageal intubations . The transducer was placed transversely on the neck just superior to the suprasternal notch . The position of the tracheal tube was determined by the sonographer within 3 seconds of tracheal tube placement in the trachea or in the esophagus . RESULTS We successfully identified 150 correct tracheal tube placements in tracheas and esophagi , result ing in sensitivity of 100 % ( 95 % confidence interval , 84%-100 % ) and specificity of 100 % ( 95 % confidence interval , 84%-100 % ) . CONCLUSIONS This investigation shows that sonography for confirming tracheal intubation is a fast and effective technique OBJECTIVE This study aim ed to evaluate the accuracy of tracheal ultrasonography for assessing endotracheal tube position during cardiopulmonary resuscitation ( CPR ) . METHODS We performed a prospect i ve observational study of patients undergoing emergency intubation during CPR . Real-time tracheal ultrasonography was performed during the intubation with the transducer placed transversely just above the suprasternal notch , to assess for endotracheal tube positioning and exclude esophageal intubation . The position of trachea was identified by a hyperechoic air-mucosa ( A-M ) interface with posterior reverberation artifact ( comet-tail artifact ) . The endotracheal tube position was defined as endotracheal if single A-M interface with comet-tail artifact was observed . Endotracheal tube position was defined as intraesophageal if a second A-M interface appeared , suggesting a false second airway ( double tract sign ) . The gold st and ard of correct endotracheal intubation was the combination of clinical auscultation and quantitative waveform capnography . The main outcome was the accuracy of tracheal ultrasonography in assessing endotracheal tube position during CPR . RESULTS Among the 89 patients enrolled , 7 ( 7.8 % ) had esophageal intubations . The sensitivity , specificity , positive predictive value , and negative predictive value of tracheal ultrasonography were 100 % ( 95 % confidence interval [ CI ] : 94.4 - 100 % ) , 85.7 % ( 95 % CI : 42.0 - 99.2 % ) , 98.8 % ( 95 % CI : 92.5 - 99.0 % ) and 100 % ( 95 % CI : 54.7 - 100 % ) , respectively . Positive and negative likelihood ratios were 7.0 ( 95 % CI : 1.1 - 43.0 ) and 0.0 , respectively . CONCLUSIONS Real-time tracheal ultrasonography is an accurate method for identifying endotracheal tube position during CPR without the need for interruption of chest compression . Tracheal ultrasonography in resuscitation management may serve as a powerful adjunct in trained h and |
13,786 | 30,483,083 | Results showed a predominance of greater prefrontal/frontal activity related to meditation , which might indicate the increased recruitment of cognitive/attentional control re sources in naïve and long-term meditators .
This increased frontal activity was also observed when participants were asked to simply react to negative stimuli .
Findings from emotion-related areas were scarce but suggested increased insular activity in meditators , potentially indicating that meditation might be associated with greater bodily awareness .
Conclusions : Meditation practice prompts regulatory mechanisms when participants face aversive stimuli , even without an explicit request .
Moreover , some studies reported increased insular activity in meditators , consistent with the hypothesis that meditation helps foster an interoceptive awareness of bodily and emotional states | Background : Despite several attempts to review and explain how meditation alters the brain and facilitates emotion regulation , the extent to which meditation and emotion regulation strategies share the same neural mechanisms remains unclear .
Objective : We aim to underst and the influence of meditation on the neural processing of negative emotional stimuli in participants who underwent meditation interventions ( naive meditators ) and long-term meditators . | 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 Decentering has been proposed as a potential mechanism of mindfulness-based interventions but has received limited empirical examination to date in experimental studies comparing mindfulness meditation to active comparison conditions . In the present study , we compared the immediate effects of mindful breathing ( MB ) to two alternative stress-management techniques : progressive muscle relaxation ( PMR ) and loving-kindness meditation ( LKM ) to test whether decentering is unique to mindfulness meditation or common across approaches . Novice meditators ( 190 female undergraduates ) were r and omly assigned to complete one of three 15-min stress-management exercises ( MB , PMR , or LKM ) presented by audio recording . Immediately after the exercise , participants completed measures of decentering , frequency of repetitive thoughts during the exercise , and degree of negative reaction to thoughts . As predicted , participants in the MB condition reported greater decentering relative to the other two conditions . The association between frequency of repetitive thought and negative reactions to thoughts was relatively weaker in the MB condition than in the PMR and LKM conditions , in which these two variables were strongly and positively correlated . Consistent with the construct of decentering , the relative independence between these two variables in the MB condition suggests that mindful breathing may help to reduce reactivity to repetitive thoughts . Taken together , results help to provide further evidence of decentering as a potential mechanism that distinguishes mindfulness practice from other credible stress-management approaches Mindfulness meditation is a set of attention-based , regulatory , and self-inquiry training regimes . Although the impact of mindfulness training ( MT ) on self-regulation is well established , the neural mechanisms supporting such plasticity are poorly understood . MT is thought to act through interoceptive salience and attentional control mechanisms , but until now conflicting evidence from behavioral and neural measures renders difficult distinguishing their respective roles . To resolve this question we conducted a fully r and omized 6 week longitudinal trial of MT , explicitly controlling for cognitive and treatment effects with an active-control group . We measured behavioral metacognition and whole-brain blood oxygenation level-dependent ( BOLD ) signals using functional MRI during an affective Stroop task before and after intervention in healthy human subjects . Although both groups improved significantly on a response-inhibition task , only the MT group showed reduced affective Stroop conflict . Moreover , the MT group displayed greater dorsolateral prefrontal cortex responses during executive processing , consistent with increased recruitment of top-down mechanisms to resolve conflict . In contrast , we did not observe overall group-by-time interactions on negative affect-related reaction times or BOLD responses . However , only participants with the greatest amount of MT practice showed improvements in response inhibition and increased recruitment of dorsal anterior cingulate cortex , medial prefrontal cortex , and right anterior insula during negative valence processing . Our findings highlight the importance of active control in MT research , indicate unique neural mechanisms for progressive stages of mindfulness training , and suggest that optimal application of MT may differ depending on context , contrary to a one-size-fits-all approach 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 Mindfulness training aims to impact emotion regulation . Generalized anxiety disorder ( GAD ) symptoms can be successfully addressed through mindfulness-based interventions . This preliminary study is the first to investigate neural mechanisms of symptom improvements in GAD following mindfulness training . Furthermore , we compared brain activation between GAD patients and healthy participants at baseline . 26 patients with a current DSM-IV GAD diagnosis were r and omized to an 8-week Mindfulness Based Stress Reduction ( MBSR , N = 15 ) or a stress management education ( SME , N = 11 ) active control program . 26 healthy participants were included for baseline comparisons . BOLD response was assessed with fMRI during affect labeling of angry and neutral facial expressions . At baseline , GAD patients showed higher amygdala activation than healthy participants in response to neutral , but not angry faces , suggesting that ambiguous stimuli reveal stronger reactivity in GAD patients . In patients , amygdala activation in response to neutral faces decreased following both interventions . BOLD response in ventrolateral prefrontal regions ( VLPFC ) showed greater increase in MBSR than SME participants . Functional connectivity between amygdala and PFC regions increased significantly pre- to post-intervention within the MBSR , but not SME group . Both , change in VLPFC activation and amygdala – prefrontal connectivity were correlated with change in Beck Anxiety Inventory ( BAI ) scores , suggesting clinical relevance of these changes . Amygdala – prefrontal connectivity turned from negative coupling ( typically seen in down-regulation of emotions ) , to positive coupling ; potentially suggesting a unique mechanism of mindfulness . Findings suggest that in GAD , mindfulness training leads to changes in fronto-limbic areas crucial for the regulation of emotion ; these changes correspond with reported symptom improvements Cardiovascular fitness is thought to offset declines in cognitive performance , but little is known about the cortical mechanisms that underlie these changes in humans . Research using animal models shows that aerobic training increases cortical capillary supplies , the number of synaptic connections , and the development of new neurons . The end result is a brain that is more efficient , plastic , and adaptive , which translates into better performance in aging animals . Here , in two separate experiments , we demonstrate for the first time to our knowledge , in humans that increases in cardiovascular fitness results in increased functioning of key aspects of the attentional network of the brain during a cognitively challenging task . Specifically , highly fit ( Study 1 ) or aerobically trained ( Study 2 ) persons show greater task-related activity in regions of the prefrontal and parietal cortices that are involved in spatial selection and inhibitory functioning , when compared with low-fit ( Study 1 ) or nonaerobic control ( Study 2 ) participants . Additionally , in both studies there exist groupwise differences in activation of the anterior cingulate cortex , which is thought to monitor for conflict in the attentional system , and signal the need for adaptation in the attentional network . These data suggest that increased cardiovascular fitness can affect improvements in the plasticity of the aging human brain , and may serve to reduce both biological and cognitive senescence in humans Mindfulness-based stress reduction ( MBSR ) is an established program shown to reduce symptoms of stress , anxiety , and depression . MBSR is believed to alter emotional responding by modifying cognitive-affective processes . Given that social anxiety disorder ( SAD ) is characterized by emotional and attentional biases as well as distorted negative self-beliefs , we examined MBSR-related changes in the brain-behavior indices of emotional reactivity and regulation of negative self-beliefs in patients with SAD . Sixteen patients underwent functional MRI while reacting to negative self-beliefs and while regulating negative emotions using 2 types of attention deployment emotion regulation-breath-focused attention and distraction-focused attention . Post-MBSR , 14 patients completed neuroimaging assessment s. Compared with baseline , MBSR completers showed improvement in anxiety and depression symptoms and self-esteem . During the breath-focused attention task ( but not the distraction-focused attention task ) , they also showed ( a ) decreased negative emotion experience , ( b ) reduced amygdala activity , and ( c ) increased activity in brain regions implicated in attentional deployment . MBSR training in patients with SAD may reduce emotional reactivity while enhancing emotion regulation . These changes might facilitate reduction in SAD-related avoidance behaviors , clinical symptoms , and automatic emotional reactivity to negative self-beliefs in adults with SAD Inhibitory control and error detection are among the highest evolved human self-monitoring functions . Attempts in functional neuroimaging to effectively isolate inhibitory motor control from other cognitive functions have met with limited success . Different brain regions in inferior , mesial , and dorsolateral prefrontal cortices and parietal and temporal lobes have been related to inhibitory control in go/no-go and stop tasks . The widespread activation reflects the fact that the design s used so far have comeasured additional noninhibitory cognitive functions such as selective attention , response competition , decision making , target detection , and inhibition failure . Here we use rapid , mixed trial , event-related functional magnetic resonance imaging to correlate brain activation with an extremely difficult situation of inhibitory control in a challenging stop task that controls for noninhibitory functions . The difficulty of the stop task , requiring withholding of a triggered motor response , was assured by an algorithm that adjusted the task individually so that each subject only succeeded on half of all stop trials , failing on the other half . This design allowed to elegantly separate brain activation related to successful motor response inhibition and to inhibition failure or error detection . Brain activation correlating with successful inhibitory control in 20 healthy volunteers could be isolated in right inferior prefrontal cortex . Failure to inhibit was associated with activation in mesial frontopolar and bilateral inferior parietal cortices , presumably reflecting an attention network for error detection |
13,787 | 30,449,435 | Higher incidences of adverse effects were associated with IV oxycodone .
Conclusions : IV oxycodone can be considered as effective analgesia for acute postoperative pain with careful regards to its adverse effects | Purpose : Intravenous ( IV ) opioids are administered for management of acute postoperative pain in the postanesthesia care unit .
The benefits of parenteral oxycodone for acute pain management are understudied .
The purpose of this review was to evaluate the effectiveness of IV oxycodone for acute postoperative pain . | Background We planned to compare the effect of intravenous oxycodone and fentanyl on post-operative pain after laparoscopic hysterectomy . Methods We examined 60 patients were r and omized to postoperative pain treatment with either oxycodone ( n = 30 , Group O ) or fentanyl ( n = 30 , Group F ) . The patients received 10 mg oxycodone/100 µg fentanyl with ketorolac 30 mg before the end of anesthesia and then continued with patient-controlled analgesia for 48 h postoperatively . Results The accumulated oxycodone consumption was less than fentanyl during 8 , 24 and 48 h postoperatively . Numeric rating score of Group O showed significantly lower than that of Group F during 30 min , 2 , 4 , 8 and 24 h postoperatively . The incidences of adverse reactions were similar in the two groups , though the incidence of nausea was higher in the Group O during the 24 and 48 h postoperative period . Conclusions Oxycodone IV-PCA was more advantageous than fentanyl IV-PCA for laparoscopic hysterectomy in view of accumulated oxycodone consumption , pain control and cost beneficial effect . However , patient satisfaction was not good in the group O compared to group Intravenous morphine and oxycodone were given double blind in doses of 0.05 mg/kg after major abdominal surgery to 39 patients . The dosing interval was 5 min , until the patient did not want any further analgesics . Less oxycodone was needed than morphine , both to achieve the “ first state of pain relief ” ( 13.2 mg vs. 24.9 mg ) and during the whole 2‐h study period ( 21.8 mg vs. 34.2 mg ) . The “ first state of pain relief ” was achieved faster ( 28 min vs. 46 min ) and lasted longer ( 39 min vs. 27 min ) with oxycodone than morphine . Morphine caused more sedation and a greater decrease in the mean arterial blood pressure than oxycodone . In other respects the two opioids were comparable Objectives Oxycodone is semi-synthetic opioid , oral and parenteral preparations have been widely used for acute and chronic pain . The aim of this study was to assess the efficacy and side effects of oxycodone and fentanyl in patient controlled analgesia ( PCA ) after laparoscopic cholecystectomy . Methods A prospect i ve , r and omized , double-blind study was conducted . 81 patients were r and omly divided into two groups ; fentanyl ( 10 mcg fentanyl and 1.5 mg ketorolac ) and oxycodone group ( 1 mg oxycodone and 1.5 mg ketorolac ) . After the operation , a blinded observer assessed pain using a numerical rating scale ( NRS ) , infused PCA dose , side effects , sedation levels , and satisfaction . Results Cumulative PCA dose of oxycodone group at 48 h ( 31.4 ± 16.0 ml ) was significantly less than that of fentanyl group ( 43.8 ± 23.1 ml , P = 0.009 ) . Oxycodone group showed more nausea at 6 - 24 h after the operation ( P = 0.001 ) , but there was no difference in satisfaction score ( P = 0.073 ) . There were no significant differences in other side effects , sedation and NRS scores between two groups . Conclusion Oxycodone showed comparable effects for pain relief compared to fentanyl in spite of less cumulative PCA dose . Based on these results , we could conclude that oxycodone may be useful as an alternative to fentanyl for PCA after laparoscopic cholecystectomy Background Opioids are widely used in boluses and patient-controlled analgesia ( PCA ) for postoperative pain control . In this study , we compared the effects of oxycodone and fentanyl on postoperative pain in patients with intravenous patient-controlled analgesia ( IV-PCA ) after laparoscopic gynecological surgery . Methods Seventy-four patients undergoing elective total laparoscopic hysterectomy or laparoscopic myomectomy were r and omly assigned to the administration of either fentanyl or oxycodone using IV-PCA ( potency ratio 1 : 60 ) . The cumulative dose administered in the patient-controlled mode during the initial 48 hours after the operation was measured . Patients were also assessed for postoperative pain severity , adverse effects , and patient satisfaction . Results No significant differences were observed in patient satisfaction with the analgesia during the postoperative period . Patients in the oxycodone group experienced significantly more dizziness compared to the fentanyl group . Patients in the oxycodone group showed significantly lower consumption of opioid in the patient-controlled mode ( 10.1 ± 8.5 ml vs. 16.6 ± 12.0 ml , P = 0.013 ) . Conclusions Our data suggest that oxycodone and fentanyl demonstrated similar effects , and therefore oxycodone may be a good alternative to fentanyl in postoperative pain management . Further studies in various clinical setting s will be needed to determine the adequate potency ratio The single-dose pharmacokinetics and pharmacodynamics of oxycodone administered by the intravenous and rectal routes were determined in 12 adult cancer patients with moderate to severe cancer pain ( visual analog scale [ VAS ] score , approximately 5 ) . Oxycodone was administered by the intravenous and rectal routes with open drug administration and a cross-over design . After single-dose intravenous administration ( 7.9 + /- 1.5 mg , mean + /- SD ) , the mean ( + /- SD ) terminal half-life was 3.4 h ( + /- 1.1 ) , the mean ( + /- SD ) plasma clearance was 45.4 L/h ( + /- 10.1 ) , and the mean ( + /- SD ) volume of distribution in the terminal phase was 3.0 L/kg ( + /- 1.1 ) . After rectal oxycodone ( 30 mg ) , the mean ( + /- SD ) absorption lag time was 0.52 h ( + /- 0.29 ) and the mean ( + /- SD ) absolute bioavailability was 61.6 % ( + /- 30.2 % ) . Intravenous oxycodone was associated with a rapid onset of pain relief ( 5 - 8 min ) in contrast to the 0.5- to 1.0-h delay observed after rectal administration . However , rectal oxycodone provided analgesia of much longer duration ( approximate equals 8 - 12 h ) than did intravenous oxycodone ( approximate equals 4 h ) . There were no significant differences ( P > 0.05 ) in the incidence and severity of side effects between intravenous and rectal oxycodone . The marked interindividual variation observed in the pharmacokinetics and pharmacodynamics of oxycodone in this study emphasizes the need for individualized dosing regimens . ( Anesth Analg 1995;80:296 - 302 Abstract Visceral pain can be difficult to treat with classical & mgr;‐opioid agonists and it has been suggested to use opioids with distinct pharmacological profiles . In animal experiments , oxycodone has shown different effects compared to morphine , and clinical observations have shown that oxycodone may occasionally be superior to , e.g. , morphine in the treatment of visceral pain . In the current study , we r and omised 24 healthy subjects to treatment with either morphine ( 30 mg ) , oxycodone ( 15 mg ) or placebo in a crossover study . The experimental pain model involved multi‐modal ( mechanical , thermal and electrical ) pain tests in the skin , muscles and viscera . The pain tests were carried out at baseline and 30 , 60 and 90 min after oral administration of the drugs . The model showed effect of the two opioids compared to placebo on all stimulus modalities in all three types of tissues ( all P values < 0.001 ) . Both opioids attenuated the sensory response mainly to painful stimulations . Morphine and oxycodone were equipotent in pain modulation of the skin and muscles , but oxycodone had superior analgesic effect to both morphine and placebo on the mechanical ( P < 0.001 ) and thermal ( P < 0.001 ) stimulations of the oesophagus . In conclusion , the multi‐modal and tissue‐differentiated pain model could link findings from animal experiments to clinical findings . A different pharmacological profile of oxycodone compared to that of morphine was shown , and thus oxycodone may be a useful alternative to morphine in the treatment of visceral pain syndromes According to previous studies oxycodone might have some advantages over morphine in the treatment of visceral pain . This study investigated the opioid consumption ( primary outcome ) , pain relief and side effects ( secondary outcomes ) of morphine versus oxycodone after percutaneous nephrolithotomy using a method where the somatic pain component was minimized . Forty-four adult patients were studied . The patients were r and omised to receive either morphine or oxycodone intravenously as postoperative pain treatment . During the first 4 h after surgery the opioid consumption , pain scores and side effects ( nausea , dizziness , sedation , respiratory effects and itching ) were registered . The postoperative opioid consumption varied considerably between the patients but the mean opioid consumption in the morphine and oxycodone group was comparable ( 18.93 mg versus 16.15 mg , P = 0.7 ) . Nausea was significantly less frequent with morphine ( P = 0.03 ) . In this study morphine and oxycodone produced similar analgesia the first 4 h after surgery but the frequency of nausea was significantly less patient-reported with morphine . The hypothesis that oxycodone would be superior in the treatment of visceral pain after percutaneous kidney stone operation was not confirmed Background : Morphine has been the st and ard opioid in patient‐controlled analgesia ( PCA ) . Oxycodone , the analgesic potency of which in i.v . administration has been suggested to be slightly greater than that of morphine , has not yet been studied for its efficacy in PCA |
13,788 | 30,588,053 | The effect on depression was small , while there was no effect on health-related quality of life .
Exploratory subgroup analyses suggested that interventions using motivational interviewing and individual interventions were associated with incremental effects on DD .
Likewise , intensive interventions were associated with significant reductions in both DD and HbA1c | Diabetes distress ( DD ) disproportionately affects vulnerable people with type 2 diabetes mellitus and interventions targeting this population are therefore relevant .
A systematic review and meta- analysis was performed to assess the evidence for an effect of psychosocial interventions for reducing DD , and , secondly HbA1c , depression , and health-related quality of life in vulnerable people with type 2 diabetes mellitus .
Vulnerability encompasses poor glycemic control ( HbA1c > 7.5 % ) and at least one additional risk factor for poor diabetes outcomes such as low educational level , comorbidity , and risky lifestyle behavior .
The interventions should be theoretically founded and include cognition- or emotion-focused elements . | Adults with type 2 diabetes mellitus often struggle with their antihyperglycemic medication regimens . To improve medication management , providers must ensure that their patients underst and potential benefits , harms , and burdens of available options and elicit patients ' preferences and barriers to taking medications . Patients who are actively involved in treatment decision making tend to be more satisfied with their health care , be more adherent to treatment , and have improved clinical outcomes ( 13 ) . Such discussion s , however , can be too time-consuming for clinic visits . For inner-city low-income African American and Latino adults , low health literacy and limited English proficiency are often additional barriers ( 4 ) that reduce the exchange of information and decrease patient participation during primary care visits ( 58 ) . This contributes to less optimal treatment decisions and lower patient satisfaction , leading to poor medication adherence and outcomes ( 3 , 911 ) . There is therefore an urgent need for cost-effective approaches to enable low-re source health systems to help these high-risk population s gain information and decision support so that they can more actively participate in and improve satisfaction with their treatment decision making . Since 2000 , the REACH ( Racial and Ethnic Approaches to Community Health 2010 ) Detroit Partnership , a coalition of community , health system , and academic partners , has used community-based participatory research principles to guide development , implementation , and evaluation of interventions to meet this need among African American and Latino adults with diabetes in Detroit , Michigan . These interventions have built on evidence that community health workers ( CHWs ) are effective in improving diabetes outcomes , particularly among racial and ethnic minority communities ( 12 ) . CHW interventions train community members to work as bridges between their ethnic , cultural , or geographic communities and health care providers ( 13 ) . Two cohorts of participants in our previous CHW-led diabetes self-management support interventions improved hemoglobin A1c ( HbA1c ) levels and diabetes distress compared with usual care ( 14 , 15 ) . An important next step in increasing the potential effect of CHWs and other lay health care workers is to develop and test effective tools they can use to better present evidence -based information to patients and to help patients make better self-management decisions ( 16 ) . Little is known about the effectiveness of different approaches for nontraditional care providers , such as CHWs , to deliver health information to ethnic minority and low-literacy population s ( 17 ) . By definition , CHWs and other lay workers do not have medical expertise and thus rely on effectively sharing printed educational and support material s with patients as part of their coaching and counseling efforts . Decision aids can increase satisfaction with treatment decisions and result in treatments that better reflect patients ' preferences ( 18 , 19 ) . There is also evidence that tailored health messages are more effective than generic group messages ( 20 , 21 ) , including for patients with diabetes ( 22 , 23 ) . Tailoring individualizes information and behavior change strategies to reach each person based on characteristics unique to that person derived from an individual assessment and related to the outcome of interest ( 24 ) . Software programs that are being developed to automatically embed tailored content into portable e-health Web applications show promise in improving health behaviors and outcomes ( 25 , 26 ) . To date , however , most e-health applications have been design ed for use by patients with relatively high literacy and the skills to navigate them ( 27 ) . Do more sophisticated , tailored , interactive e-health tools increase the effectiveness of CHW outreach with underserved patients compared with reliance on printed educational material s alone ? We addressed this question by developing and evaluating a personally tailored , interactive diabetes medication decision aid ( iDecide [ in English ] or iDecido [ in Spanish ] ) design ed for CHWs to deliver on tablet computers with 3 G wireless access to African American and Latino adults with diabetes and low health literacy . We then evaluated the effectiveness of iDecide in improving key diabetes outcomes compared with CHW delivery of the same evidence -based information , without tailoring , through print consumer booklets developed by the Agency for Healthcare Research and Quality ( AHRQ ) . Methods Setting This study was developed and implemented by using community-based participatory research principles ( 28 ) in partnership with the REACH Detroit Partnership and the Community Health and Social Services Center ( CHASS ) , a federally qualified health center in Southwest Detroit serving more than 13000 patients with 47099 visits in 2012 ( 29 ) . The University of Michigan and CHASS institutional review boards approved the study . Content of AHRQ Consumer Guides The AHRQ guides ( Pills for Type 2 Diabetes and Premixed Insulin for Type 2 Diabetes ) ( 30 , 31 ) provide information on diabetes and summarize the effectiveness of currently available medication classes ( oral and insulin ) on HbA1c . They also provide information on administration methods , costs , medication adverse effects , risks for diabetes complications , suggested questions to discuss with health care providers , and prompts to make notes of any questions for the doctor . The booklets include pictures of patients and tables and graphs summarizing information . Content of iDecide The development process and content of the iDecide program have been described in detail elsewhere ( 32 ) . Briefly , we used community-based participatory research and user-centered design ( 33 , 34 ) principles to iteratively develop and refine the iDecide tool . iDecide is available in English and Spanish , can be delivered via tablet computers , and enables navigation by the CHW and participant to selectively explore issues most important to the participant . The iDecide program is organized into 4 main sections and includes the same content as the AHRQ consumer guides . However , its information is presented in a more graphical style suited to patients with low literacy . Table 1 summarizes key differences between the presentation of information in iDecide and the printed material s. The first section illustrates , through animations , how diabetes affects the way glucose is processed in the body and how different medication classes , foods , and physical activity affect blood glucose . The second section includes pictographs showing participants ' own risk for diabetes complications ( tailored according to their baseline HbA1c ) and enabling participants to explore how their risk for different complications changes with their HbA1c levels . In the third section , participants review their current diabetes medications and barriers to taking the medications they had reported on the baseline survey . This section includes an interactive issue card approach to help elicit patient preferences and priorities about different medication characteristics ( for example , cost , adverse effects , effects on weight , and dosing schedules ) ( 22 , 35 ) . The fourth section prompts participants to set goals and develop specific action plans to address identified barriers or other concerns and identify specific questions and concerns to discuss with their doctor about their medications or making lifestyle changes . Personal information from the baseline assessment is interwoven throughout the program ( high-depth tailoring within sentences ) . Motivational interviewingbased , tailored discussion prompts encourage autonomy-supportive CHWpatient interactions at key points with open-ended questions and values exploration to help participants discover their motivation , overcome barriers to change , and develop an action plan ( 36 ) . Table 1 . Comparison of Content and Mode of Delivery Between the iDecide Study Group and the Printed Material s Group Recruitment and R and omization From September 2011 to August 2012 , potentially eligible participants were identified from a computer-generated list of CHASS patients with physician-diagnosed type 2 diabetes . Inclusion criteria required a HbA1c value greater than 7.5 % in the previous 6 months or expressed concerns about current diabetes medications during the screening assessment . Exclusion criteria were age younger than 21 years , terminal health conditions , self-reported alcohol or drug abuse , and conditions ( such as blindness and dementia ) that would impede meaningful participation . Pregnant women and individuals who reported that they could not be contacted by telephone were also excluded . Introductory letters were sent in timed batches . Research staff then telephoned patients and screened them for eligibility . Interested eligible patients met with research staff , who facilitated completion of written informed consent , administered baseline surveys in English or Spanish , and measured HbA1c and blood pressure . Participants received a stipend of $ 20 after each assessment . Within 1 to 14 days , participants were scheduled for a visit with a CHW ( at home , the clinic , or another agreed-upon place ) . At the beginning of the CHW visits , participants were registered into the iDecide program and r and omly assigned by the computer program , through use of a r and om-sequence algorithm , into 1 of 2 study groups . There were no differences between the steps to participate in either study group . Patients , research staff , and CHWs were blinded to r and omization results through completion of all baseline measures up to the start of the intervention . Data assessors remained blinded to group assignment throughout the study . CHW Intervention for Both Study Groups All participants received an initial one-on-one , face-to-face session with a CHW and a copy of the printed material s to take home . The iDecide sessions lasted approximately 2 hours , and the sessions using printed material s lasted OBJECTIVE To compare glycemic control and secondary outcomes of a 4-month telephonic couples behavioral intervention to individual intervention , and to education , for adults with type 2 diabetes . RESEARCH DESIGN AND METHODS A r and omized trial with the following three arms : couples calls ( CC ) ( n = 104 ) ; individual calls ( IC ) ( n = 94 ) ; and diabetes education ( DE ) ( n = 82 ) . All arms had self-management education ( two calls ) . CC and IC had 10 additional behavior change calls . CC addressed collaboration and relationships/communication . Participants consisted of 280 couples , among whom one partner had type 2 diabetes and an A1C level ≥7.5 % . Blinded assessment s occurred at 4 , 8 , and 12 months . The primary outcome was change in A1C ; and secondary outcomes were BMI , waist circumference , blood pressure , depressive symptoms , diabetes self-efficacy , and diabetes distress . RESULTS Patients had a mean age of 56.8 years ; 61.6 % were male , and 30.4 % were minorities . The baseline mean A1C level was 9.1 % . Intention-to-treat analyses found significant A1C reductions for all ( 12 months : CC −0.47 % , IC −0.52 % , DE −0.57 % ) , with no differences between arms . Preplanned within-arm analyses were stratified by baseline A1C tertiles : lowest tertile ( 7.5–8.2 % ) , no change from baseline ; middle tertile ( 8.3–9.2 % ) , only CC led to significantly lower A1C level ; and highest tertile ( ≥9.3 % ) , significant improvement for all interventions . For BMI , CC showed significant improvement , and CC and DE led to decreased waist circumference . The IC group showed greater blood pressure improvement . Results for secondary psychosocial outcomes favored the CC group . CONCLUSIONS In adults with poorly controlled type 2 diabetes , a collaborative couples intervention result ed in significant , lasting improvement in A1C levels , obesity measures , and some psychosocial outcomes . For those with exceedingly high A1C levels , education alone was beneficial , but additional intervention is needed to achieve glycemic targets OBJECTIVE To determine the concurrent , prospect i ve , and time-concordant relationships among major depressive disorder ( MDD ) , depressive symptoms , and diabetes distress with glycemic control . RESEARCH DESIGN AND METHODS In a noninterventional study , we assessed 506 type 2 diabetic patients for MDD ( Composite International Diagnostic Interview ) , for depressive symptoms ( Center for Epidemiological Studies -Depression ) , and for diabetes distress ( Diabetes Distress Scale ) , along with self-management , stress , demographics , and diabetes status , at baseline and 9 and 18 months later . Using multilevel modeling ( MLM ) , we explored the cross-sectional relationships of the three affective variables with A1C , the prospect i ve relationships of baseline variables with change in A1C over time , and the time-concordant relationships with A1C . RESULTS All three affective variables were moderately intercorrelated , although the relationship between depressive symptoms and diabetes distress was greater than the relationship of either with MDD . In the cross-sectional MLM , only diabetes distress but not MDD or depressive symptoms was significantly associated with A1C . None of the three affective variables were linked with A1C in prospect i ve analyses . Only diabetes distress displayed significant time-concordant relationships with A1C . CONCLUSIONS We found no concurrent or longitudinal association between MDD or depressive symptoms with A1C , whereas both concurrent and time-concordant relationships were found between diabetes distress and A1C . What has been called “ depression ” among type 2 diabetic patients may really be two conditions , MDD and diabetes distress , with only the latter displaying significant associations with A1C . Ongoing evaluation of both diabetes distress and MDD may be helpful in clinical setting Technology and improved care coordination models can help diabetes educators and providers meet national care st and ards and provide culturally sensitive diabetes education that may improve diabetes outcomes . The purpose of the study was to evaluate the clinical usefulness of a nurse-led diabetes care program ( Comprehensive Diabetes Management Program , CDMP ) for poorly controlled Hispanic type 2 diabetes ( T2DM ) patients in an urban community health center setting . Patients were r and omized to the intervention condition ( IC ; n = 21 ) or an attention control condition ( AC ; n = 18 ) . IC and AC conditions were compared on rates of adherence to national clinical practice guidelines ( blood glucose , blood pressure , foot exam , eye exam ) , and levels of diabetes distress , depression , and treatment satisfaction . IC patients had a significant improvement in A1C from baseline to 12-month follow-up compared with AC ( −1.6 % ± 1.4 % versus −0.6 % ± 1.1 % ; P = .01 ) . The proportion of IC patients meeting clinical goals at follow-up tended to be higher than AC for A1c ( IC = 45 % ; AC = 28 % ) , systolic blood pressure ( IC = 55 % ; AC = 28 % ) , eye screening ( IC = 91 % ; AC = 78 % ) , and foot screening , ( IC = 86 % ; AC = 72 % ) . Diabetes distress and treatment satisfaction also showed greater improvement for IC than AC ( P = .05 and P = .06 , respectively ) , with no differences for depression . The CDMP intervention was more effective than an attention control condition in helping patients meet evidence -based guidelines for diabetes care Purpose The purpose of the study was to investigate the effects of a family-based self-management support intervention for adults with type 2 diabetes ( T2DM ) . Methods Using a 2-group , experimental repeated measures design , 157 dyads ( participant with T2DM and family member ) were r and omly assigned to an intervention ( education , social support , home visits , and telephone calls ) or a wait list control group . Data were collected at baseline , postintervention ( 3 months ) , and 6 months postintervention . A series of 2 × 3 repeated measures ANOVAs were used to test the hypotheses with interaction contrasts to assess immediate and sustained intervention effects . Results Significant changes over time were reported in diet self-management , exercise self-management , total self-management , diabetes self-efficacy for general health and total diabetes self-efficacy , physician distress , regimen distress , interpersonal distress , and total distress . There were likewise sustained effects for diet self-management , total self-management , diabetes self-efficacy for general health , total self-efficacy , physician distress , regimen distress , and interpersonal distress . Conclusions Results support and extend prior research documenting the value of culturally relevant family-based interventions to improve diabetes self-management and substantiate the need for intensive , longer , tailored interventions to achieve glycemic control OBJECTIVE Cross-sectional and longitudinal associations among regimen distress ( RD ) , self-management , and glycemic control were undertaken to explore mechanisms of operation among these variables . RESEARCH DESIGN AND METHODS In a behavioral r and omized control trial ( RCT ) to reduce RD , 392 adults with type 2 diabetes were assessed for RD , diet , exercise , medication adherence , and HbA1c at baseline and at 4 and 12 months . Associations among RD , self-management , and HbA1c were examined in cross-sectional analyses at baseline , in prospect i ve analyses using baseline values to predict change over time , and in time-varying analyses . RESULTS At baseline , greater RD and poorer medication adherence were independently associated with higher HbA1c ( P = 0.05 and P < 0.001 , respectively ) , and greater RD was associated with poorer medication adherence ( P = 0.03 ) . No consistent pattern of significant prospect i ve associations was found . Significant time-varying findings showed that decreases in RD were associated with improvements in medication adherence ( P < 0.01 ) , physical activity ( P < 0.001 ) , and HbA1c ( P = 0.02 ) over time following intervention . Changes in self-management were not associated with changes in HbA1c over time . CONCLUSIONS In the context of an RCT to reduce distress , RD , self-management , and HbA1c were interrelated in cross-sectional and time-varying analyses . Decreases in RD were associated with improvements in both self-management and HbA1c over 12 months . Findings point to the complex and likely multifaceted pathways of association among these key constructs , with results indicating significant linkages between RD and both self-management and glycemic control over time Native Hawaiians and other Pacific Isl and ers ( NH/PI ; e.g. , Samoan and Chuukese ) have higher type 2 diabetes prevalence compared to other groups in Hawai‘i . Partners in Care ( PIC ) , a culturally tailored , community-based , diabetes self-management education intervention ( DSME ) , is effective at improving participants ' glycemic control and self-care behaviors . Maintenance of improvements is challenging . Diabetes-related social support groups ( SSG ) are a promising maintenance component for DSME . This study examined the effects of a diabetes-specific SSG component relative to a control group , after the receipt of the 3-month PIC intervention , which was delivered to 47 adult NH/PI with type 2 diabetes . Participants were then r and omized to either a 3-month , 6-session SSG or a control group . Hemoglobin A1c ( HbA1c ) , blood pressure , triglycerides , cholesterol , and diabetes self-management knowledge and behaviors were assessed at baseline , 3 months , and 6 months . Results indicated significant improvements in HbA1c , diabetes-related self-management knowledge , and behaviors from baseline to 3-month assessment . However , no differences between the SSG and control group from 3-month to 6-month assessment suggest that all participants were able to maintain initial improvements . The SSG group had a significant decrease in systolic blood pressure from 3-month to 6-month assessment while the control group did not . Study limitations and future directions are discussed AIMS To test the efficacy of a community health worker ( CHW ) delivered stress management ( SM ) intervention on psychosocial , glycemic , and cortisol outcomes among U.S. Latinos with type 2 diabetes . METHODS A r and omized , controlled trial compared CHW-delivered diabetes education ( DE ; one group session ) to DE plus CHW-delivered SM ( DE+SM ; 8 group sessions ) . Psychosocial variables and urinary cortisol were measured at baseline and posttreatment . HbA1c was measured at baseline , posttreatment , and 3-month follow-up . RESULTS In intent to treat analysis , compared to DE ( n=46 ) , DE+SM ( n=61 ) showed significantly improved symptoms of depression , anxiety , and self-reported health status . There were no significant group effects for HbA1c , diabetes distress , or urinary cortisol . However , there was a dose response effect for HbA1c and diabetes distress ; increasing attendance at SM sessions was associated with greater improvements in HbA1c and diabetes distress . CONCLUSIONS This is the first r and omized , controlled trial demonstrating that CHWs can improve psychological symptoms and self-reported health among Latinos with type 2 diabetes . Efforts to increase intervention attendance may improve HbA1c and diabetes distress 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 OBJECTIVES We tested the effectiveness of a culturally tailored , behavioral theory-based community health worker intervention for improving glycemic control . METHODS We used a r and omized , 6-month delayed control group design among 164 African American and Latino adult participants recruited from 2 health systems in Detroit , Michigan . Our study was guided by the principles of community-based participatory research . Hemoglobin A1c ( HbA1c ) level was the primary outcome measure . Using an empowerment-based approach , community health workers provided participants with diabetes self-management education and regular home visits , and accompanied them to a clinic visit during the 6-month intervention period . RESULTS Participants in the intervention group had a mean HbA1c value of 8.6 % at baseline , which improved to a value of 7.8 % at 6 months , for an adjusted change of -0.8 percentage points ( P < .01 ) . There was no change in mean HbA1c among the control group ( 8.5 % ) . Intervention participants also had significantly greater improvements in self-reported diabetes underst and ing compared with the control group . CONCLUSIONS This study contributes to the growing evidence for the effectiveness of community health workers and their role in multidisciplinary teams engaged in culturally appropriate health care delivery AIM To determine whether glycemic control is improved when motivational interviewing ( MI ) , a patient-centered behavior change strategy , is used with diabetes self management education ( DSME ) as compared to DSME alone . METHODS poorly controlled type 2 diabetes ( T2DM ) patients ( n=234 ) were r and omized into 4 groups : MI+DSME or DSME alone , with or without use of a computerized summary of patient self management barriers . We compared HbA1c changes between groups at 6 months and investigated mediators of HbA1c change . RESULTS study patients attended the majority of the four intervention visits ( mean 3.4 ) , but drop-out rate was high at follow-up research visits ( 35 % ) . Multiple regression showed that groups receiving MI had a mean change in HbA1c that was significantly lower ( less improved ) than those not receiving MI ( t=2.10 ; p=0.037 ) . Mediators of HbA1c change for the total group were diabetes self-care behaviors and diabetes distress ; no between-group differences were found . CONCLUSIONS DSME improved blood glucose control , underlining its benefit for T2DM management . However , MI+DSME was less effective than DSME alone . Overall , weak support was found for the clinical utility of MI in the management of T2DM delivered by diabetes educators Context Many patients have both diabetes and depression . Some hypothesize that treating depression might improve diabetes outcomes . Contribution In this r and omized trial , 12 months of depression care management for depressed patients with diabetes improved depression-related outcomes and increased the frequency of exercise . However , care management did not affect diet , diabetes medication adherence , glucose testing , or glycemic control . Caution s The study sample had reasonably good diabetes control at baseline . Whether patients with poorly controlled diabetes would benefit from depression care is not known . The Editors Major depression and dysthymic disorder affect 5 % to 10 % of older adults seen in primary care setting s ( 1 - 3 ) . Late-life depression is often chronic or recurrent ( 4 - 6 ) and is associated with substantial suffering , functional impairment , and diminished health-related quality of life ( 7 ) . Diabetes mellitus affects 7.8 % of all adults and almost 1 in 5 of those age 60 years and older ( 8) . Individuals with diabetes mellitus have a 2-fold higher rate of major depression than those without diabetes ( 9 , 10 ) . Depression adversely affects the course of coexisting medical illness , contributing to increased symptom burden , functional impairment , and mortality ( 11 , 12 ) . For patients with diabetes mellitus , depression is associated with decreased glycemic control and increased number of micro- and macrovascular complications ( 13 , 14 ) . The mechanism of effect is not understood but may be related to depression-induced abnormalities in neuroendocrine and neurotransmitter function or decreased self-care behaviors ( 15 - 20 ) . Integrating evidence -based depression care for persons with diabetes may improve both depression and diabetes outcomes . Three small r and omized , controlled trials have studied the effect of treatment for depression on affective and glycemic outcomes in patients with depression and diabetes mellitus ( 21 - 23 ) . These studies have consistently shown improvements in affective outcomes , but effects on glycemic control have been mixed . Primary care physicians are well positioned to provide integrated care for depression and diabetes mellitus but face many barriers . Controlled trials report that treatment for depression is efficacious in approximately 70 % of persons who complete treatment compared with 30 % of those who receive placebo ( 24 ) . However , these results are difficult to replicate in routine primary care practice . Barriers to high- quality care include suboptimal recognition ; inconsistent treatment with lack of close follow-up and monitoring ; and organizational barriers , such as brief visits , poor integration with specialty mental health care , competing clinical priorities , and lack of decision support systems ( 25 - 27 ) . Simple interventions , such as depression screening and physician education , have little impact on these barriers and patient outcomes ( 28 - 30 ) . Treatment models that use a depression specialist working collaboratively with primary care physicians have shown clinical ly important improvement in patient outcomes ( 31 - 37 ) . We recently reported robust effects of such a model for older adults with major depression or dysthymia ( 37 ) . In this preplanned analysis , we evaluate the effects on affective and diabetes-specific outcomes . If effective care for depression also benefits adherence to self-care regimens , functional status , and other medical illness outcomes , it would add powerful quality -of-care and economic incentives for the dissemination and maintenance of these models . In addition , if effective care for depression improves self-care behaviors , it may also positively affect other chronic medical illnesses with important self-care components . For this prespecified subgroup analysis , we focused on older adults with clinical depression and coexisting diabetes mellitus . We hypothesized that the collaborative care intervention would improve affective symptoms , functional status , self-care behaviors , and glycemic control . In addition , we hypothesized that effects on glycemic control would be greatest for patients with baseline hemoglobin A1c values of 8.0 % or greater . Methods The Improving MoodPromoting Access to Collaborative Treatment ( IMPACT ) study is a multisite r and omized , controlled trial of a collaborative care intervention program for late-life depression in primary care ( 37 , 38 ) . Institutional review boards at participating sites approved study protocol s , and all participants gave written informed consent . Patients Seven study sites representing 8 diverse health care organizations with a total of 18 primary care clinics in 5 states participated in the study . From July 1999 to August 2001 , depressed older adults were recruited through referrals from primary care practitioners and other clinic staff or through systematic depression screening with a 2-item depression screener adapted from the Primary Care Evaluation of Mental Disorders ( 39 ) . Of the 2190 patients referred to the study , 308 ( 14 % ) declined the initial eligibility screening or additional interviews , 54 ( 3 % ) had incomplete initial screenings , and 202 ( 9 % ) were ineligible because they were younger than 60 years of age or they did not plan to use the participating clinic over the coming 12 months . Of the 32908 patients approached for screening , 5246 ( 16 % ) declined the initial screening or follow-up interviews . A total of 1791 ( 5 % ) of the initial screenings were incomplete and 23233 ( 71 % ) of those screened were not eligible because they did not have one of the core depression symptoms ( 95 % ) or because of logistic reasons such as lack of transportation or access to a telephone ( 5 % ) . The remaining 1626 ( 74 % ) of those referred and 2638 ( 8 % ) of those screened completed a computer-assisted structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders , fourth edition ( DSM-IV ) , to assess whether patients met research diagnostic criteria for major depression or dysthymia ( 40 ) . Inclusion criteria were age 60 years or older , plans to use one of the participating clinics as the main source of general medical care in the coming year , and a diagnosis of current major depression or dysthymic disorder according to the structured clinical interview for DSM-IV . Otherwise eligible persons were excluded because of a current drinking problem ( a score of 2 on the CAGE question naire ) ( 41 ) , a history of bipolar disorder or psychosis ( 38 ) , ongoing treatment with a psychiatrist , or severe cognitive impairment defined by a score less than 3 on a 6-item cognitive screener ( 42 ) . We identified 2102 eligible older adults with major depression or dysthymic disorder , of whom 1801 ( 86 % ) enrolled in the study . As part of the structured baseline interview , enrolled patients were asked Has a doctor or another health care worker diagnosed you with or treated you for high blood sugar or diabetes in the past 3 years ? The 417 patients who endorsed this question are the focus of the diabetes-specific analyses . After the baseline interview , we r and omly assigned participants to the IMPACT intervention or usual care . The r and omization was stratified by recruitment method ( screening or referral ) and clinic . R and omization information was contained in a set of numbered , sealed envelopes for each stratum that were used sequentially for newly enrolled patients at each clinic ( 38 ) . Diagnoses were communicated to enrolled patients and their primary care physicians . Intervention Patients in the intervention group received a 20-minute educational videotape and a booklet about late-life depression and were encouraged to have an initial visit with a depression care manager at the primary care clinic ( 43 , 44 ) . Care managers were nurses or psychologists who were trained for the study as a depression clinical specialist ( 38 , 45 ) . During the initial visit , the depression clinical specialist conducted a clinical and psychosocial history , review ed the educational material s , and discussed patient preferences for depression treatment ( antidepressant medications or psychotherapy ) . New patients and patients needing treatment plan adjustments were discussed with a supervising team psychiatrist and a liaison primary care physician during a weekly team meeting . The depression clinical specialist then worked with the patient and his or her regular primary care provider to establish a treatment plan according to an evidence -based treatment algorithm ( 38 ) . The IMPACT algorithm suggested an initial choice of an antidepressant ( usually a selective serotonin reuptake inhibitor ) or a course of Problem-Solving Treatment in Primary Care ( PST-PC ) , which consisted of 6 to 8 brief sessions of structured psychotherapy for depression , delivered by the depression clinical specialist in primary care ( 46 - 49 ) . For patients who were already receiving antidepressant medications but who were still depressed , the recommendation for partial responders was to increase the dose or augment the antidepressant with a trial of PSTPC ; the recommendation for nonresponders was to switch to a different medication or use a trial of PSTPC . Depression clinical specialists also encouraged patients to increase behavioral activation and referred them to additional health or social services , as clinical ly indicated . The intervention did not specifically address diabetes mellitus or other coexisting medical illnesses . As care managers , depression clinical specialists attempted to follow patients for up to 12 months ; they monitored treatment response with the Primary Care Evaluation of Mental Disorders Patient Health Question naire ( 50 ) and a Web-based clinical information system ( 51 ) . During the acute treatment phase , in-person or telephone follow-up contacts were suggested at least every other week . Patients who recovered from depression ( 50 % reduction in the Patient Health Question naire score and <3 of 9 symptoms of major depression ) were engaged in developing a relapse prevention plan and were then OBJECTIVE To evaluate an online disease management system supporting patients with uncontrolled type 2 diabetes . MATERIAL S AND METHODS Engaging and Motivating Patients Online With Enhanced Re sources for Diabetes was a 12-month parallel r and omized controlled trial of 415 patients with type 2 diabetes with baseline glycosylated hemoglobin ( A1C ) values ≥7.5 % from primary care sites sharing an electronic health record . The intervention included : ( 1 ) wirelessly uploaded home glucometer readings with graphical feedback ; ( 2 ) comprehensive patient-specific diabetes summary status report ; ( 3 ) nutrition and exercise logs ; ( 4 ) insulin record ; ( 5 ) online messaging with the patient 's health team ; ( 6 ) nurse care manager and dietitian providing advice and medication management ; and ( 7 ) personalized text and video educational ' nuggets ' dispensed electronically by the care team . A1C was the primary outcome variable . RESULTS Compared with usual care ( UC , n=189 ) , patients in the intervention ( INT , n=193 ) group had significantly reduced A1C at 6 months ( -1.32 % INT vs -0.66 % UC ; p<0.001 ) . At 12 months , the differences were not significant ( -1.14 % INT vs -0.95 % UC ; p=0.133 ) . In post hoc analysis , significantly more INT patients had improved diabetes control ( > 0.5 % reduction in A1C ) than UC patients at 12 months ( 69.9 ( 95 % CI 63.2 to 76.5 ) vs 55.4 ( 95 % CI 48.4 to 62.5 ) ; p=0.006 ) . CONCLUSIONS A nurse-led , multidisciplinary health team can manage a population of diabetic patients in an online disease management program . INT patients achieved greater decreases in A1C at 6 months than UC patients , but the differences were not sustained at 12 months . More INT than UC patients achieved improvement in A1C ( > 0.5 % decrease ) . Trial registered in clinical trials.gov : # NCT00542204 Background The ' Hawthorne Effect ' may be an important factor affecting the generalisability of clinical research to routine practice , but has been little studied . Hawthorne Effects have been reported in previous clinical trials in dementia but to our knowledge , no attempt has been made to quantify them . Our aim was to compare minimal follow-up to intensive follow-up in participants in a placebo controlled trial of Ginkgo biloba for treating mild-moderate dementia . Methods Participants in a dementia trial were r and omised to intensive follow-up ( with comprehensive assessment visits at baseline and two , four and six months post r and omisation ) or minimal follow-up ( with an abbreviated assessment at baseline and a full assessment at six months ) . Our primary outcomes were cognitive functioning ( ADAS-Cog ) and participant and carer-rated quality of life ( QOL-AD ) . Results We recruited 176 participants , mainly through general practice s. The main analysis was based on Intention to treat ( ITT ) , with available data . In the ANCOVA model with baseline score as a co-variate , follow-up group had a significant effect on outcome at six months on the ADAS-Cog score ( n = 140 ; mean difference = -2.018 ; 95%CI -3.914 , -0.121 ; p = 0.037 favouring the intensive follow-up group ) , and on participant-rated quality of life score ( n = 142 ; mean difference = -1.382 ; 95%CI -2.642 , -0.122 ; p = 0.032 favouring minimal follow-up group ) . There was no significant difference on carer quality of life . Conclusion We found that more intensive follow-up of individuals in a placebo-controlled clinical trial of Ginkgo biloba for treating mild-moderate dementia result ed in a better outcome than minimal follow-up , as measured by their cognitive functioning . Trial registration Current controlled trials : IS RCT OBJECTIVE To compare usual diabetes care ( UDC ) to a comprehensive diabetes care intervention condition ( IC ) involving an Internet-based “ diabetes dashboard ” management tool used by clinicians . RESEARCH DESIGN AND METHODS We used a parallel-group r and omized design . Diabetes nurses , diabetes dietitians , and providers used the diabetes dashboard as a clinical decision support system to deliver a five-visit , 6-month intervention to 199 poorly controlled ( HbA1c > 7.5 % [ 58 mmol/mol ] ) Latino type 2 diabetic ( T2D ) patients ( mean age 55 years , 60 % female ) at urban community health centers . We compared this intervention to an established , in-house UDC program ( n = 200 ) for its impact on blood glucose control and psychosocial outcomes . RESULTS Recruitment and retention rates were 79.0 and 88.5 % , respectively . Compared with UDC , more IC patients reached HbA1c targets of < 7 % ( 53 mmol/mol ; 15.8 vs. 7.0 % , respectively , P < 0.01 ) and < 8 % ( 64 mmol/mol ; 45.2 vs. 25.3 % , respectively , P < 0.001 ) . In multiple linear regression adjusting for baseline HbA1c , adjusted mean ± SE HbA1c at follow-up was significantly lower in the IC compared with the UDC group ( P < 0.001 ; IC 8.4 ± 0.10 % ; UDC 9.2 ± 0.10 % ) . The results showed lower diabetes distress at follow-up for IC patients ( 40.4 ± 2.1 ) as compared with UDC patients ( 48.3 ± 2.0 ) ( P < 0.01 ) , and also lower social distress ( 32.2 ± 1.3 vs. 27.2 ± 1.4 , P < 0.01 ) . There was a similar , statistically significant ( P < 0.01 ) improvement for both groups in the proportion of patients moving from depressed status at baseline to nondepressed at follow-up ( 41.8 vs. 40 % ; no significance between groups ) . CONCLUSIONS The diabetes dashboard intervention significantly improved diabetes-related outcomes among Latinos with poorly controlled T2D compared with a similar diabetes team condition without access to the diabetes dashboard OBJECTIVES To evaluate whether outcomes from diabetes self-management education for patients with suboptimal control were sustained . STUDY DESIGN A r and omized controlled trial of 623 adults with type 2 diabetes and glycated hemoglobin ( A1C ) > 7 % assigned to receive conventional individual education ( IE ) , group education ( GE ) using US Diabetes Conversation Maps , or usual care ( UC ) with no education . METHODS A1C tests , Problem Areas in Diabetes ( PAID ) , Diabetes Self-Efficacy ( DES ) , Recommended Food Score ( RFS ) , physical activity , and medication use were quantified at baseline and 1 year of follow-up through electronic health records and quarterly mailed surveys . Short-term ( mean 6.8 months ) and long-term ( 12.8 months ) outcomes were evaluated using linear mixed models . In addition , follow-up trajectories were plotted in a r and om effects generalized additive model with smooth splines . RESULTS Compared with UC , IE result ed in long-term improved DES and PAID scores ( DES , + .11 , P = .03 and PAID , -2.94 , P = .04 ) , but not significantly improved long-term RFS or physical activity change . The A1C trajectory declined more steeply in IE than GE and UC for the first 150 days post r and omization . However , by 250 days , there was no treatment group A1C difference . The model fit likelihood ratio test for A1C intervention trends was significant for 3 distinct non-linear trajectories ( P = .02 ) . CONCLUSIONS Conventional IE ( but not GE ) result ed in significant and sustained improvements in self-efficacy and reduced diabetes distress compared with UC , but short-term improvements in A1C , nutrition , and physical activity were not sustained . Patients may need ongoing reinforcement to achieve lasting behavioral change and glucose control BACKGROUND The aim of the present study was to determine whether the addition of nurse case managers ( NCMs ) trained in motivational interviewing ( MI ) to usual care would result in improved outcomes in high-risk type 2 diabetes patients . METHODS A 2-year r and omized controlled pragmatic trial r and omized 545 patients to usual care control ( n=313 ) or those who received the intervention ( n=232 ) with additional practice -embedded NCM care , including MI-guided behavior change counseling . The NCMs received intensive MI training with ongoing fidelity assessment . RESULTS Systolic blood pressure ( SBP ) was better in the intervention than usual care group ( 131 ± 15 vs. 135 ± 18 mmHg , respectively ; P<0.05 ) . Improvements were seen in both the control and intervention groups in terms of HbA1c ( from 9.1 % to 8.0 % and from 8.8 % to 7.8 % , respectively ) , low-density lipoprotein ( LDL ; from 127 to 100 mg/dL and from 128 to 102 mg/dL , respectively ) , and diastolic blood pressure ( from 78 to 74 mmHg and from 80 to 74 mmHg , respectively ) . Depression symptom scores were better in the intervention group . The reduction in diabetes-related distress approached statistical significance . CONCLUSIONS The NCMs and MI improved SBP and complications screening . The large decrease in HbA1C and LDL in the control group may have obscured any further intervention effect . Although nurses prompted providers for medication titration , strategies to reduce provider clinical inertia may also be needed AIMS Care management may improve the quality of diabetes care by enhancing contact between high-risk patients and their providers . This prospect i ve , longitudinal , r and omized trial sought to investigate whether telephone or online care management improves diabetes-related outcomes over time compared with usual care supplemented with Internet access and training . SUBJECTS AND METHODS One hundred fifty-one adult subjects with type 2 diabetes mellitus and an elevated hemoglobin A1c ( A1c ) level ( ≥8.5 % ) were r and omly assigned to online care management ( n=51 ) , telephone-based care management ( n=51 ) , or Web training ( n=49 ) groups . Online and telephone participants interacted with a care manager through a diabetes education and care management Web site and by telephone , respectively . The Web training group was provided with online diabetes self-management re sources but no care management support . The primary outcome measure was A1c measured every 3 months for a year . RESULTS A1c declined significantly and substantially in all groups over 12 months . A1c declined linearly at a rate of 0.32 % ( P<0.0001 ) per quarter for the online group , 0.36 % ( P<0.0001 ) for the telephone group , and 0.41 % for the Web training group ( P<0.0001 ) . The rate of change over time did not differ significantly among groups . The groups converged at 12 months with average absolute A1c difference of -1.5 % . The number of interactions with care providers was not significantly associated with the change in A1c . Blood pressure , weight , lipid levels , and diabetes distress did not differ among groups over time . CONCLUSIONS Online , telephone-based care management , and Web training for diabetes patients with elevated A1c were each associated with a substantial improvement in A1c over a 1-year period . Internet access and training alone may be as effective as care management in patients with poorly controlled diabetes Information on cost-effectiveness of multiple-risk-factor lifestyle interventions for Latinas with diabetes is lacking . The aim of this paper is to evaluate costs and cost-effectiveness for ¡ Viva Bien ! , a r and omized trial targeting Latinas with type 2 diabetes . We estimated 6-month costs ; calculated incremental costs per behavioral , biologic , and quality -of-life change ; and performed sensitivity analyses from health plan and participant perspectives . Recruitment , intervention , and participant costs were estimated at $ 45,896 , $ 432,433 , and $ 179,697 , respectively . This translates to $ 4,634 in intervention costs per ¡ Viva Bien ! participant ; $ 7,723 in both per unit reduction in hemoglobin A1c and per unit reduction in body mass index . Although costs may be higher than interventions that address one risk factor , potential risks for longer-term health-care costs are high for this at-risk group . Given the benefits of ¡ Viva Bien ! , cost reductions are recommended to enhance its efficiency , adoption , and long-term maintenance without diluting its effectiveness AIMS The aim of this study was to examine whether a nurse-administered minimal psychological intervention for depressive symptoms improves diabetes-specific quality of life and glycaemic control in older persons with diabetes . BACKGROUND Depression is common among persons with diabetes and may have a negative impact on diabetes . Interventions aim ed at reducing depressive symptoms may positively influence diabetes-specific quality of life as well . METHODS A pragmatic , r and omized controlled trial was carried out comparing the intervention with usual care among 208 Dutch primary care patients of ≥60 years with type 2 diabetes and co-occurring minor to moderate depression . Data on symptom distress and emotional distress were collected during 2003 - 2006 , and haemoglobin A1c levels were obtained from general practice s. Data were analysed using mixed model , repeated measures ANCOVAS . Hba1c was collected retrospectively from general practice s between December 2006-February 2007 . In July 2007 we retrieved some additional HbA1c data from the medical records of the university hospital . RESULTS Only in higher-educated persons did the intervention have statistically significant effect on both emotional distress and symptom distress ( DSC-R total score at 9 months P=0.001 ; PAID , 9 months P=0.03 ) . Furthermore , we found an effect on symptom distress in men ( 9 months P=0.01 ) , and on emotional distress in persons with a shorter diabetes duration ( < 7 years ) ( 9 months P=0.04 ) . A significant trend over time for haemoglobin A1c was found in favour of the intervention , with a statistically significant difference between groups after 9 months ( P=0.02 ) . CONCLUSION The nurse-administered intervention had limited effects on diabetes-specific quality of life . As only certain subgroups benefited , ways of increasing effectiveness in other groups should be explored . The potentially beneficial effect on glycaemic control is encouraging and needs further research because of small numbers in the analysis OBJECTIVE In a r and omized , multi-centre trial , the effect of an education programme ( MEDIAS 2 ICT ) involving intensive insulin treatment for people with type 2 diabetes was compared with an established education programme as an active comparator condition ( ACC ) . METHODS We investigated whether MEDIAS 2 ICT was non-inferior to ACC in overall glycaemic control . Secondary outcomes were the diabetes-related distress , diabetes knowledge , quality of life , self-care behavior , lipids , blood pressure and weight . RESULTS 186 subjects were r and omized . After a six month follow-up the mean HbA1c decrease was 0.37 % ( from 8.2±1.1 % to 7.8±1.5 % ) in the ACC and 0.63 % ( from 8.5±1.5 % to 7.9±1.2 % ) in MEDIAS 2 ICT . The mean difference between both groups was -0.26 % ( 95 % CI -0.63 to -0.14 ) in favor of MEDIAS 2 ICT . This result was within the predefined limit for non-inferiority . Diabetes-related distress was significantly more reduced in MEDIAS 2 ICT ( -3.4±7.1 ) than in ACC ( 0.4±9.0 ; p=0.31 ) . CONCLUSION MEDIAS 2 ICT is as effective in lowering HbA1c as previously established education programmes , but showed superiority in reducing diabetes-related distress . PRACTICAL IMPLICATION S MEDIAS 2 ICT provides an alternative for education of people with type 2 diabetes treated by multiple injection therapy OBJECTIVES : This study was conducted to determine if an empowerment-based Diabetes Self-Management Consultant ( DSMC ) was more effective than a group receiving Mailed metabolic Assessment s Only ( MAO ) in improving diabetes-related quality of life and blood glucose control . MATERIAL S AND METHODS : A two-year clinical trial , in which 310 patients with type 2 diabetes were r and omized to the DSMC intervention or the MAO group . The DSMC met with the patient to review the baseline assessment s , then met with this review was patient and the patient 's physician . Subsequently patients received monthly telephone calls from the DSMC who used the empowerment approach to help patients identify self-management problems , consider options , set goals and make adjustments to their diabetes self-management plans . RESULTS : The Diabetes Self-Management Consultant ( DSMC ) intervention result ed in improvements in diabetes related quality of life ( PAID ) p= .008 , the Empowerment Scale p= .024 , A1C p= .016 , Perceived underst and ing of diabetes p= .001 and satisfaction with diabetes care p= .019 as compared to the MAO group . DISCUSSION / CONCLUSION : The DSMC the intervention result ed in a broad array of modest diabetes related improvements . A promising area for future research would be to test the efficacy of combining an empowerment-based DSMC intervention with case management using algorithm-based medication adjustments for higher risk patients PURPOSE The purpose of this pilot study was to determine the efficacy of a 6-month nurse-coaching intervention that was provided after diabetes education for women with type 2 diabetes . METHODS In this pilot study , 53 women were r and omized to the nurse-coaching intervention or a st and ard care control condition . The nurse-coaching intervention consisted of 5 individualized sessions and 2 follow-up phone calls over 6 months . The nurse-coaching sessions included educational , behavioral , and affective strategies . Data were collected on physiologic adaptation ( hemoglobin A1c [ A1C ] and body mass index [ BMI ] ) , self-management ( dietary and exercise ) , psychosocial adaptation ( diabetes-related distress and integration ) , and treatment satisfaction at baseline , 3 months , and 6 months . RESULTS Women in the treatment group demonstrated better diet self-management , less diabetes-related distress , better integration , and more satisfaction with care , and had trends of better exercise self-management and BMI . The A1C levels improved in both groups at 3 months , yet the difference between the groups was not significant . Attendance at nurse-coaching sessions was 96 % . CONCLUSIONS This nurse-coaching intervention demonstrates promise as a means of improving self-management and psychosocial outcomes in women with type 2 diabetes Aims /hypothesisIn type 2 diabetes mellitus , heart failure is a frequent , potentially fatal and often forgotten complication . Glucose-lowering agents and adjuvant therapies modify the risk of heart failure . We recently reported that 7.8 years of intensified compared with conventional multifactorial intervention in individuals with type 2 diabetes and microalbuminuria in the Steno-2 study reduced the risk of cardiovascular disease and prolonged life over 21.2 years of follow-up . In this post hoc analysis , we examine the impact of intensified multifactorial intervention on the risk of hospitalisation for heart failure . Methods One hundred and sixty individuals were r and omised to conventional or intensified multifactorial intervention , using sealed envelopes . The trial was conducted using the Prospect i ve , R and omised , Open , Blinded Endpoints ( PROBE ) design . After 7.8 years , all individuals were offered intensified therapy and the study continued as an observational follow-up study for an additional 13.4 years . Heart-failure hospitalisations were adjudicated from patient records by an external expert committee blinded for treatment allocation . Event rates were compared using a Cox regression model adjusted for age and sex . Results Eighty patients were assigned to each treatment group . Ten patients undergoing intensive therapy vs 24 undergoing conventional therapy were hospitalised for heart failure during follow-up . The HR ( 95 % CI ) was 0.30 ( 0.14 , 0.64 ) , p = 0.002 in the intensive-therapy group compared with the conventional-therapy group . Including death in the endpoint did not lead to an alternate overall outcome ; HR 0.51 ( 0.34 , 0.76 ) , p = 0.001 . In a pooled cohort analysis , an increase in plasma N-terminal pro-B-type natriuretic peptide ( NT-proBNP ) during the first two years of the trial was associated with incident heart failure . Conclusions /interpretationIntensified , multifactorial intervention for 7.8 years in type 2 diabetic individuals with microalbuminuria reduced the risk of hospitalisation for heart failure by 70 % during a total of 21.2 years of observation . Trial registration : Clinical Trials.gov NCT00320008 Purpose The purpose of the study was to assess the value of reinforcing diabetes self-management for improving glycemia and self-care among adults with type 2 diabetes who had at least 3 hours of prior diabetes education . Methods In this r and omized controlled trial , 134 participants ( 75 % white , 51 % female , 59 ± 9 years old , 13 ± 8 years with diabetes , A1C = 8.4 % ± 1.2 % ) were r and omized to either a group map-based program ( intervention ) or group education on cholesterol and blood pressure ( control ) . Participants were assessed for A1C levels , diabetes self-care behaviors ( 3-day pedometer readings , 6-minute walk test , blood glucose checks , frequency of self-care ) , and psychosocial factors ( distress , frustration , quality of life ) at baseline , 3 , 6 , and 12 months post intervention and health literacy at baseline . Results Groups did not differ on baseline characteristics including A1C levels , health literacy , or self-care ; however , the intervention group had more years of education than controls . Intervention arm participants modestly improved A1C levels at 3 months post intervention but did not maintain that improvement at 6 and 12 months while control patients did not improve A1C levels at any time during follow-up . Importantly , frequency of self-reported self-care , diabetes quality of life , diabetes-related distress , and frustration with diabetes self-care improved in both groups over time . Conclusions Reinforcing self-care with diabetes education for patients who have not met glycemic targets helps improve A1C and could be considered a necessary component of ongoing diabetes care . The best method to accomplish reinforcement needs to be established |
13,789 | 14,586,924 | The evidence for the use of traction in LBP remains inconclusive because of the continued lack of method ologic rigor and the limited application of clinical parameters as used in clinical practice . | OBJECTIVE To assess the efficacy of traction for patients with low back pain ( LBP ) with or without radiating pain , taking into account the clinical technique or parameters used . | Four treatments for sciatic symptoms -- traction , exercises , manipulation , and corset -- were assessed in a r and omised controlled trial in 322 out patients . The design was factorial . There were thus sixteen treatment groups , enabling a comparison of combinations of methods as well as of individual methods . Treatment lasted for four weeks . Patients were review ed at the end of this period and at four and sixteen months after entry to the trial . Progress was measured by the patient 's account of symptomatic improvement or deterioration and by return to work or normal activities . At four weeks each of the treatments was associated with a small degree of benefit over and above the high rate of spontaneous improvement . For manipulation , the benefit was statistically significant on one of the scales used to measure progress . There was a significant increase in symptomatic improvement with increasing numbers of treatments used in combination . This was complemented by a clear tendency for those who had received fewer types of treatment during the trial to have further treatment in the ensuing three months . There were no beneficial effects of treatment detectable at four or sixteen months . In the short-term , active physiotherapy with several treatments appears to be of value in the outpatient management of patients with sciatic symptoms , but it does not seem to confer any longer-term benefit BACKGROUND AND PURPOSE Since the release of acute low back pain management guidelines in 1994 , little was known about the effect of these guidelines on clinical practice . The purpose of this study was to examine physical therapists ' reported management of acute and subacute lumbar impairment . SUBJECTS One in 10 registered physical therapists who were r and omly selected from southern Ontario , Canada , ( n=454 ) and all registered physical therapists from northern Ontario ( n=331 ) were surveyed . METHODS In the question naire , case scenarios covered 3 areas related to the management of lumbar impairment : ( 1 ) physical examination , ( 2 ) treatment and recommendations , and ( 3 ) therapists ' beliefs regarding its management . RESULTS Five hundred sixty-nine question naires were returned ( response rate=72.5 % ) . Only data obtained for therapists ( n=274 ) whose weekly workload included more than 10 % of people with lumbar impairment were used in the analysis . Overall , patient education , exercise , and electrotherapeutic and thermal modalities were the preferred interventions for acute lumbar impairment ( symptom onset of less than 5 weeks ) with or without sciatica , whereas exercise and work modification were preferred for subacute lumbar impairment ( symptom onset of 5 weeks or longer ) . There was a trend of using electrotherapeutic and thermal modalities with uncertain effectiveness . Only 46.3 % of the therapists agreed or strongly agreed that practice guidelines were useful for managing lumbar impairment . DISCUSSION AND CONCLUSION Although the physical therapists surveyed , in general , followed the guidelines in managing acute lumbar impairment , they felt uncertain regarding the value of practice guidelines . Future research should focus on identifying effective treatment approaches and exploring the effectiveness of practice guidelines STUDY DESIGN A descriptive question naire of chartered physiotherapists . OBJECTIVE To investigate current physiotherapeutic management of low back pain throughout Britain and Irel and . SUMMARY OF BACKGROUND DATA Physiotherapists play a key role in low back pain management . Although clinical guidelines for best practice have been developed recently , there has been no large-scale attempt to describe current physiotherapeutic treatment approaches within Britain or Irel and . METHODS After semi-structured interviews ( n = 6 ) and two pilot studies ( n = 77 ) were done , postal question naires were distributed to four regional cluster sample s of the membership of two physiotherapy professional organizations ( n = 2654 ) . After two mailings , a r and om sample of 90 nonresponders were followed up . Data were analyzed using the Statistical Package for the Social Sciences ( SPSS Ltd. , Woking , Surrey , UK ) , and precision of the survey estimates was assessed by calculation of sampling errors and intraclass correlation coefficients for cluster sampling . RESULTS Results were received from 1548 therapists ( total response rate , 58.3 % ) ; of these , 813 reported that they were practicing in setting s in which they treated patients with low back pain . Analysis of the results indicated the overall popularity of the Maitl and mobilization and McKenzie approaches among physiotherapists . Although exercise per se was mentioned frequently by respondents , a marked difference in opinion among therapists regarding the optimal type of exercise for low back pain was obvious . Little evidence was demonstrated of the use of manipulation , fitness programs , or multidisciplinary efforts involving behavioral and physical aspects of treatment . Commonly used methods of electrotherapy were interferential therapy , ultrasound , pulsed short-wave diathermy , and transcutaneous electrical nerve stimulation . CONCLUSIONS The results of this study emphasize the need to evaluate further and improve the dissemination of findings regarding the effectiveness of specific physiotherapy approaches for low back pain management Traction therapy for low back pain with sciatica has been evaluated in a double blind study . 60 patients hospitalized for sciatica with or without signs of sensory or motor deficiency were r and omized to 3 treatment groups : " placebo traction " ( 5 kg ) , " light traction " ( 15 kg ) and " normal traction " ( 50 kg ) . Clinical evaluation after 4 , 8 and 12 traction sessions showed no difference between the three groups Four treatment regimens for patients with specified combinations of low back pain and sciatica were evaluated . The largest group studied had low back pain with limited straight-leg raising ( SLR ) and in them the beneficial effect of manipulation in hastening pain relief was highly significant . In similar patients without limitation of SLR , the effect was of borderline significance . In all the other groups , treated patients also recovered more quickly than their controls . Traction , for patients with low back pain and sciatica , and epidural injections when a root palsy was present also produced some significant pain relief . The effect of sclerosants for back pain was less clear STUDY DESIGN A r and omized trial design ed to compare interferential therapy with motorized lumbar traction and massage management for low back pain in a primary care setting . OBJECTIVE To measure and compare the outcome of interferential therapy and management by motorized lumbar traction and massage . SUMMARY OF BACKGROUND DATA Management of low back pain by interferential therapy and motorized lumbar traction and massage is common in Germany . No reports of previous r and omized trials for the outcome from interferential therapy were found . METHODS Consenting patients were r and omly assigned into one of two groups . A pretreatment interview was performed by the patient using a computer-based question naire . It also incorporated the Oswestry Disability Index and a pain visual analog scale . Management consisted of six sessions over a 2- to 3-week period . Oswestry Disability Indexes and pain visual analog scale scores also were obtained immediately after and at 3 months after treatment . RESULTS A total of 152 patients were recruited . The two treatment groups had similar demographic and clinical baseline characteristics . The mean Oswestry Disability Index before treatment was 30 for both groups ( n = 147 ) . After treatment , this had dropped to 25 , and , at 3 months , were 21 ( interferential therapy ) and 22 ( motorized lumbar traction and massage ) . The mean pain visual analog scale score before treatment was 50 ( interferential therapy ) and 51 ( motorized lumbar traction and massage ) . This had dropped , respectively , to 46 and 44 after treatment and to 42 and 39 at 3 months . CONCLUSIONS This study shows a progressive fall in Oswestry Disability Index and pain visual analog scale scores in patients with low back pain treated with either-interferential therapy or motorized lumbar traction and massage . There was no difference in the improvement between the two groups at the end of treatment . Although there is evidence from several trials that traction alone is ineffective in the management of low back pain , this study could not exclude some effect from the concomitant massage Previous trials to assess the efficacy of lumbar traction for back pain have been method ologically flawed . To avoid these shortcomings , we conducted a r and omised controlled trial in which high-dose traction was compared with sham traction . The sham traction was given with a specially developed brace that tightens in the back during traction . To the patient , the experience is that of traction . The patients and outcome assessor were blinded for the assigned treatment . 151 patients with at least six weeks of non-specific low back pain were r and omised . Intention to treat analysis showed no differences between the groups on all outcome measures ( patients ' global perceived effect , severity of main complaints , functional status and pain ) ; all 95 % confidence intervals included the value zero . The number of withdrawals from treatment , loss to follow-up , and protocol deviations was low . Consequently , the per- protocol analysis showed results similar to the intention to treat analysis . Subgroup analyses did not show any group for which traction might seem promising . Our data do not support the cl aim that traction is effective for patients with low back pain Autotraction ( AT ) is a treatment for low-back pain syndrome of benign etiology that uses a specially design ed traction table divided into two movable sections . While lying on the table , the pelvis secured , the patient controls the traction forces by grasping and pulling the bars at the head of the table . There are controls for the therapist to apply , through movable sections of the table , rotation and bending forces to help restore mobility to the lumbar spine without inducing pain . The present study is based upon a r and omized treatment trial comparing conventional passive traction ( PT ) to AT . The following outcome indicators were used : ( 1 ) subjective response concerning overall improvement , ( 2 ) pain intensity ( visual analog scale , 0 - 100 ) , ( 3 ) qualitative pain severity ( McGill Pain Question naire , short-form , 0 - 45 ) , and ( 4 ) pain related disability ( Oswestry Low Back Pain Disability Score , 0 - 100 ) . The favorable response to AT was 75 % ( 30 of the 40 patients ) versus the 22 % ( 6 of 27 patients ) to PT ( p < 0.001 ) . After 3 months , 19 of the 30 responders to AT ( 63 % ) reported continued improvement . In these patients , pain ratings remained stable and the disability scores decreased to 0 to 23 % of the pretreatment value ( median and mean respectively , p < 0.001 ) Forty-nine patients with lumbago-sciatica and prolapsed lumbar intervertebral discs , comparable concerning anamnestical and clinical data were r and omized for autotraction and manual traction given by the same therapist for a period of one week while strict bed rest was prescribed . A blind overall assessment performed immediately after the traction period , after two weeks follow-up training and three months after hospitalization showed that the two traction modalities are equally efficient . As treatment for hospitalized patients with lumbar intervertebral disc prolapses the relatively simple manual traction variety should be preferred , if any . Traction is suggested to be used as a prognostical aid . Pain intensity was significantly reduced in all body parts . About one fourth of patients avoided operation . After two years there was no recurrence of symptoms Study Design A clinical study was conducted on 39 patients with acute , first‐episode , unilateral low back pain and unilateral , segmental inhibition of the multifidus muscle . Patients were allocated r and omly to a control or treatment group . Objectives To document the natural course of lumbar multifidus recovery and to evaluate the effectiveness of specific , localized , exercise therapy on muscle recovery . Summary of Background Data Acute low back pain usually resolves spontaneously , but the recurrence rate is high . Inhibition of multifidus occurs with acute , first‐episode , low back pain , and pathologic changes in this muscle have been linked with poor outcome and recurrence of symptoms . Methods Patients in group 1 received medical treatment only . Patients in group 2 received medical treatment and specific , localized , exercise therapy . Outcome measures for both groups included 4 weekly assessment s of pain , disability , range of motion , and size of the multifidus cross‐sectional area . Independent examiners were blinded to group allocation . Patients were reassessed at a 10‐week follow‐up examination . Results Multifidus muscle recovery was not spontaneous on remission of painful symptoms in patients in group 1 . Muscle recovery was more rapid and more complete in patients in group 2 who received exercise therapy ( P = 0.0001 ) . Other outcome measurements were similar for the two groups at the 4‐week examination . Although they resumed normal levels of activity , patients in group 1 still had decreased multifidus muscle size at the 10‐week follow‐up examination . Conclusions Multifidus muscle recovery is not spontaneous on remission of painful symptoms . Lack of localized , muscle support may be one reason for the high recurrence rate of low back pain following the initial episode A double-blind control study of lumbar traction for sciatica has been carried out . Although there is a tendency for traction to produce improvement in pain and straight-leg raise the extent does not achieve statistical significance . Changing ' control ' patients to ' treatment ' seemed to produce worthwhile relief of pain for all who were not already improving . It is suggested that a large trial using more discriminating criteria might delineate a group of patients susceptible to help by traction This study investigates whether there is a difference in electromyographic activity in the lumbar sacrospinalis musculature during continuous and intermittent pelvic traction . Twenty-nine normal subjects were r and omly assigned to a control group , a continuous traction group , or an intermittent traction group . Electromyographic activity was recorded at specific timed intervals . Myoelectric activity increased with the onset of either type of traction , but by the third recording both groups had returned to their normal initial resting myoelectric recordings . The myoelectric patterns over time were similar for the two treatment groups . No significant difference in electromyographic activity of the lumbar sacrospinalis musculature during intermittent or continuous pelvic traction was found . J Orthop Sports Phys Ther 1981;2(3):137 - 141 Abstract Low back pain is one of the most significant medical and socioeconomic problems in modern society . International guidelines call for evidence -based management for the pain and disability associated with musculoskeletal disorders . The purpose of this r and omized controlled trial is to address the question of efficacy and appropriateness of vertebral axial decompression ( VAX-D ) therapy , a new technology that has been shown in clinical research to create negative intradiscal pressures , and has been shown to be effective in treating patients presenting with chronic low back pain ( > 3 months duration ) with associated leg pain . Successful outcome was defined as a 50 % reduction in pain utilizing a 10 cm Visual Analog Pain Scale and an improvement in the level of functioning as measured by patient-nominated disability ratings . Patients were r and omly assigned to VAX-D or to TENS which was used as a control treatment or placebo . The TENS treatment demonstrated a success rate of 0 % , while VAX-D demonstrated a success rate of 68.4 % ( p < 0.001 ) . A statistically significant reduction in pain and improvement in functional outcome was obtained in patients with chronic low back pain treated with VAX-D. [ Neurol Res 2001 ; 23 : 780 - 784 In this controlled prospect i ve study of the Auto-traction method for the treatment of lumbago-sciatica , 82 patients were r and omly allocated to either treatment with Auto-traction for up to three 1-hour sessions in 1 week , or they were given a corset and advised to rest . The orthopaedic surgeons participating in the study worked at six different hospitals and all had limited experience of the Auto-traction method obtained during a 1-week course . All patients were clinical ly evaluated by an independent observer who also performed the follow-up examinations 1 and 3 weeks after the treatment sessions . In addition a 3-month follow-up was performed by letter . The Auto-traction method gave prompt relief of pain and a normalizing of the SLR test more often than treatment with only a corset and rest . The difference between the two treatment groups was statistically significant . The immediate difference noted between the treatment groups had decreased slightly at 3 weeks but was still statistically significant at this time |
13,790 | 25,876,919 | The studies included in this review show evidence of improvements in protective behaviours and knowledge among children exposed to school-based programmes , regardless of the type of programme .
There is evidence that children 's knowledge does not deteriorate over time , although this requires further research with longer-term follow-up .
Programme participation does not generate increased or decreased child anxiety or fear , however there is a need for ongoing monitoring of both positive and negative short- and long-term effects .
The results show that programme participation may increase the odds of disclosure , however there is a need for more programme evaluations to routinely collect such data . | BACKGROUND Child sexual abuse is a significant global problem in both magnitude and sequelae .
The most widely used primary prevention strategy has been the provision of school-based education programmes .
Although programmes have been taught in schools since the 1980s , their effectiveness requires ongoing scrutiny .
OBJECTIVES To systematic ally assess evidence of the effectiveness of school-based education programmes for the prevention of child sexual abuse .
Specifically , to assess whether : programmes are effective in improving students ' protective behaviours and knowledge about sexual abuse prevention ; behaviours and skills are retained over time ; and participation results in disclosures of sexual abuse , produces harms , or both . | Reports of cluster r and omised trials require additional information to allow readers to interpret them accurately The effective reporting of r and omised controlled trials has received useful attention in recent years . Many journals now require that reports conform to the guidelines in the Consoli date d St and ards of Reporting Trials ( CONSORT ) statement , first published in 1996 and revised in 2001 . The statement includes a checklist of items that should be included in the trial report . These items are evidence based whenever possible and are regularly review ed . The statement also recommends including a flow diagram to show the flow of participants from group assignment through to the final analysis . The CONSORT statement focused on reporting parallel group r and omised trials in which individual participants are r and omly assigned to study groups . However , in some situations it is preferable to r and omly assign groups of individuals ( such as families or medical practice s ) rather than individuals . Reasons include the threat of contamination of some interventions ( such as dietary interventions ) if individual r and omisation is used . 5 Also , in certain setting s r and omisation by group may be the only feasible method of conducting a trial . Trials with this design are variously known as field trials , community based trials , place based trials , or ( as in this paper ) cluster r and omised trials . In an earlier discussion paper we considered the implication s of the CONSORT statement for the reporting of cluster r and omised trials . Here we present up date d guidance , based on the 2001 revision of the CONSORT statement This article describes and evaluates a K-6 child sexual abuse prevention curriculum that was piloted in a large northwestern school district 1986–89 . Paired t-tests using pre-test and post-test scores from a r and om sample of 1,391 K-6 students indicates that significant learning occurred at all grade levels . Analysis of variance results suggest that , overall , learning is not related to students ' gender or to the school 's socioeconomic level . Responses by 197 teachers concerning their evaluations of curriculum material s and training were positive . Study limitations and future research plans and needs are discussed The authors evaluated a coeducational program for teenagers on preventing sexual coercion in dating situations . Students examined individual and social attitudes underlying coercive sexual behavior and learned communication skills aim ed at preventing or dealing with unwanted sexual advances . Instruction was enhanced by video and an interactive video " virtual date . " Outcomes were assessed using sexual attitude scales with a sample of 458 high school students . Student health education classes were r and omly assigned to either a treatment or a control condition . Findings , based on a latent variable model of differential effectiveness , showed that students in the treatment group with initial coercive attitude scores at or above the mean benefited significantly more than students with the same range of scores in the control group This paper reports the outcome of an attempt to teach children in grade s 5 and 6 about child abuse and neglect . The Child Abuse Component of the Human Relations Program described and evaluated here is a unique effort to provide children with an opportunity to discuss and learn about this aspect of family violence . An impact assessment was conducted by documenting possible changes in student knowledge and attitudes regarding child abuse as a result of exposure to the Child Abuse Component of the Human Relations Program . The test group of children consisted of 315 boys and girls in grade s 5 and 6 . A comparison group of 298 children was closely matched with the test group on the basis of age and sex . These groups were formed by r and omly selecting 12 teachers from all teachers agreeing to use the Component and 10 teachers choosing not to employ the Component . The students in the classrooms of these teachers received the same curriculum for their grade level with the exception of the field-test group additionally receiving the Component . Selected child abuse knowledge , attitude , and personality ( security ) measures were given all subjects in a post-test with comparison group research design . Teacher knowledge and attitude were also assessed . The results of the data analysis , teacher , and special observer reports suggest that the Component was effective in meeting its objectives and was not disturbing to test subjects . Apparently , the test children profited by experiencing the Component mainly because of the opportunity it provided for class discussion . Moreover , the knowledge levels and interest of the children in both groups was seriously underestimated Young children ( ages 4 and 5 ) and school-aged children ( 6 to 10 ) from a day-care center were r and omly assigned to a sexual abuse prevention training group and a wait-list control group . Children in the prevention training group were exposed to a three-hour program teaching common sexual abuse prevention concepts ( e.g. , the difference between OK and not-OK touches ) . Children in both groups were given a structured interview before and after the prevention group received training . Results of a repeated measures multivariate analysis of variance indicate that children in the prevention training group significantly increased their knowledge of prevention concepts while children in the control group did not . Older children learned more than younger children . Both younger and older children had greater difficulty learning prevention concepts of an abstract nature than concepts of a specific nature OBJECTIVES This study assessed the effects of the Safe Date s program on the primary and secondary prevention of adolescent dating violence . METHODS Fourteen schools were r and omly allocated to treatment conditions . Eighty percent ( n=1886 ) of the eighth and ninth grade rs in a rural county completed baseline question naires , and 1700 ( 90 % ) completed follow-up question naires . RESULTS Treatment and control groups were comparable at baseline . In the full sample at follow-up , less psychological abuse , sexual violence , and violence perpetrated against the current dating partner were reported in treatment than in control schools . In a sub sample of adolescents reporting no dating violence at baseline ( a primary prevention sub sample ) , there was less initiation of psychological abuse in treatment than in control schools . In a sub sample of adolescents reporting dating violence at baseline ( a secondary prevention sub sample ) , there was less psychological abuse and sexual violence perpetration reported at follow-up in treatment than in control schools . Most program effects were explained by changes in dating violence norms , gender stereotyping , and awareness of services . CONCLUSIONS The Safe Date s program shows promise for preventing dating violence among adolescents OBJECTIVE The research evaluated a sexual abuse prevention program for elementary school-aged children . Although other evaluations of similar programs have demonstrated significant improvements in knowledge and skills , a number of key questions with respect to their efficacy remain . METHOD 231 children were r and omly assigned ( matched by age ) to participate in the program ( N = 117 ) or in a wait-list control condition ( N = 114 ) . Knowledge of abuse prevention concepts were tested using the 33-item Children 's Knowledge of Abuse Question naire-Revised ( CKAQ-R ) , a st and ardized measure with strong psychometric properties ( Tutty , 1995 ) , with a new subscale on Appropriate Touch . RESULTS An analysis of covariance showed that children who received the program increased their knowledge levels of both Inappropriate Touch ( p = .000 ) and Appropriate Touch ( p = .012 ) to a significantly greater degree than children in the control group . Age also significantly differentiated the knowledge levels regarding Inappropriate Touch , with younger children knowing fewer concepts both at pretest and posttest ( p = .000 ) . Parallel results apply to the Appropriate Touch subscale ( p = .04 ) . CONCLUSIONS The results are consistent with other evaluations of child sexual abuse prevention programs , however the statistically significant though small gains suggest that the programs need to be presented in a more powerful manner OBJECTIVE The purpose of this study was to describe the extent to which childhood abuse and neglect increase a person 's risk for subsequent posttraumatic stress disorder ( PTSD ) and to determine whether the relationship to PTSD persists despite controls for family , individual , and lifestyle characteristics associated with both childhood victimization and PTSD . METHOD Victims of substantiated child abuse and neglect from 1967 to 1971 in a Midwestern metropolitan county area were matched on the basis of age , race , sex , and approximate family socioeconomic class with a group of nonabused and nonneglected children and followed prospect ively into young adulthood . Subjects ( N = 1,196 ) were located and administered a 2-hour interview that included the National Institute of Mental Health Diagnostic Interview Schedule to assess PTSD . RESULTS Childhood victimization was associated with increased risk for lifetime and current PTSD . Slightly more than a third of the childhood victims of sexual abuse ( 37.5 % ) , 32.7 % of those physically abused , and 30.6 % of victims of childhood neglect met DSM-III-R criteria for lifetime PTSD . The relationship between childhood victimization and number of PTSD symptoms persisted despite the introduction of covariates associated with risk for both . CONCLUSIONS Victims of child abuse ( sexual and physical ) and neglect are at increased risk for developing PTSD , but childhood victimization is not a sufficient condition . Family , individual , and lifestyle variables also place individuals at risk and contribute to the symptoms of PTSD This paper presents results from a third grade sexual abuse prevention program . A 24-item question naire was administered as a pretest and post-test to an experimental group ( n = 236 ) and a control group ( n = 195 ) of third grade students . Those receiving the sexual abuse prevention program significantly increased their sexual abuse knowledge scores from pretest to post-test . In addition , differences in knowledge were significantly higher in the experimental compared to the control group . Students who received the sexual abuse curriculum significantly improved from pretest to post-test on their behavioral intention scores . Results from this evaluation indicated a modest improvement can be obtained through use of this two-hour sexual abuse prevention curriculum In this experiment , 123 sixth and seventh grade classrooms from Clevel and area schools were r and omly assigned to one of two five-session curricula addressing gender violence/sexual harassment ( GV/SH ) or to a no-treatment control . Three-student surveys were administered . Students in the law and justice curricula , compared to the control group , had significantly improved outcomes in awareness of their abusive behaviors , attitudes toward GV/SH and personal space , and knowledge . Students in the interaction curricula experienced lower rates of victimization , increased awareness of abusive behaviors , and improved attitudes toward personal space . Neither curricula affected perpetration or victimization of sexual harassment . While the intervention appeared to reduce peer violence victimization and perpetration , a conflicting finding emerged — the intervention may have increased dating violence perpetration ( or at least the reporting of it ) but not dating violence victimization PURPOSE Dating violence (DV)--physical , sexual , and psychological aggression in adolescent romantic relationships -- is prevalent among youth . Despite broad calls for primary prevention , few programs with demonstrated effectiveness exist . This cluster-r and omized trial examined the effectiveness of a DV perpetration prevention program targeting coaches and high school male athletes . METHODS The unit of r and omization was the high school ( 16 schools ) , and the unit of analysis was the athlete ( N = 2,006 students ) . Primary outcomes were intentions to intervene , recognition of abusive behaviors , and gender-equitable attitudes . Secondary outcomes explored byst and er behaviors and abuse perpetration . Regression models for clustered , longitudinal data assessed between-arm differences in over-time changes in mean levels of continuous outcomes in 1,798 athletes followed up at 3 months . RESULTS Intervention athletes ' changes in intentions to intervene were positive compared with control subjects , result ing in an estimated intervention effect of .12 ( 95 % CI : .003 , .24 ) . Intervention athletes also reported higher levels of positive byst and er intervention behavior than control subjects ( .25 , 95 % CI : .13 , .38 ) . Changes in gender-equitable attitudes , recognition of abusive behaviors , and DV perpetration were not significant . Secondary analyses estimated intervention impacts according to intensity of program implementation . Compared with control subjects , athletes exposed to full-intensity implementation of the intervention demonstrated improvements in intentions to intervene ( .16 , 95 % CI : .04 , .27 ) , recognition of abusive behaviors ( .13 , 95 % CI : .003 , .25 ) , and positive byst and er intervention ( .28 , 95 % CI : .14 , .41 ) . CONCLUSION This cluster-r and omized controlled trial supports the effectiveness of a school athletics-based prevention program as one promising strategy to reduce DV perpetration BACKGROUND Perpetration of physical , sexual , and psychological abuse is prevalent in adolescent relationships . One strategy for reducing such violence is to increase the likelihood that youth will intervene when they see peers engaging in disrespectful and abusive behaviors . PURPOSE This 12-month follow-up of a cluster RCT examined the longer-term effectiveness of Coaching Boys Into Men , a dating violence prevention program targeting high school male athletes . DESIGN This cluster RCT was conducted from 2009 to 2011 . The unit of r and omization was the school , and the unit of analysis was the athlete . Data were analyzed in 2012 . SETTING / PARTICIPANTS Participants were male athletes in Grade s 9 - 11 ( N=1513 ) participating in athletics in 16 high schools . INTERVENTION The intervention consisted of training athletic coaches to integrate violence prevention messages into coaching activities through brief , weekly , scripted discussion s with athletes . MAIN OUTCOME MEASURES Primary outcomes were intentions to intervene , recognition of abusive behaviors , and gender-equitable attitudes . Secondary outcomes included byst and er behaviors and abuse perpetration . Intervention effects were expressed as adjusted mean between-arm differences in changes in outcomes over time , estimated via regression models for clustered , longitudinal data . RESULTS Perpetration of dating violence in the past 3 months was less prevalent among intervention athletes relative to control athletes , result ing in an estimated intervention effect of -0.15 ( 95 % CI=-0.27 , -0.03 ) . Intervention athletes also reported lower levels of negative byst and er behaviors ( i.e. , laughing and going along with peers ' abusive behaviors ) compared to controls ( -0.41 , 95 % CI=-0.72 , -0.10 ) . No differences were observed in intentions to intervene ( 0.04 , 95 % CI=-0.07 , 0.16 ) ; gender-equitable attitudes ( -0.04 , 95 % CI=-0.11 , 0.04 ) ; recognition of abusive behaviors ( -0.03 , 95 % CI=-0.15 , 0.09 ) ; or positive byst and er behaviors ( 0.04 , 95 % CI=-0.11 , 0.19 ) . CONCLUSIONS This school athletics-based dating violence prevention program is a promising approach to reduce perpetration and negative byst and er behaviors that condone dating violence among male athletes . TRIAL REGISTRATION This study is registered at www . clinical trials.gov NCTO1367704 We compared the relative effectiveness of two educational approaches for teaching personal safety skills with 100 preschoolers . A behavioral skills training program was compared with a feelings-based program , which instructs children to trust their feelings when making safety decisions . Children 's abilities to discriminate between appropriate- and inappropriate-touch requests , their prevention skills , and levels of emotional distress were assessed before , immediately , and one month after program participation . Parents and teachers were surveyed regarding children 's reactions . Compared with a control presentation , both programs were effective in enhancing children 's knowledge and prevention skills without making them fearful , suggesting that preschool children can benefit from such programs . However , children in the feelings-based program had difficulty recognizing the appropriateness of certain touch requests , suggesting that this approach may have limited utility with preschool-age children Approximately 20 % of adolescents have experienced violence from a dating partner . The Safe Date s Project tests the effects of a program on the primary and secondary prevention of dating violence among adolescents living in a rural North Carolina county . The program being evaluated aims to prevent dating violence by changing dating violence norms , gender stereotyping , conflict-management skills , help-seeking , and cognitive factors associated with help-seeking . School activities include a theater production , a 10-session curriculum , and a poster contest . Community activities include special services for adolescents in violent relationships and community service provider training . A pretest-posttest experimental design with r and om allocation of 14 schools to treatment condition was used to test study hypotheses . Data were collected in schools using self-administered question naires . Eighty-one percent ( n = 1,967 ) of the eighth- and ninth- grade rs in the county completed baseline question naires , and 91 % of those adolescents completed follow-up question naires . The sample is 75.9 % Caucasian and 50.4 % female . Baseline data indicate that 25.4 % and 8.0 % of this sample have been victims of nonsexual and sexual dating violence , respectively , and 14.0 % and 2.0 % have been perpetrators of nonsexual and sexual dating violence , respectively . Consistent with other adolescent dating violence studies , both boys and girls report being victims and perpetrators of dating violence . Control and treatment groups are similar at baseline on all demographic , mediating , and outcome variables . Findings suggest that dating violence is prevalent among adolescents and that prevention programs are warranted We tested the prediction that a sexual abuse prevention program that included participant modeling ( PM ) would result in superior skill acquisition compared with a symbolic modeling ( SM ) program . Twenty-six kindergarten children were assigned to one of the two programs after being matched for initial skill level . The PM program taught self-protective skills through modeling and active rehearsal ; the SM program taught the same skills , but the children watched as skills were modeled by the experimenter . Results provided evidence for the greater efficacy of PM relative to SM for the learning of personal safety skills and , thus , support the inclusion of active rehearsal in prevention programs for young children . In response to the high incidence of sexual abuse among children ( National Committee for the Prevention of Child Abuse , 1985 ) , many prevention programs aim ed at known-offende r abuse have been developed for implementation in school systems . As a result of their consistent and longitudinal contact with children and families , schools appear to be the most promising institution for the delivery of preventive instruction ( Brassard , Tyler , & Kehle , 1983 ) . A number of books , plays , films , small-group discussion s , and structured curricula are being promoted for school usage ( see review s by Conte , Rosen , & Saperstein , 1986 ; Wurtele , in press ) . Although school-based prevention programs have been widely implemented , little effort has been made to systematic all y evaluate what children learn and which teaching method is most effective or to determine if knowledge and skill gains are retained over time . Recently , we compared the effectiveness of the film " Touch " ( Illusion Theater Company & Media Ventures , 1984 ) with a control presentation ( Saslawsky & Wurtele , 1986 ) and , subsequently , with a multifaceted behavioral skills training ( BST ) package design ed to teach children self-protective skills ( Wurtele , Saslawsky , Miller , Marrs , & Britcher , 1986 ) . Results from this latter study indicated that children in the BST group OBJECTIVE To present accounts of the prevalence of childhood sexual abuse ( CSA ) and social , family , and related factors that are associated with increased risk of CSA , using data gathered during an 18-year longitudinal study of a New Zeal and birth cohort . METHOD A birth cohort of more than 1,000 children born in Christchurch ( New Zeal and ) was studied prospect ively to the age of 16 years . At age 18 , retrospective reports of CSA were obtained . RESULTS Of the cohort , 10.4 % ( 17.3 % of females and 3.4 % of males ) reported having experienced CSA before the age of 16 years . Rates of severe abusive experiences involving intercourse were lower : 5.6 % of females and 1.4 % of males reported abuse involving attempted or completed intercouse . Multivariate analyses that the risk of CSA was elevated among females ( p < .0001 ) , those exposed to high levels of marital conflict ( p < .005 ) , those reporting low parental attachment ( p < .001 ) , those reporting high levels of paternal overprotection ( p < .005 ) , and those with parents who reported alcoholism/alcohol problems ( p < .05 ) . The level of prediction of CSA from childhood and family factors was not sufficient to identify individuals at risk of CSA with any degree of accuracy . CONCLUSIONS CSA was not an uncommon experience in this cohort . Those most likely to be exposed to CSA were girls reared in families in families characterized by high levels of marital conflict and impaired parenting and in families having parents with adjustment problems The purpose of the current study was to develop and evaluate the efficacy of a school-based child sexual abuse prevention program for Taiwanese children . Forty-six Taiwanese children age 6 to 13 were divided into one of two groups based on their school grade and then r and omly assigned to a skills-based child sexual abuse prevention program who received training immediately or a waiting-list control condition who received the training after a delay . Children 's self-protection skills improved regardless of age after participation in the program . The program , however , did not successfully improve children 's knowledge of sexuality and safety . Although future studies should modify the program content to better target knowledge of sexuality and safety , these results are promising for a pilot of this skills-based CSA prevention program in Taiwan The CONSORT statement is used worldwide to improve the reporting of r and omised controlled trials . Kenneth Schulz and colleagues describe the latest version , CONSORT 2010 , which up date s the reporting guideline based on new method ological evidence and accumulating OBJECTIVE To provide reliable measures of the prevalence of all forms of child maltreatment in the UK that will be robust in the context of social and cultural differences due to social class , ethnicity and , region . METHODS Two thous and eight hundred sixty-nine ( 2,869 ) young adults aged 18=-24 , obtained by r and om probability sampling throughout the UK , were interviewed face to face by trained interviewers . Maltreatment was defined using a post hoc assessment of a range of experienced behaviors and treatments while the respondents were aged 16 or under . RESULTS Over 90 % of respondents reported that they came from a warm and loving family background . Maltreatment ( both intra and extrafamilial ) was experienced by 16 % of the sample . Serious maltreatment was experienced by 7 % of respondents for physical abuse , 6 % for emotional abuse , 6 % for absence of care , and 5 % for absence of supervision , and 11 % reported sexual abuse involving contact . Attitudes to maltreatment were explored through the examination of respondents ' views of different behaviors and experiences that children may have been exposed to . CONCLUSION The maltreatment of children in the UK today remains an extensive social problem . Prevalence data reveal that children are most at risk in the home for physical and emotional abuse and neglect . They are at greater risk of sexual abuse outside the home , particularly in dating relationships This study employed a Posttest-Only Control Group Design to assess the effects of a victimization prevention program , Project TRUST , on elementary school students ' knowledge of general prevention concepts , knowledge of difficult-to-acquire prevention concepts , anxiety , and reporting of abuse . A selected subgroup of experimental subjects was also assessed for retention of acquired concepts over time . Students exposed to Project TRUST demonstrated significantly greater knowledge of maltreatment prevention information , as well as difficult-to-acquire concepts , than control group students . A 3-month delayed re assessment of the experimental subgroup showed no loss in acquired prevention information . No differences in anxiety scores existed between experimental and control groups . First-time student abuse disclosures were greater in the experimental than in the control group . These findings support the effectiveness of Project TRUST as a strategy to increase prevention knowledge and generate abuse disclosures without creating student anxiety AIMS ( 1 ) To study the prevalence of childhood sexual abuse before the age of 18 years ( CSA ) and life-time sexual abuse ( LSA ) in a Swedish female , general population , ( 2 ) to analyse associations between CSA and life-time alcohol dependence or abuse ( ADA ) , and ( 3 ) to identify possible confounding factors . DESIGN AND PARTICIPANTS The study was conducted in two phases . Phase 1 : an alcohol problem screening question naire was sent to 3130 women aged 25 - 65 . The answers were scored . Phase 2 : based on the question naire scores , a r and omly selected stratified sample of 479 women was invited for an interview . Of these , 316 women participated in a structured face-to-face interview . SETTING A sector of Göteborg city with 100,000 inhabitants . MEASUREMENTS The interviews focused on substance use and on social , psychological and behavioural characteristics , including experiences of sexual abuse . Clinical psychiatric diagnoses were made according to DSM-III-R. Bivariate analyses and multivariate logistic regression analyses were performed . FINDINGS The prevalence of CSA and LSA was 9.8 % and 13.9 % , respectively . CSA increased the risk for life-time ADA and anxiety , but not for depression . When potential confounding factors ( e.g. early background factors , depression and anxiety ) were adjusted for , CSA under 13 years of age still predicted ADA in multivariate analyses , but CSA under 18 years of age did not . CONCLUSIONS LSA , and especially CSA under 13 years of age , are factors that should be considered in treatment of women with ADA and in psychiatric treatment of women |
13,791 | 25,162,181 | AND RELEVANCE Photodynamic therapy has a 14%better chance of complete lesion clearance at 3 months after treatment than cryotherapy for thin AKs on the face and scalp | IMPORTANCE Photodynamic therapy ( PDT ) is used extensively to treat actinic keratoses(AKs ) .
An analysis of the effectiveness of PDT compared with other treatments may help physicians decide what role it should play in their own clinical practice s. OBJECTIVE To determine the effectiveness of PDT for the treatment of AKs relative to other methods . | BACKGROUND There is no completely satisfactory treatment for multiple actinic keratoses ( AKs ) . OBJECTIVE To evaluate the efficacy of short incubation , broad-area application of delta-aminolevulinic acid followed by exposure to activating light-photodynamic therapy ( delta-ALA/PDT ) for treatment of AKs and background photodamage . The benefit of pretreatment with 40 % urea cream to enhance penetration and the use of topical 3 % lidocaine hydrochloride to decrease discomfort were also evaluated . METHODS Eighteen patients with at least 4 nonhypertrophic facial AKs and mild to moderate diffuse facial photodamage were enrolled in the study . For 7 days , 40 % urea cream or vehicle was applied to half of the treatment area , and then delta-ALA was applied to the entire area for 1 , 2 , or 3 hours . Lidocaine hydrochloride ( 3 % ) or vehicle cream was also applied to the entire area 45 minutes before exposure to 10 J/cm(2 ) of blue light . Pain , phototoxic reactions , AK counts , and photodamage improvement were evaluated 1 day , 1 week , and 1 month after treatment in all patients and after 5 months in 10 patients . RESULTS All patients experienced mild to moderate discomfort during treatment and moderate phototoxic effects for 1 week . At 1 and 5 months there was significant reduction in AKs in all groups and significant improvement of several photodamage parameters . Different delta-ALA application times and pretreatment with urea cream or lidocaine had no significant effect on the results . CONCLUSIONS This delta-ALA/PDT protocol is safe and effective for AK treatment as well as for improving photodamage . Further studies with a larger cohort , longer follow-up , and histologic confirmation of the clinical data would be of value This double-blind , vehicle-controlled , multicenter study evaluated the efficacy and safety of a new topical antineoplastic agent , masoprocol , in the treatment of actinic keratoses of the head and neck . Of the 113 patients who applied topical masoprocol twice a day for 14 to 28 days , there was a mean decrease in actinic keratoses from 15.0 to 5.4 and a median percent reduction from baseline actinic keratosis count of 71.4 % at the 1-month follow-up visit . Comparable numbers for the vehicle-treated group were 13.4 to 11.1 actinic keratoses and 4.3 % median percent reduction . Irritation , as manifested by erythema or flaking , occurred in 61.5 % of topical masoprocol-treated patients versus 26.7 % of those treated with vehicle and did not correlate with clinical response . Topical masoprocol appears to be useful in the treatment of actinic keratoses The efficacy of photodynamic therapy ( PDT ) using broad area treatment with 5-aminolevulinic acid ( ALA ) has not been compared to topical 5-fluorouracil ( 5-FU ) in the treatment of actinic keratoses ( AK ) . The purpose of this study was to compare the efficacy and tolerability of PDT using short incubation time , broad area treatment with ALA plus activation with either blue light or laser light to topical 5-FU in the treatment of AK of the face and scalp . Thirty-six subjects with AK of either the face or scalp were r and omized to receive either application of ALA for 1 hour followed by activation with blue light or pulsed dye laser or topical 5-FU . Efficacy was evaluated by grading AK lesions and photoaging signs . Tolerability was assessed by scoring crusting/erosions , erythema and stinging/burning . Treatment with PDT using ALA plus blue light was as effective as topical 5-FU in clearing AK . PDT using ALA plus laser light was the least effective treatment . All treatments made improvements in the signs of photoaging . Both PDT treatments were better tolerated than 5-FU . In conclusion , broad area PDT treatment with ALA plus activation with blue light appears to be as effective as 5-FU in the treatment of AK . ALA plus laser light is somewhat less effective than the above therapies . Efficacy could likely be improved with further study of laser parameters and incubation times Background . Organ transplant recipients on long-term immunosuppressive therapy are at increased risk of non-melanoma skin lesions . Repeated field photodynamic therapy using topical methyl aminolevulinate ( MAL ) may have potential as a preventive treatment . Methods . This open r and omized , intrapatient , comparative , multicenter study included 81 transplant recipients with 889 lesions ( 90 % actinic keratoses ( AK ) ] . In each patient , the study treatment was initially administered to one 50 cm2 area on the face , scalp , neck , trunk , or extremities ( n=476 lesions ) twice ( 1 week apart ) , with additional single treatments at 3 , 9 , and 15 months . On each occasion , the area was debrided gently and MAL cream ( 160 mg/g ) applied for 3 hr , before illumination with noncoherent red light ( 630 nm , 37 J/cm2 ) . The control , 50 cm2 area ( n=413 lesions ) received lesion-specific treatment ( 83 % cryotherapy ) at baseline and 3 , 9 , and 15 months . Additionally , all visible lesions were given lesion-specific treatment 21 and 27 months in both treatment and control areas . Results . At 3 months , MAL photodynamic therapy significantly reduced the occurrence of new lesions ( 65 vs. 103 lesions in the control area ; P=0.01 ) , mainly AK ( 46 % reduction ; 43 vs. 80 ; P=0.006 ) . This effect was not significant at 27 months ( 253 vs. 312 ; P=0.06 ) . Hypopigmentation , as assessed by the investigator , was less evident in the treatment than control areas ( 16 % vs. 51 % of patients ; P<0.001 ) at 27 months . Conclusion . Our results suggest that repeated field photodynamic therapy using topical MAL may prevent new AK in transplant recipients although further studies are needed Background Photodynamic therapy ( PDT ) is increasingly used for treatment of actinic keratoses ( AKs ) but is a cumbersome procedure . A thin self‐adhesive patch ( PD P 506 A ) containing 5‐aminolaevulinic acid ( 5‐ALA ) was developed to facilitate PDT BACKGROUND Photodynamic therapy has been proved to be effective in skin rejuvenation . OBJECTIVE To evaluate clinical efficacy and side effects of photodynamic therapy using topical 5-methyl aminolevulinate and red light for photorejuvenation . METHODS A r and omized , prospect i ve , split-face comparison study of 10 white , adult patients with moderate photodamage , Fitzpatrick skin types 2 or 3 , and no occurrence of actinic keratosis was performed . Three treatments using topical methyl aminolevulinate cream , applied for 1 hour on one half of the face and 3 hours on the other half before illumination with red light . A blinded investigator prior to treatment and 2 months after the third treatment evaluated each side of the subject 's faces . RESULTS A moderate improvement in fine lines , tactile roughness , and skin tightness was observed in most of the patients , mostly on the 3-hour time side . There were no changes in mottled pigmentation or telangiectasias . Side effects were observed in all subjects ( erythema , edema , scaling ) mainly in the 3-hour incubation time side . LIMITATIONS The small number of patients and the lack of placebo group . CONCLUSION Methyl aminolevulinic-photodynamic therapy with red light can improve fine lines , tactile roughness and skin tightness in patients with moderate photoaging and no occurrence of actinic keratosis BACKGROUND Actinic keratoses ( AKs ) are the most common premalignant tumors . Without treatment , a significant number of patients with AK will experience squamous cell carcinoma . Photodynamic therapy ( PDT ) using the new highly selective photosensitizer methyl 5-aminolevulinate is a promising new treatment modality for AK . OBJECTIVE We investigated the complete response rates , cosmetic outcome , and patient satisfaction after photodynamic therapy ( PDT ) using methyl 5-aminolevulinate ( Metvix ) versus cryotherapy in the treatment of AKs . METHODS Patients were r and omized to receive either cryotherapy with liquid nitrogen spray or PDT using methyl 5-aminolevulinate cream 160 mg/g , 3 hours application time , and red light ( 75 J/cm(2 ) ) . RESULTS Efficacy results from 193 patients with 699 lesions ( 92 % face/scalp and 93 % thin/moderately thick ) were analyzed . Overall complete response rates after 3 months were 69 % for PDT and 75 % for cryotherapy . Both treatments gave higher response rates in thin lesions ( PDT 75 % , cryotherapy 80 % ) . PDT gave better cosmetic results and higher patient satisfaction than cryotherapy . CONCLUSION PDT using methyl 5-aminolevulinate is an attractive treatment option for patients with AK , with a response rate similar to that of cryotherapy , but with superior cosmetic results and high patient satisfaction BACKGROUND Actinic keratoses are the most common actinic lesions on Caucasian skin . Cryosurgery with liquid nitrogen is commonly used to treat actinic keratoses , but there have been few studies examining the true rate of cure in everyday dermatologic practice . AIM To determine prospect ively the true efficacy of cryosurgery as a treatment for actinic keratoses in everyday dermatologic practice . METHODS A prospect i ve , multicentered study ( a subsidiary study of a photodynamic therapy trial ) was performed . Patients with untreated actinic keratoses greater than 5 mm in diameter on the face and scalp were recruited . Eligible lesions received a single freeze-thaw cycle with liquid nitrogen given via a spray device and were review ed 3 months thereafter . Each center used their preferred freeze time . The only treatment criterion was complete freezing of actinic keratoses and a 1-mm rim of normal skin . Treated lesions were assessed as complete response or noncomplete response . The influence of the duration of freeze , cosmetic outcomes , and adverse events were examined . RESULTS Ninety adult patients from the community with 421 eligible actinic keratoses were recruited . The overall individual complete response rate was 67.2%[SEM = + /-3.5 % ; 95 % confidence interval ( CI ) = 60.4 - 74.1 % ] . Complete response was 39 % for freeze times of less than 5 s , 69 % for freeze times greater than 5 s , and 83 % for freeze times greater than 20 s. Cosmetic outcomes were good to excellent in 94 % of complete response lesions . The main adverse events were pain , stinging , and burning during treatment , and hypopigmentation after healing . CONCLUSIONS Cryosurgery is an effective treatment for actinic keratoses . The true complete response rate is significantly lower than that previously reported . The freeze duration influences successful treatment . Adverse events are mild and well tolerated BACKGROUND Actinic keratoses ( AKs ) are considered as in situ squamous cell carcinoma . Early and effective treatment is important . Objective To compare the efficacy , cosmetic outcome and patient preference of 5-aminolevulinic acid photodynamic therapy ( ALA-PDT ) with that of 5 % imiquimod ( IMIQ ) cream in patients with AKs on the dorsa of h and s and forearms . METHODS Subjects received two ALA-PDT treatment sessions and one or two courses of imiquimod ( three times per week for 4 weeks each ) . Treatments were r and omly allocated to alternate upper extremities . Assessment s included lesion response one and six months after treatment , cosmetic outcome evaluated by the investigators and patients ' preference 6 months after treatment . Efficacy end point included the individual AK lesion clearance rate . RESULTS Thirty patients with 256 lesions were included in the study . At the first follow-up , treatment with ALA-PDT result ed in significantly larger rate of cured lesions relative to 5 % IMIQ cream ( 70.16 % vs. 18.26 % ) . At the second follow-up both treatments showed a high rate of cured lesions ( 65.32 % for PDT vs. 55.65 % for IMIQ cream ) . Response rates obtained in grade I lesions were higher for both treatments ( 71.64 % for PDT vs. 72.13 % for IMIQ ) , while treatment with PDT result ed in a significant larger rate of cured grade II lesions ( 57.89 % for PDT vs. 37.03 for IMIQ ) . Difference in cosmetic outcome was not statistically significant . Results for subject preference favoured ALA-PDT . CONCLUSIONS Our study shows that ALA-PDT and 5 % IMIQ cream are both attractive treatment options for upper extremities AKs with comparable efficacy and cosmetic outcomes OBJECTIVE To examine clinical and molecular changes after topical fluorouracil treatment of photodamaged human facial skin for actinic keratoses . DESIGN Nonr and omized , open-label 2-week treatment with fluorouracil cream , 5 % , followed by clinical and molecular evaluation . SETTING Academic referral center . PATIENTS Twenty-one healthy volunteers , 56 to 85 years old , with actinic keratoses and photodamage . Interventions Twice-daily application of fluorouracil cream for 2 weeks and biopsies and clinical evaluation at baseline and periodically after treatment . MAIN OUTCOME MEASURES Gene and protein expression of molecular effectors of epidermal injury , inflammation , and extracellular matrix remodeling 24 hours after fluorouracil treatment ; clinical improvement measured by evaluators , photography , and patient question naires . RESULTS One day after the final fluorouracil treatment , gene expression of the effectors of epidermal injury ( keratin 16 ) , inflammation ( interleukin 1beta ) , and extracellular matrix degradation ( matrix metalloproteinases 1 and 3 ) was significantly increased . Types I and III procollagen messenger RNA were induced at week 4 ( 7-fold and 3-fold , respectively ) . Type I procollagen protein levels were increased 2-fold at week 24 . Actinic keratoses and photoaging were statistically significantly improved . Most patients rated photoaging as improved and were willing to undergo the therapy again . CONCLUSIONS Topical fluorouracil causes epidermal injury , which stimulates wound healing and dermal remodeling result ing in improved appearance . The mechanism of topical fluorouracil in photoaged skin follows a predictable wound healing pattern of events reminiscent of that seen with laser treatment of photoaging BACKGROUND Photodynamic therapy ( PDT ) and imiquimod are the treatments of choice for actinic keratosis ( AK ) . As they have different mechanisms of action , it seems reasonable to assume that applying both treatments sequentially would be efficacious . OBJECTIVES We sought to determine which of these therapeutic modalities provides a better clinical and histologic response in patients with AK and whether sequential use of both was more efficacious than each separately . METHODS Patients were r and omly assigned to one treatment group : group 1 , PDT only ; group 2 , imiquimod only ; or group 3 , sequential use of PDT and imiquimod . The primary outcome measure was complete clinical response . Partial clinical response was defined as a reduction of more than 75 % in the initial number of lesions . A complete clinicopathologic response was defined as lack of evidence of AK in the biopsy specimen . RESULTS In all , 105 patients completed the study ( group 1 , 40 patients ; group 2 , 33 patients ; group 3 , 32 patients ) . Sequential application of PDT and imiquimod was more efficacious in all the outcome measures . More patients were satisfied with PDT than with the other two modalities ( P = .003 ) . No significant differences were observed among the 3 modalities and tolerance to treatment . LIMITATIONS Only one cycle of imiquimod was administered . The follow-up period was brief . CONCLUSIONS Sequential application of PDT and imiquimod provides a significantly better clinical and histologic response in the treatment of AK than PDT or imiquimod monotherapy . It also produces less intense local reactions and better tolerance and satisfaction than imiquimod monotherapy Background Photodynamic therapy ( PDT ) with 5‐aminolaevulinic acid ( ALA ) provides a therapeutic option for the treatment of actinic keratosis ( AK ) . Different strategies are applied to overcome the chemical instability of ALA in solution and to improve skin penetration . A new stable nanoemulsion‐based ALA formulation , BF‐200 ALA , is currently in clinical development for PDT of AK BACKGROUND Field-directed therapies for actinic keratosis include photodynamic therapy and imiquimod . OBJECTIVES The author design ed a r and omized , vehicle-controlled , split-face study to explore the safety and efficacy of photodynamic therapy followed by imiquimod . METHODS The entire face of adults with > or = 10 facial actinic keratoses were treated with photodynamic therapy with aminolevulinic acid 20 % at baseline and at month 1 . At month 2 , imiquimod 5 % cream was applied to one-half of the face and vehicle to the other half , 2-times-per-week for 16 weeks . Lesion counts were performed at baseline and months 1 , 2 , 3 , 4 , 6 , and 12 ; and local skin reactions assessment s at months 2 , 3 , 4 , and 6 . RESULTS Of 25 participants enrolled , 24 completed the study . Baseline median lesions were 23.5 and 21.5 for the imiquimod- and vehicle-treated sides , respectively . At month 12 , median lesion reductions was 89.9 % versus 74.5 % ( P=.0023 ) , respectively . No subject discontinued for an adverse event . Severe local skin reactions occurring in the most participants were erythema ( 17 % ) and flaking/scaling/dryness ( 13 % ) . CONCLUSIONS Photodynamic therapy followed by imiquimod was well tolerated and improved reduction of actinic keratoses BACKGROUND Photodynamic therapy ( PDT ) has not been compared with topical 5-fluorouracil ( 5-FU ) in the treatment of epidermal dysplasia . OBJECTIVE The purpose of this study was to assess the efficacy and tolerability of these two treatment modalities in 17 patients with actinic keratoses on the backs of the h and s. METHODS Each patient 's right and left h and s were r and omized to receive either a 3-week course of topical 5-FU applied twice per day or PDT using topical 5-aminolevulinic acid ( 5-ALA ) and then , after 4 hours , irradiation with an incoherent light source consisting of a 1200 W metal halogen lamp emitting red light ( 580 to 740 nm ) . Each h and r and omized for PDT received 150 J/cm(2 ) . The observed median fluence rate was 86 mW/cm(2 ) ( interquartile range , 53 to 100 mW/cm(2 ) ) . All patients were review ed at 1 , 4 , and 24 weeks after starting treatment . RESULTS Fourteen of 17 patients ( 82 % ) completed the study . The mean lesional area treated with topical 5-FU decreased from 1390 mm(2 ) ( st and ard deviation [ SD ] , 1130 ) to 297 mm(2 ) ( SD , 209 ) . This represents a mean reduction in lesional area of 70 % ( confidence interval [ CI ] , 61%-80 % ) . The mean lesional area treated with topical PDT decreased from 1322 mm(2 ) ( SD , 1280 ) to 291 mm(2 ) ( SD , 274 ) , representing a mean reduction in lesional area of 73 % ( CI , 61%-84 % ) . The reduction in lesional area elicited by the two treatment methods was similar ( CI , -25 % to 17 % ) . There was no statistically significant difference between the treatment methods in overall symptom scores for pain and redness . CONCLUSION One treatment with PDT using topical 5-ALA appears to be as effective and well tolerated as 3 weeks of twice-daily topical 5-FU , a cheap and widely available alternative Background Topical photodynamic therapy ( PDT ) with aminolevulinic acid ( ALA ) and 5 % imiquimod cream are effective therapies for the treatment of actinic keratoses ( AKs ) , but no split‐face studies directly comparing these treatment options are available in the literature . Objective To compare the efficacy and tolerability of ALA‐PDT and imiquimod 5 % cream for the treatment of AKs . Results Sixty‐one patients were enrolled from the Salt Lake City Veterans Affairs Hospital ; 51 completed the study and were included in the analysis . All patients were r and omized to receive half of a sachet of imiquimod 5 % cream twice weekly on half of their face and two sessions of PDT with 20 % solution of ALA applied for 1 hour to the other side of the face . The 75 % AK clearance rate was 34.6 % for ALA‐PDT and 25 % for imiquimod 5 % cream ( p = .30 ) . The mean reduction in AK count was 59.2 % for ALA‐PDT and 41.4 % for imiquimod 5 % cream ( p = .002 ) . Dermatology Life Quality Index ( DLQI ) scores were assessed for each treatment modality at week 4 and were 1.95 and 1.38 , respectively ( p = .20 ) . Limitations The sample size was small , and patients applied a small amount of imiquimod 5 % cream ( half a sachet ) to a large surface area . Conclusion There was no statistically significant difference in treatment response when the 100 % or 75 % clearance rate cutoff was used , but our secondary outcome suggests that two sessions of ALA‐PDT is superior to imiquimod 5 % cream for the treatment of AKs . There was no statistically significant difference in effect on quality of life as assessed using the DLQI |
13,792 | 23,102,770 | The Skin Cancer Index demonstrates the most evidence of its usefulness in patients with BCC/SCC .
The Patient Outcomes of Surgery-Head/Neck may be beneficial to assess perceptions in appearance before and after surgical intervention | BACKGROUND Treatment of basal cell carcinoma ( BCC ) and squamous cell carcinoma ( SCC ) has traditionally focused on minimizing recurrence and complication rates .
However , the assessment of patient satisfaction and quality of life ( QOL ) is also important .
These outcomes are best assessed by patient-reported outcome ( PRO ) instruments .
OBJECTIVES We sought to conduct a systematic review of published PRO instruments purporting to measure aspects associated with QOL and /or patient satisfaction in the dermatologic BCC/SCC population and evaluate their development , content , and psychometric properties . | OBJECTIVE To identify predictors of skin-related quality of life ( QOL ) after treatment of nonmelanoma skin cancer ( NMSC ) . DESIGN Prospect i ve cohort study of consecutive patients with NMSC diagnosed in 1999 and 2000 . SETTING University-affiliated private practice and a Veterans Affairs clinic . PATIENTS A total of 633 patients who responded to a question naire before treatment . MAIN OUTCOME MEASURE Skin-related QOL , measured with the 16-item version of Skindex-16 , a vali date d measure . Skindex-16 scores vary from 0 ( best QOL ) to 100 ( worst QOL ) and are reported in 3 domains : symptoms , emotional effects , and effects on functioning . RESULTS Controlling for treatment group , the strongest independent predictor of skin-related QOL after treatment of NMSC was pretreatment skin-related QOL . Other patient characteristics that predicted better QOL included less comorbidity and better mental health status . No tumor or care characteristic ( including location of tumor , size of tumor , site of therapy , or training level of treating clinician [ attending physician , resident , or nurse practitioner ] ) was found to predict better skin-related QOL after treatment of NMSC . CONCLUSIONS Patients with better pretreatment skin-related QOL , less comorbidity , and better mental health status had better skin-related QOL after treatment of NMSC . These findings may be useful for pretreatment assessment and counseling BACKGROUND Patient satisfaction is an important aspect of patient‐centered care but has not been systematic ally studied after treatment of nonmelanoma skin cancer ( NMSC ) , the most prevalent cancer . OBJECTIVE To compare patient satisfaction after treatment for NMSC and to determine factors associated with better satisfaction . METHODS We prospect ively measured patient , tumor , and care characteristics in 834 consecutive patients at two centers before and after destruction , excision , and Mohs surgery . We evaluated factors associated with short‐term and long‐term satisfaction . RESULTS In all treatment groups , patients were more satisfied with the interpersonal manners of the staff , communication , and financial aspects of their care than with the technical quality , time with the clinician , and accessibility of their care ( p<.05 ) . Short‐term satisfaction did not differ across treatment groups . In multivariable regression models adjusting for patient , tumor , and care characteristics , higher long‐term satisfaction was independently associated with younger age , better pretreatment mental health and skin‐related quality of life , and treatment with Mohs surgery ( p<.05 ) . CONCLUSIONS Long‐term patient satisfaction after treatment of NMSC is related to pretreatment patient characteristics ( mental health , skin‐related quality of life ) and treatment type ( Mohs ) but not tumor characteristics . These results can guide informed decision‐making for treatment of NMSC . The authors have indicated no significant interest with commercial supporters BACKGROUND Quality of life ( QOL ) has been identified as an important outcome in cancer research , yet the most common malignancy among humans , nonmelanoma skin cancer ( NMSC ) , has been poorly studied in this regard . OBJECTIVE To determine whether change occurred in the QOL of NMSC patients after surgery using a general , vali date d dermatology QOL instrument : the Dermatology Life Quality Index ( DLQI ) . METHODS A prospect i ve study was conducted on 121 consecutive patients referred to a dermatologic Mohs surgery clinic with NMSC of the head and neck . QOL assessment was performed using the DLQI before ( n=121 ) and after surgical treatment at 4 months ( n=101 ) . RESULTS QOL scores demonstrated little h and icap at initial diagnosis . The total DLQI scores showed little change over time , but an item analysis revealed that 2 of the 10 items demonstrated statistically significant change over time , with QOL improving after treatment — decreased painfulness/itchiness/soreness and less necessity to use concealing clothing . CONCLUSIONS General dermatology QOL instruments demonstrated minimal h and icap at initial diagnosis and little change after treatment of NMSC . Although the associations were modest , improvement in some aspects of well-being after treatment of NMSC was demonstrated . A more disease-specific instrument may be necessary to study this disease process further Background An accurate , sensitive , but brief quality -of-life outcomes measure is needed for studies of dermatologic care . Objective To construct a single-page version of Skindex ( a dermatologic quality -of-life instrument ) that would have two new features compared with the current 29-item version : ( 1 ) fewer items to which a majority of patients choose the same response , and ( 2 ) measurement ofbother rather than frequency of patient experiences . Methods R and om sample s of patients waiting for dermatology appointments in clinics of Veterans Affairs hospitals and in private dermatology practice s completed question naires ; 692 patients responded to the parent instrument and 541 additional patients responded to the brief version . Reproducibility , internal consistency reliability , validity , and responsiveness of the brief version of Skindex were determined . Results For 16 items of the current 29-item version ( 55 % ) , more than 50 % of patients responded “ Never . ” After an explicit process of item analysis and elimination , a single-page 16-item version was composed that asks patients about bother from their experiences ; responses are reported as three scales , Symptoms , Emotions , and Functioning . For 6 items of the 16-item version ( 38 % ) , more than 50 % of patients responded “ Never . ” Scale scores were reproducible after 72 hours ( r = 0.88 - 0.90 ) and were internally reliable ( Cronbach ’s α = 0.86 - 0.93 ) . The instrument demonstrated both content and construct validity : Most patients ’ responses to an open-ended question about their skin disease was addressed by the items ; patients with inflammatory dermatoses had higher scores than those with isolated lesions ; and in an exploratory principal axes factor analysis with an oblique rotation , 74 % of the common variance was explained by three factors that correlated with thea priori scales . Mean scale scores stayed the same or changed in the expected direction in patients who reported that their skin was the same or had improved . Conclusion This brief single-page version of Skindex accurately and sensitively measures how much patients are bothered by their skin conditions . SommaireAntécédentsLa mesure des résultats relatifs à la qualité de vie lors d’études sur les soins dermatologiques doit être précise , sensible mais concise . ObjectifÉlaborer une version en une seule page du Skindex ( instrument de mesure de la qualité de vie sur le plan dermatologique ) qui comporterait deux nouvelles caractéristiques par rapport à la version actuelle de 29 questions : ( 1 ) moins de questions pour lesquelles la majorité des patients choisissent la même réponse , et ( 2 ) la mesure des ennuis causés par la maladie plutôt que celle de la fréquence des épisodes . MéthodesDes échantillonnages r and omisés de patients en attente de rendezvous à la clinique de dermatologie des hôpitaux des Anciens Combattants et en cabinets privés ont rempli les question naires ; 692 patients ont répondu à l’instrument de mesure principal et 541 à la version simplifiée . La reproductibilité , la cohérence interne , la fiabilité , la validité et la réactivité de la version simplifée du Skindex ont été évaluées . RésultatsPlus de 50 % des patients ont répondu « jamais » à 16 des 29 questions de la version actuelle ( 55 % ) . Après un travail en profondeur d’analyse et d’élimination des questions , on a rédigé une version d’une page comportant 16 questions sur les ennuis causés par la maladie , les réponses étant rapportées selon trois échelles : symptômes , émotions et fonctionnement . Plus de 50 % des patients ont répondu « jamais » à 6 des 16 questions ( 38 % ) . Les résultats de l’échelle étaient reproductibles après 72 heures ( r = 0 , 88 - 0,90 ) et fiables sur le plan interne ( Cronbach ’s α = 0,86 - 0,93 ) . L’instrument de mesure a permis de démontrer la validité du contenu et de la conception : la plupart des réponses des patients à une question ouverte sur leur affection cutanée étaient abordées dans la question ; les patients atteints de dermatoses inflammatoires avaient des résultats plus élevés que ceux présentant des lésions isolées ; et dans une analyse factorielle exploratoire des principaux axes , la variance commune s’expliquait à 74 % par trois facteurs qui étaient en corrélation avec les échelles établies a priori . Les résultats moyens sont demeurés les mêmes ou ont changé dans le sens attendu chez les patients qui avaient rapporté que l’état de leur peau était le même ou qu’il s’était amélioré . Conclusion Cette version simplifiée d’une page du Skindex mesure de façon précise et sensible l ’ importance des ennuis que causent les affections cutanées aux patients OBJECTIVE To establish the clinical responsiveness of the Skin Cancer Index ( SCI ) , a new disease-specific quality of life ( QOL ) instrument , and to assess demographic and clinical factors which impact QOL in patients with nonmelanoma skin cancer ( NMSC ) . STUDY DESIGN Prospect i ve study of 183 patients with NMSC of the face and neck referred to a tertiary care Mohs surgery clinic . METHODS The SCI is a 15 item , vali date d , disease-specific QOL instrument with 3 distinct subscales , Emotion , Social , and Appearance . Higher scores reflect better QOL . The SCI and the Dermatology Life Quality Index ( DLQI ) , a general dermatology instrument , was administered at initial consultation and 4 months after surgical treatment . Multivariate analysis was conducted to assess demographic and clinical factors predictive of QOL for both instruments . RESULTS The SCI total score and all three subscale scores increased with treatment , demonstrating strong evidence of responsiveness over time ( P < .001 ) in contrast with the DLQI ( P = .46 ) . Predictors of poorer QOL for the SCI included female sex and cancers located on the lip . Patients who demonstrated greatest improvement in QOL with treatment included those who were younger ( < 50 yr ) and had lower reported household income . Also , first time NMSC patients and those patients who underwent less extensive reconstructions demonstrated greater improvements in QOL . CONCLUSION The SCI is a sensitive and responsive QOL instrument for patients with NMSC . Distinct demographic and clinical variables that impact QOL have been demonstrated using this multidimensional , disease-specific instrument CONTEXT Nonmelanoma skin cancer ( NMSC ) is the most common cancer among humans , yet risk perceptions and preventive health behaviors in those who survive this cancer are relatively unknown . OBJECTIVES To assess the impact of the disease and its treatment on sun-protective behaviors , general preventive health behaviors , and risk perception in NMSC patients , and to determine factors associated with behavioral change . DESIGN AND SETTING A prospect i ve study was conducted of 211 consecutive NMSC patients presenting to a dermatologic surgery clinic at a tertiary care university medical center from February 2005 to March 2006 . These patients were all adults , were fluent in English , and had NMSC of the head and neck . Of the 211 eligible patients , complete data was obtained for 183 ( 87 % ) . The most common reasons for dropout were voluntary withdrawal and incompletely answered surveys . INTERVENTION AND OUTCOME MEASURES Surveys that assessed disease-specific quality of life ( QoL ) , preventive health behaviors , sun-protective behaviors , and risk perception were administered before and after surgical treatment of NMSC . RESULTS Sun-protective behaviors improved postsurgery even after controlling for seasons ( P<0.001 ) . Predictor factors associated with increased sun-protective behavior included poor skin tanning ability , summer season , no employment , less comorbid conditions , and previous NMSC treatment . Baseline QoL was not predictive of behavioral change . As for risk perception , respondents thought they were more likely than someone similar to themselves to develop future NMSCs but thought they had similar risks of developing melanoma or other non-skin cancers ( P<0.001 ) . NMSC patients demonstrated disease-specific behavior modifications by selectively improving their sun habits but showed no significant improvement in other preventive health behaviors . This finding is consistent with patients ' specific perception of increased risk for future NMSCs , but surprisingly , not for melanoma . Increased patient education of associated cancer risks with NMSC is warranted . CONCLUSIONS NMSC patients demonstrated disease-specific behavior modifications by selectively improving their sun habits but showed no significant improvement in other preventive health behaviors . This finding is consistent with patients ' specific perception of increased risk for future NMSCs , but surprisingly , not for melanoma . Increased patient education of associated cancer risks with NMSC is warranted BACKGROUND Keratinocyte carcinomas ( KCs ) are the most common malignancies of the skin . As lesions have a low mortality rate , underst and ing quality -of-life ( QoL ) factors is necessary in their management . OBJECTIVE To assess QoL and associated patient characteristics in those with a history of keratinocyte carcinomas . METHODS We conducted a cross-sectional study of veterans with a history of KCs enrolled in a r and omized controlled trial for chemoprevention of keratinocyte carcinomas . Study dermatologists counted actinic keratoses ( AKs ) and assessed for skin photodamage . QoL was assessed using Skindex-29 and KC-specific questions . Demographics were self-reported . RESULTS Participants ( n = 931 ) enrolled at 5 clinical sites had worse QoL on all subscales ( emotions , functioning , and symptoms ) compared to a reference group of patients without skin disease . Univariate analysis demonstrated worse QoL associated with higher AK count , past 5-fluorouracil ( 5-FU ) use , and greater sun sensitivity . Multivariate analysis demonstrated that higher AK count and past 5-FU use were independently related to diminished QoL. Higher comorbidities showed modest associations on the symptoms and functioning subscales . Number of previous KCs was not independently associated with any QoL differences . LIMITATIONS Study population may not be generalizable to the general population . Counting of AKs is of limited reliability . Previous 5-FU use is self reported . CONCLUSIONS A history of ever use of 5-FU and present AKs was strongly associated with worse QoL. We find it more useful to consider these patients as having the chronic condition " actinic neoplasia syndrome , " whose burden may be best measured by factors other than their history of KCs Quality of life is an important treatment outcome for conditions that are rarely fatal , such as cutaneous basal cell carcinoma and squamous cell carcinoma ( typically called nonmelanoma skin cancer ( NMSC ) ) . The purpose of this study was to compare quality -of-life outcomes of treatments for NMSC . We performed a prospect i ve cohort study of 633 consecutive patients with NMSC diagnosed in 1999 and 2000 and followed for 2 years after treatment at a university-based private practice or a Veterans Affairs clinic . The main outcome was tumor-related quality of life 1 to 2 years after therapy , measured with the 16-item version of Skindex , a vali date d measure . Skindex scores vary from 0 ( best ) to 100 ( worst ) in three domains : Symptoms , Emotions , and Function . Treatments were electrodessication and curettage ( ED&C ) in 21 % , surgical excision in 40 % , and Mohs surgery in 39 % . Five hundred and eight patients ( 80 % ) responded after treatment . Patients treated with excision or Mohs surgery improved in all quality -of-life domains , but quality of life did not improve after ED&C. There was no difference in the amount of improvement after excision or Mohs surgery . For example , mean Skindex Symptom scores improved 9.7 ( 95 % CI : 6.9 , 12.5 ) after excision , 10.2 ( 7.4 , 12.9 ) after Mohs surgery , and 3.4 ( -0.9 , 7.6 ) after ED&C. We conclude that , for NMSC , quality -of-life outcomes were similar after excision and Mohs surgery , and both therapies had better outcomes than BACKGROUND We identified factors that influence patient perceptions of their skin cancer surgery through a prospect i ve study of patients referred to a single surgeon during 18 months . METHOD Patients having surgery result ing in a wound sutured and dressed were surveyed 6 to 9 months later . Monitoring for complaints continued for 3 years . RESULTS In all , 74 % of patients returned the survey ( 576 of 778 ) . A total of 250 ( 43 % ) rated their scar excellent , 177 ( 31 % ) very good , 72 ( 12.5 % ) good , 40 fair ( 6.9 % ) , and 14 ( 2.4 % ) poor or very poor . Age , sex , diagnosis , or closure method did not result in a variation in scar perception . In all , 27.3 % of scars ( 21/77 ) on the trunk were rated neutral or negative compared with 6.9 % ( 33/476 ) of scars elsewhere ( P < .001 ) and only 5 % ( 15/305 ) of head and neck scars ( P < .001 ) . Complications did not change scar or overall evaluation ratings . In all , 393 patients ( 68 % ) rated the overall service excellent , 145 ( 25 % ) very good , 22 ( 4 % ) good , and 3 ( 0.5 % ) fair . No patient rated the service poor or very poor . Patients rating the service lower were most dissatisfied with scar appearance , time waiting before surgery , pain from the local anesthetic , nursing care , follow-up care , cost , and written material . In all , 99 % of patients who rated their scar very good or excellent rated the overall service optimally , compared with only 85 % of patients who rated their scar as good or worse . LIMITATIONS A single experienced surgeon in a southern Australia locale might not reflect the perceptions in other clinicians and locations . CONCLUSION Complications and patient complaints do not identify patient dissatisfaction from cutaneous surgery . The patients ' perception of their scars markedly influences their overall service perception . Patients experienced more dissatisfaction with repairs on the trunk |
13,793 | 26,329,455 | Results Existing evidence suggests that , compared with st and ard care , using CHWs in health programmes can be a cost-effective intervention in LMICs , particularly for tuberculosis , but also – although evidence is weaker – in other areas such as reproductive , maternal , newborn and child health ( RMNCH ) and malaria .
Conclusion Notwithst and ing important caveats about the heterogeneity of the studies and their method ological limitations , findings reinforce the hypothesis that CHWs may represent , in some setting s , a cost-effective approach for the delivery of essential health services .
The less conclusive evidence about the cost-effectiveness of CHWs in other areas may reflect that these areas have been evaluated less ( and less rigorously ) than others , rather than an actual difference in cost-effectiveness in the various service delivery areas or interventions . | Objective This study sought to synthesize and critically review evidence on costs and cost-effectiveness of community health worker ( CHW ) programmes in low- and middle-income countries ( LMICs ) to inform policy dialogue around their role in health systems . | Background — Evidence on economically efficient strategies to lower blood pressure ( BP ) from low- and middle-income countries remains scarce . The Control of Blood Pressure and Risk Attenuation ( COBRA ) trial r and omized 1341 hypertensive subjects in 12 r and omly selected communities in Karachi , Pakistan , to 3 intervention programs : ( 1 ) combined home health education ( HHE ) plus trained general practitioner ( GP ) ; ( 2 ) HHE only ; and ( 3 ) trained GP only . The comparator was no intervention ( or usual care ) . The reduction in BP was most pronounced in the combined group . The present study examined the cost-effectiveness of these strategies . Methods and Results — Total costs were assessed at baseline and 2 years to estimate incremental cost-effectiveness ratios based on ( 1 ) intervention cost ; ( 2 ) cost of physician consultation , medications , diagnostics , changes in lifestyle , and productivity loss ; and ( 3 ) change in systolic BP . Precision of the incremental cost-effectiveness ratio estimates was assessed by 1000 bootstrapping replications . Bayesian probabilistic sensitivity analysis was also performed . The annual costs per participant associated with the combined HHE plus trained GP , HHE alone , and trained GP alone were $ 3.99 , $ 3.34 , and $ 0.65 , respectively . HHE plus trained GP was the most cost-effective intervention , with an incremental cost-effectiveness ratio of $ 23 ( 95 confidence interval , 6–99 ) per mm Hg reduction in systolic BP compared with usual care , and remained so in 97.7 of 1000 bootstrapped replications . Conclusions — The combined intervention of HHE plus trained GP is potentially affordable and more cost-effective for BP control than usual care or either strategy alone in some communities in Pakistan , and possibly other countries in Indochina with similar healthcare infrastructure . Clinical Trial Registration — http://www . clinical trials.gov . Unique identifier : NCT00327574 Background Intermittent preventive treatment of malaria in children ( IPTc ) involves the administration of a course of anti-malarial drugs at specified time intervals to children at risk of malaria regardless of whether or not they are known to be infected . IPTc provides a high level of protection against uncomplicated and severe malaria , with monthly sulphadoxine-pyrimethamine plus amodiaquine ( SP&AQ ) and sulphadoxine-pyrimethamine plus piperaquine being the most efficacious regimens . A key challenge is the identification of a cost-effective delivery strategy . Methods A community r and omized trial was undertaken in Jasikan district , Ghana to assess IPTc effectiveness and costs using SP&AQ delivered in three different ways . Twelve villages were r and omly selected to receive IPTc from village health workers ( VHWs ) or facility-based nurses working at health centres ' outpatient departments ( OPD ) or EPI outreach clinics . Children aged 3 to 59 months-old received one IPT course ( three doses ) in May , June , September and October . Effectiveness was measured in terms of children covered and adherent to a course and delivery costs were calculated in financial and economic terms using an ingredient approach from the provider perspective . Results The economic cost per child receiving at least the first dose of all 4 courses was US$ 4.58 when IPTc was delivered by VHWs , US$ 4.93 by OPD nurses and US$ 5.65 by EPI nurses . The unit economic cost of receiving all 3 doses of all 4 courses was US$ 7.56 and US$ 8.51 when IPTc was delivered by VHWs or facility-based nurses respectively . The main cost driver for the VHW delivery was supervision , reflecting re sources used for travelling to more remote communities rather than more intense supervision , and for OPD and EPI delivery , it was the opportunity cost of the time spent by nurses in dispensing IPTc . Conclusions VHWs achieve higher IPTc coverage and adherence at lower costs than facility-based nurses in Jasikan district , Ghana . Trial Registration Clinical Trials.gov NCT00119132 Background We assessed overall annual and unit cost of delivering package of services and specific services at sub-centre level by CHWs and cost effectiveness of Government of India ’s policy of introducing a second auxiliary nurse midwife ( ANM ) at the sub-centre compared to scenario of single ANM sub-centre . Methods We undertook an economic costing of health services delivered by CHWs , from a health system perspective . Bottom-up costing method was used to collect data on re sources spent in 50 r and omly selected sub-centres selected from 4 districts . Mean unit cost along with its 95 % confidence intervals were estimated using bootstrap method . Multiple linear regression model was used to st and ardize cost and assess its determinants . Results Annually it costs INR 1.03 million ( USD 19,381 ) , or INR 187 ( USD 3.5 ) per capita per year , to provide a package of preventive , curative and promotive services through community health workers . Unit costs for antenatal care , postnatal care , DOTS treatment and immunization were INR 525 ( USD 10 ) per full ANC care , INR 767 ( USD 14 ) per PNC case registered , INR 974 ( USD 18 ) per DOTS treatment completed and INR 97 ( USD 1.8 ) per child immunized in routine immunization respectively . A 10 % increase in human re source costs results in 6 % rise in per capita cost . Similarly , 10 % increment in the ANC case registered per provider through-put results in a decline in unit cost ranging from 2 % in the event of current capacity utilization to 3 % reduction in case of full capacity utilization . Incremental cost of introducing 2nd ANM at sub-centre level per unit percent increase ANC coverage was INR 23,058 ( USD 432 ) . Conclusion Our estimates would be useful in undertaking full economic evaluations or equity analysis of CHW programs . Government of India ’s policy of hiring 2nd ANM at sub-centre level is very cost effective from Indian health system perspective BACKGROUND AND METHODS In the setting of a cluster r and omized study to assess impact of the Integrated Management of Neonatal and Childhood Illnesses ( IMNCI ) program in the district of Faridabad in India , we r and omly selected auxiliary nurse midwives ( ANM ) , anganwadi workers ( AWW ) and accredited social health activists ( ASHA ) from intervention and control areas to collect cost data using an economic perspective . Bootstrap method was used to estimate 95 % confidence interval . RESULTS The annual per-child cost of providing health services through an ANM , AWW and ASHA is INR 348 ( USD 7.7 ) , INR 588 ( USD 13.1 ) and INR 87 ( USD 1.9 ) , respectively . The annual per-child incremental cost of delivering IMNCI is INR 124.8 ( USD 2.77 ) , INR 26 ( USD 0.6 ) and INR 31 ( USD 0.7 ) at the ANM , AWW and ASHA level , respectively . CONCLUSION Implementation of IMNCI imposes additional costs to the health system . A comprehensive economic evaluation of the IMNCI is imperative to estimate the net cost implication s in India We did a cost-effectiveness analysis alongside a cluster-r and omised controlled trial of a participatory intervention with women 's groups to improve birth outcomes in rural Nepal . The average provider cost of the women 's group intervention was US0.75 dollars per person per year ( 0.90 dollars with health-service strengthening ) in a population of 86,704 . The incremental cost per life-year saved ( LYS ) was 211 dollars ( 251 dollars ) , and expansion could rationalise on start-up costs and technical assistance , reducing the cost per LYS to 138 dollars ( 179 dollars ) . Sensitivity analysis showed a variation from 83 dollars to 263 dollars per LYS for most variables . This intervention could provide a cost-effective way of reducing neonatal deaths OBJECTIVE To carry out an economic evaluation of a task-shifting intervention for the treatment of depressive and anxiety disorders in primary -care setting s in Goa , India . METHODS Cost-utility and cost-effectiveness analyses based on generalized linear models were performed within a trial set in 24 public and private primary -care facilities . Subjects were r and omly assigned to an intervention or a control arm . Eligible subjects in the intervention arm were given psycho-education , case management , interpersonal psychotherapy and /or antidepressants by lay health workers . Subjects in the control arm were treated by physicians . The use of health-care re sources , the disability of each subject and degree of psychiatric morbidity , as measured by the Revised Clinical Interview Schedule , were determined at 2 , 6 and 12 months . FINDINGS Complete data , from all three follow-ups , were collected from 1243 ( 75.4 % ) and 938 ( 81.7 % ) of the subjects enrolled in the study facilities from the public and private sectors , respectively . Within the public facilities , subjects in the intervention arm showed greater improvement in all the health outcomes investigated than those in the control arm . Time costs were also significantly lower in the intervention arm than in the control arm , whereas health system costs in the two arms were similar . Within the private facilities , however , the effectiveness and costs recorded in the two arms were similar . CONCLUSION Within public primary -care facilities in Goa , the use of lay health workers in the care of subjects with common mental disorders was not only cost-effective but also cost-saving Background Intermittent preventive treatment for malaria in children ( IPTc ) involves the administration of a full course of an anti-malarial treatment to children under 5 years old at specified time points regardless of whether or not they are known to be infected , in areas where malaria transmission is seasonal . It is important to determine the costs associated with IPTc delivery via community based volunteers and also the potential savings to health care providers and caretakers due to malaria episodes averted as a consequence of IPTc . Methods Two thous and four hundred and fifty-one children aged 3–59 months were r and omly allocated to four groups to receive : three days of artesunate plus amodiaquine ( AS+AQ ) monthly , three days of AS+AQ bimonthly , one dose of sulphadoxine-pyrimethamine ( SP ) bi-monthly or placebo . This paper focuses on incremental cost effectiveness ratios ( ICERs ) of the three IPTc drug regimens as delivered by community based volunteers ( CBV ) in Hohoe , Ghana compared to current practice , i.e. case management in the absence of IPTc . Financial and economic costs from the publicly funded health system perspective are presented . Treatment costs borne by patients and their caretakers are also estimated to present societal costs . The costs and effects of IPTc during the intervention period were considered with and without a one year follow up . Probabilistic sensitivity analysis was undertaken to account for uncertainty . Results Economic costs per child receiving at least the first dose of each course of IPTc show SP bimonthly , at US$ 8.19 , is the cheapest to deliver , followed by AS+AQ bimonthly at US$ 10.67 and then by AS+AQ monthly at US$ 14.79 . Training , drug delivery and supervision accounted for approximately 20–30 % each of total unit costs . During the intervention period AS & AQ monthly was the most cost effective IPTc drug regimen at US$ 67.77 ( 61.71–74.75 , CI 95 % ) per malaria case averted based on intervention costs only , US$ 64.93 ( 58.92–71.92 , CI 95 % ) per malaria case averted once the provider cost savings are included and US$ 61.00 ( 54.98 , 67.99 , CI 95 % ) when direct household cost savings are also taken into account . SP bimonthly was US$ 105.35 ( 75.01–157.31 , CI 95 % ) and AS & AQ bimonthly US$ 211.80 ( 127.05–399.14 , CI 95 % ) per malaria case averted based on intervention costs only . The incidence of malaria in the post intervention period was higher in children who were < 1 year old when they received AS+AQ monthly compared to the placebo group leading to higher cost effectiveness ratios when one year follow up is included . The cost per child enrolled fell considerably when modelled to district level as compared to those encountered under trial conditions . Conclusions We demonstrate how cost-effective IPTc is using three different drug regimens and the possibilities for reducing costs further if the intervention was to be scaled up to the district level . The need for effective training , drug delivery channels and supervision to support a strong network of community based volunteers is emphasised Background The Lufwanyama Neonatal Survival Project ( “ LUNESP ” ) was a cluster r and omized , controlled trial that showed that training traditional birth attendants ( TBAs ) to perform interventions targeting birth asphyxia , hypothermia , and neonatal sepsis reduced all-cause neonatal mortality by 45 % . This companion analysis was undertaken to analyze intervention costs and cost-effectiveness , and factors that might improve cost-effectiveness . Methods and Findings We calculated LUNESP 's financial and economic costs and the economic cost of implementation for a forecasted ten-year program ( 2011–2020 ) . In each case , we calculated the incremental cost per death avoided and disability-adjusted life years ( DALYs ) averted in real 2011 US dollars . The forecasted 10-year program analysis included a base case as well as ‘ conservative ’ and ‘ optimistic ’ scenarios . Uncertainty was characterized using one-way sensitivity analyses and a multivariate probabilistic sensitivity analysis . The estimated financial and economic costs of LUNESP were $ 118,574 and $ 127,756 , respectively , or $ 49,469 and $ 53,550 per year . Fixed costs accounted for nearly 90 % of total costs . For the 10-year program , discounted total and annual program costs were $ 256,455 and $ 26,834 respectively ; for the base case , optimistic , and conservative scenarios , the estimated cost per death avoided was $ 1,866 , $ 591 , and $ 3,024 , and cost per DALY averted was $ 74 , $ 24 , and $ 120 , respectively . Outcomes were robust to variations in local costs , but sensitive to variations in intervention effect size , number of births attended by TBAs , and the extent of foreign consultants ' participation . Conclusions Based on established guidelines , the strategy of using trained TBAs to reduce neonatal mortality was ‘ highly cost effective ’ . We strongly recommend consideration of this approach for other remote rural population s with limited access to health care by HEWs in the health posts and general health workers at health facility were compared along a community-r and omized trial . Costs were analysed from societal perspective in 2007 in US $ using st and ard methods . We prospect ively enrolled smear positive patients , and calculated cost-effectiveness as the cost per patient successfully treated . The total cost for each successfully treated smear-positive patient was higher in health facility ( $ 158.9 ) compared with community ( $ 61.7 ) . Community-based treatment reduced the total , patient and caregiver cost by 61.2 % , 68.1 % and 79.8 % , respectively . Involving HEWs added a total cost of $ 8.80 ( 14.3 % of total cost ) on health service per patient treated in the community . Conclusions / Significance Community-based treatment by HEWs costs only 39 % of what treatment by general health workers costs for similar outcomes . Involving HEWs in TB treatment is a cost effective treatment alternative to the health service , to the patients and the family . There is an economic and public health reason to consider involving HEWs in TB treatment in Ethiopia . However , community-based treatment requires initial investment to start its implementation , training and supervision . Trial Registration Clinical Trials.gov Aim : To establish the cost-effectiveness of lay health workers ( LHWs ) in conjunction with the current , local tuberculosis ( TB ) control programme , amidst health service contraction . Method : A cost-effectiveness analysis , comparing direct time costs of the current TB management strategy among permanent farm dwellers , with an intervention , whereby LHWs are involved in TB control activities on farms . Measure of effectiveness was case finding and cure rates of adult new smear-positive ( NSP ) TB cases , alongside a r and omized control trial ( RCT ): Results : The observed cost reduction to the Bol and Health District was 74 % per case detected and cured on the intervention farms relative to the control farms . Intervention farms reached 83 % successful treatment completion rate , control farms 65 % . Although the successful treatment adherence was significantly different ( 18 % letter ) . The improved case detection and cure rates were not statistically significant ( chisquared test ) . Direct LHW costs are borne by farmers . Farmers were motivated to bear costs by reduced job absenteeism and other positive side-effects . Even without outcome improvements costs per case cured were 59 % lower on the intervention farms . Conclusion : TB control has suffered from budget reductions in South Africa . It is critically important to develop cost-effective strategies to reduce the TB burden . Costs to public budgets can be substantially reduced while maintaining or improving case detection and treatment outcomes , by using farm-based LHWs OBJECTIVE To assess the cost-effectiveness of two strategies of home management of under-five fevers in Ghana - treatment using antimalarials only ( artesunate-amodiaquine - AAQ ) and combined treatment using antimalarials and antibiotics ( artesunate-amodiaquine plus amoxicillin - AAQ + AMX ) . METHODS We assessed the costs and cost-effectiveness of AAQ and AAQ + AMX compared with a control receiving st and ard care . Data were collected as part of a cluster r and omised controlled trial with a step-wedged design . Approximately , 12,000 children aged 2 - 59 months in Dangme West District in southern Ghana were covered . Community health workers delivered the interventions . Costs were analysed from societal perspective , using anaemia cases averted , under-five deaths averted and disability-adjusted life years ( DALYs ) averted as effectiveness measures . RESULTS Total economic costs for the interventions were US$ 204,394.72 ( AAQ ) and US$ 260,931.49 ( AAQ + AMX ) . Recurrent costs constituted 89 % and 90 % of the total direct costs of AAQ and AAQ + AMX , respectively . Deaths averted were 79.1 ( AAQ ) and 79.9 ( AAQ + AMX ) , with DALYs averted being 2264.79 ( AAQ ) and 2284.57 ( AAQ + AMX ) . The results show that cost per anaemia case averted were US$ 150.18 ( AAQ ) and US$ 227.49 ( AAQ + AMX ) and cost per death averted was US$ 2585.58 for AAQ and US$ 3272.20 for AAQ + AMX . Cost per DALY averted were US$ 90.25 ( AAQ ) and US$ 114.21 ( AAQ + AMX ) . CONCLUSION Both AAQ and AAQ + AMX approaches were cost-effective , each averting one DALY at less than the st and ard US$ 150 threshold recommended by the World Health Organisation . However , AAQ was more cost-effective . Home management of under-five fevers in rural setting s is cost-effective in reducing under-five mortality |
13,794 | 28,442,274 | This suggests that women 's executive processes may benefit more from exercise than men .
Regardless of sex , compared to control , all three exercise training approaches enhanced visuospatial function , but only multimodal training enhanced episodic memory .
Overall , aerobic training led to greater benefits than resistance training in global cognitive function and executive functions , while multimodal combined training led to greater benefits than aerobic training for global cognitive function , episodic memory , and word fluency . | Exercise is a non-pharmacological strategy to mitigate the deleterious effects of aging on brain health .
However , a large amount of variation exists in its efficacy .
Sex of participants and exercise type are two possible factors contributing to this variation .
To better underst and this , we conducted a concurrent systematic review and meta- analysis of cognitively healthy older adults . | BACKGROUND in a secondary analysis of a r and omised controlled trial , we investigated whether 6 months of music-based multitask training had beneficial effects on cognitive functioning and mood in older adults . METHODS 134 community-dwellers aged ≥65 years at increased risk for falling were r and omly assigned to either an intervention group ( n = 66 ) who attended once weekly 1-h supervised group classes of multitask exercises , executed to the rhythm of piano music , or a control group with delayed intervention ( n = 68 ) who maintained usual lifestyle habits , for 6 months . A short neuropsychological test battery was administered by an intervention-blinded neuropsychologist at baseline and Month 6 , including the mini-mental state examination ( MMSE ) , the clock-drawing test , the frontal assessment battery ( FAB ) and the hospital anxiety ( HADS-A ) and depression scale . RESULTS intention-to-treat analysis showed an improvement in the sensitivity to interference subtest of the FAB ( adjusted between-group mean difference ( AMD ) , 0.12 ; 95 % CI , 0.00 to 0.25 ; P = 0.047 ) and a reduction in anxiety level ( HADS-A ; AMD , -0.88 ; 95 % CI , -1.73 to -0.05 ; P = 0.039 ) in intervention participants , as compared with the controls . Within-group analysis revealed an increase in MMSE score ( P = 0.004 ) and a reduction in the number of participants with impaired global cognitive performance ( i.e. , MMSE score ≤23 ; P = 0.003 ) with intervention . CONCLUSION six months of once weekly music-based multitask training was associated with improved cognitive function and decreased anxiety in community-dwelling older adults , compared with non-exercising controls . Studies design ed to further delineate whether training-induced changes in cognitive function could contribute to dual-task gait improvements and falls reduction , remain to be conducted Physical exercise has been shown to increase brain volume and improve cognition in r and omized trials of non-demented elderly . Although greater social engagement was found to reduce dementia risk in observational studies , r and omized trials of social interventions have not been reported . A representative sample of 120 elderly from Shanghai , China was r and omized to four groups ( Tai Chi , Walking , Social Interaction , No Intervention ) for 40 weeks . Two MRIs were obtained , one before the intervention period , the other after . A neuropsychological battery was administered at baseline , 20 weeks , and 40 weeks . Comparison of changes in brain volumes in intervention groups with the No Intervention group were assessed by t-tests . Time-intervention group interactions for neuropsychological measures were evaluated with repeated- measures mixed models . Compared to the No Intervention group , significant increases in brain volume were seen in the Tai Chi and Social Intervention groups ( p < 0.05 ) . Improvements also were observed in several neuropsychological measures in the Tai Chi group , including the Mattis Dementia Rating Scale score ( p = 0.004 ) , the Trailmaking Test A ( p = 0.002 ) and B ( p = 0.0002 ) , the Auditory Verbal Learning Test ( p = 0.009 ) , and verbal fluency for animals ( p = 0.01 ) . The Social Interaction group showed improvement on some , but fewer neuropsychological indices . No differences were observed between the Walking and No Intervention groups . The findings differ from previous clinical trials in showing increases in brain volume and improvements in cognition with a largely non-aerobic exercise ( Tai Chi ) . In addition , intellectual stimulation through social interaction was associated with increases in brain volume as well as with some cognitive improvements Strength training has been reported as a potentially useful exercise to improve psychological aspects in the elderly , but its effects remain controversial . This study investigated the effectiveness of strength training conducted twice a week for 12 weeks for improving health-related quality of life ( HRQOL ) and executive cognitive function . The study was a single-blind r and omized controlled trial with assessment s before and after intervention . HRQOL and executive function were assessed using the SF-36 Health Status Survey and a computerized neuro-cognitive assessment using task-switch reaction time trials , respectively . Subjects comprised 119 participants > or = 65 years old , r and omized to either strength training ( n=65 ) or health education classes ( controls , n=54 ) . The strength training program was design ed to strengthen the large muscle groups most important for functional activities and to improve balance . The effects of the intervention on the eight dimensions of the SF-36 in the control and training groups were analyzed . Only the mental health scale of the SF-36 was significantly improved for the training group compared with controls after 12 weeks . Task-switch reaction time and correct response rate remained unchanged . Short-term strength training might have modest positive effects on HRQOL , although this training period may not be sufficient to affect executive function in relatively healthy older people 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 The aims of this study were to examine the effects of aerobic exercise on measures of executive performance and their relationships with changes in cardiorespiratory fitness , cardiac vagal control ( heart rate variability ) and psychological variables . Thirty-six sedentary seniors aged 60 - 75 years were r and omly assigned to a swimming and aquaerobics program or a stretching program two times a week for 21 weeks . Executive functions ( inhibition , updating of working memory and cognitive flexibility ) and cardiorespiratory fitness ( estimated VO2max ) were assessed at the start , after 10 weeks of program and at the end of the program . Resting HRV and measures of psychological outcomes ( depression , self-efficacy , decisional balance ) were obtained at the start and at the end of the program . Participants of both groups significantly improved their VO2max level , their psychological state and their performance for the 2-back task . Only the participants in the aquaerobics group significantly improved their vagally-mediated HRV and their performance for the Stroop test and the verbal running-span test at the end of the program . Only improvements in cardiac vagal control and in inhibition were shown to be functionally related . These results are discussed in line with the model of neurovisceral integration Executive function declines with age , but engaging in aerobic exercise may attenuate decline . One mechanism by which aerobic exercise may preserve executive function is through the up-regulation of brain-derived neurotropic factor ( BDNF ) , which also declines with age . The present study examined BDNF as a mediator of the effects of a 1-year walking intervention on executive function in 90 older adults ( mean age = 66.82 ) . Participants were r and omized to a stretching and toning control group or a moderate intensity walking intervention group . BDNF serum levels and performance on a task-switching paradigm were collected at baseline and follow-up . We found that age moderated the effect of intervention group on changes in BDNF levels , with those in the highest age quartile showing the greatest increase in BDNF after 1-year of moderate intensity walking exercise ( p = 0.036 ) . The mediation analyses revealed that BDNF mediated the effect of the intervention on task-switch accuracy , but did so as a function of age , such that exercise-induced changes in BDNF mediated the effect of exercise on task-switch performance only for individuals over the age of 71 . These results demonstrate that both age and BDNF serum levels are important factors to consider when investigating the mechanisms by which exercise interventions influence cognitive outcomes , particularly in elderly population 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 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 OBJECTIVES To evaluate the efficacy of a municipality-led walking program under the Japanese public Long-Term Care Insurance Act to prevent mental decline . DESIGN R and omized controlled trial . SETTING The city of Takasaki . PARTICIPANTS One hundred fifty community members aged 72.0 ± 4.0 were r and omly divided into intervention ( n = 75 ) and control ( n = 75 ) groups . INTERVENTION A walking program was conducted once a week for 90 minutes for 3 months . The program encouraged participants to walk on a regular basis and to increase their steps per day gradually . The intervention was conducted in small groups of approximately six , so combined benefits of exercise and social interaction were expected . MEASUREMENTS Cognitive function was evaluated focusing on nine tests in five domains : memory , executive function , word fluency , visuospatial abilities , and sustained attention . Quality of life ( QOL ) , depressive state , functional capacity , range of activities , and social network were assessed using question naires , and motor function was evaluated . RESULTS Significant differences between the intervention and control groups were shown in word fluency related to frontal lobe function ( F(1 , 128 ) = 6.833 , P = .01 ) , QOL ( F(1,128 ) = 9.751 , P = .002 ) , functional capacity including social interaction ( F(1,128 ) = 13.055 , P < .001 ) , and motor function ( Timed Up and Go Test : F(1,127 ) = 10.117 , P = .002 ) . No significant differences were observed in other cognitive tests . CONCLUSION Walking programs may provide benefits in some aspects of cognition , QOL , and functional capacity including social interaction in elderly community members . This study could serve as the basis for implementation of a community-based intervention to prevent mental decline OBJECTIVE to test the effect of a 16-week multimodal exercise program on neurocognitive and physical functioning and brain-derived neurotrophic factor ( BDNF ) . DESIGN a single-blinded , parallel-group r and omised controlled trial . SETTING S university campus and community-based halls . SUBJECTS forty-nine women aged 65 to 75 years , with no cognitive impairment and not undertaking more than 1 h of formal exercise training per week . METHODS the intervention group attended a 60-min multimodal class twice each week which included cardiovascular , strength and motor fitness training . The primary outcome was neurocognitive functioning and secondary outcomes were physical functioning and plasma levels of BDNF . RESULTS twenty-five participants were r and omised to the intervention group and 24 to the control group . One control participant withdrew before follow-up data collection . The intervention group performed significantly better than the control group at follow-up ( when controlled for baseline ) in the Trail Making test A and B , the California Older Adult Stroop test ( Word , Interference and Total scores ) , Controlled Oral Word Association test and the Timed Up- and -Go test , Six-Minute Walk test , One-Legged Stance test and plasma BDNF . CONCLUSION this multimodal exercise program result ed in neurocognitive and physical performance improvements and increased levels of plasma BDNF , in older women , when compared with controls . This RCT provides evidence that a multimodal exercise intervention can achieve larger effect sizes than those generally result ing from single modality interventions . Increases in BDNF levels imply neurogenesis may be a component of the mechanism underpinning the cognitive improvements associated with multimodal exercise . TRIAL REGISTRATION Australian and New Zeal and Clinical Trial Registration Number : ANZCTR12612000451808 Abstract : A r and omised controlled trial was conducted to determine whether a 12–month program of group exercise had beneficial effects on physiological and cognitive functioning and mood in 187 older community – dwelling women . The exercisers ( n= 94 ) and controls ( n= 93 ) were well matched in terms of the test measures and a number of health and life – style assessment s. The mean number of classes attended by the 71 exercise subjects who completed the program was 59.0 ( range 26 to 82 ) . At the end of the trial , the exercisers showed significant improvements in reaction time , strength , memory span and measures of wellbeing when compared with the controls . There was also an indication that anxiety had been reduced in the exercisers . Within the exercise group , improvements in memory span were associated with concomitant improvements in both reaction time and muscle strength . Also , within this group , initial mood measures were significantly inversely associated with improvements at retest , which suggests that the program may have normalised mood states in subjects who had high initial depression , anxiety and stress levels , rather than inducing improvements in all subjects . These findings suggest that group exercise has beneficial effects on physiological and cognitive functioning and wellbeing in older people Background Inadequate oxygenation may cause lesions and brain atrophy during aging . Studies show a positive association between pulmonary function and the cognitive performance of individuals from middle age on . Objective To investigate the effect of aerobic physical exercises and respiratory training on the blood oxygenation , pulmonary functions , and cognition of the elderly . Design This was a r and omized and controlled trial with three parallel groups . A total of 195 community-dwelling elderly were assessed for eligibility ; only n=102 were included and allocated into the three groups , but after 6 months , n=68 were analyzed in the final sample . Participants were r and omized into a social interaction group ( the control group ) , an aerobic exercise group ( the “ walking ” group ) , or a respiratory training group ( the “ breathing ” group ) . The main outcome measures were the Wechsler Adult Intelligence Scale , Wechsler Memory Scale , Wisconsin Card Sorting Test , respiratory muscular strength , cirtometry ( thoracic – abdominal circumference ) ; oxygen saturation in arterial blood ( SpO2 ) , and hemogram . Results No differences were observed for any of the blood parameters . Aerobic exercise and respiratory training were effective in improving the pulmonary parameters . Better cognitive performance was observed for the breathing group as regards abstract ion and mental flexibility . The walking group remained stable in the cognitive performance of most of the tests , except attention . The control group presented worst performance in mental manipulation of information , abstract ion , mental flexibility , and attention . Conclusion Our results showed that both the walking and breathing groups presented improvement of pulmonary function . However , only the breathing group showed improved cognitive function ( abstract ion , mental flexibility ) . The improvement in cognitive functions can not be explained by blood parameters , such as SpO2 , erythrocytes , hemoglobin , and hematocrit 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 We have compared the effects of different 12-week exercise programs on simple and choice reaction and movement times in persons 61 to 84 years old . One hundred thirty-eight volunteers were r and omized to either a control group , a two-day exercise group ( two 60-min sessions a week of aerobic exercises ) , or a two-day physical plus cognitive exercise group ( two 60-min sessions a week of aerobic and cognitive exercises ) . At follow-up , the aerobic and cognitive exercise program was found to have result ed in significant positive effects . Improvements were found in the two-day physical plus cognitive exercise group in all of the reaction parameters , particularly improvement in choice reaction time , which is used in most daily activities . Our results suggest that to improve reaction time values , it is advisable to include cognitive features into a physical exercise routine OBJECTIVES To examine the effects of aerobic exercise on cognition and other biomarkers associated with Alzheimer disease pathology for older adults with mild cognitive impairment , and assess the role of sex as a predictor of response . DESIGN Six-month , r and omized , controlled , clinical trial . SETTING Veterans Affairs Puget Sound Health Care System clinical research unit . PARTICIPANTS Thirty-three adults ( 17 women ) with amnestic mild cognitive impairment ranging in age from 55 to 85 years ( mean age , 70 years ) . Intervention Participants were r and omized either to a high-intensity aerobic exercise or stretching control group . The aerobic group exercised under the supervision of a fitness trainer at 75 % to 85 % of heart rate reserve for 45 to 60 min/d , 4 d/wk for 6 months . The control group carried out supervised stretching activities according to the same schedule but maintained their heart rate at or below 50 % of their heart rate reserve . Before and after the study , glucometabolic and treadmill tests were performed and fat distribution was assessed using dual-energy x-ray absorptiometry . At baseline , month 3 , and month 6 , blood was collected for assay and cognitive tests were administered . MAIN OUTCOME MEASURES Performance measures on Symbol-Digit Modalities , Verbal Fluency , Stroop , Trails B , Task Switching , Story Recall , and List Learning . Fasting plasma levels of insulin , cortisol , brain-derived neurotrophic factor , insulinlike growth factor-I , and beta-amyloids 40 and 42 . RESULTS Six months of high-intensity aerobic exercise had sex-specific effects on cognition , glucose metabolism , and hypothalamic-pituitary-adrenal axis and trophic activity despite comparable gains in cardiorespiratory fitness and body fat reduction . For women , aerobic exercise improved performance on multiple tests of executive function , increased glucose disposal during the metabolic clamp , and reduced fasting plasma levels of insulin , cortisol , and brain-derived neurotrophic factor . For men , aerobic exercise increased plasma levels of insulinlike growth factor I and had a favorable effect only on Trails B performance . CONCLUSIONS This study provides support , using rigorous controlled methodology , for a potent nonpharmacologic intervention that improves executive control processes for older women at high risk of cognitive decline . Moreover , our results suggest that a sex bias in cognitive response may relate to sex-based differences in glucometabolic and hypothalamic-pituitary-adrenal axis responses to aerobic exercise 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 We used a moderate aerobic exercise program for 24 weeks to measure the positive impact of physical activity on oxidative stress and inflammatory markers and its association with cognitive performance in healthy older adults . A total of 100 healthy subjects ( 65–95 Yrs ) were r and omly classified into two groups : control group ( n = 50 ) and exercise group ( n = 50 ) . Cognitive functioning , physical activity score , MDA , 8-OHdG , TAC , and hs-CRP were assessed using LOTCA battery , prevali date d PA question naire , and immunoassay techniques . LOTCA 7-set scores of cognitive performance showed a significant correlation with physical activity status and the regulation of both oxidative stress free radicals and inflammatory markers in all older subjects following 24 weeks of moderate exercise . Physically active persons showed a higher cognitive performance along with reduction in the levels of MDA , 8-OHdG , and hs-CRP and increase in TAC activity compared with sedentary participants . Cognitive performance correlated positively with the increase in TAC activity and physical fitness scores and negatively with MDA , 8-OHdG , and hs-CRP , respectively . There was a significant improvement in motor praxis , vasomotor organization , thinking operations , and attention and concentration among older adults . In conclusion , moderate aerobic training for 24 weeks has a positive significant effect in improving cognitive functions via modulating redox and inflammatory status of older adults Epidemiological studies suggest a dose-response relationship exists between physical activity and cognitive outcomes . However , no direct data from r and omized trials exists to support these indirect observations . The purpose of this study was to explore the possible relationship of aerobic exercise dose on cognition . Underactive or sedentary participants without cognitive impairment were r and omized to one of four groups : no-change control , 75 , 150 , and 225 minutes per week of moderate-intensity semi-supervised aerobic exercise for 26-weeks in a community setting . Cognitive outcomes were latent residual scores derived from a battery of 16 cognitive tests : Verbal Memory , Visuospatial Processing , Simple Attention , Set Maintenance and Shifting , and Reasoning . Other outcome measures were cardiorespiratory fitness ( peak oxygen consumption ) and measures of function functional health . In intent-to-treat ( ITT ) analyses ( n = 101 ) , cardiorespiratory fitness increased and perceived disability decreased in a dose-dependent manner across the 4 groups . No other exercise-related effects were observed in ITT analyses . Analyses restricted to individuals who exercised per- protocol ( n = 77 ) demonstrated that Simple Attention improved equivalently across all exercise groups compared to controls and a dose-response relationship was present for Visuospatial Processing . A clear dose-response relationship exists between exercise and cardiorespiratory fitness . Cognitive benefits were apparent at low doses with possible increased benefits in visuospatial function at higher doses but only in those who adhered to the exercise protocol . An individual ’s cardiorespiratory fitness response was a better predictor of cognitive gains than exercise dose ( i.e. , duration ) and thus maximizing an individual ’s cardiorespiratory fitness may be an important therapeutic target for achieving cognitive benefits . Trial Registration Clinical Trials.gov Cardiovascular fitness is thought to offset declines in cognitive performance , but little is known about the cortical mechanisms that underlie these changes in humans . Research using animal models shows that aerobic training increases cortical capillary supplies , the number of synaptic connections , and the development of new neurons . The end result is a brain that is more efficient , plastic , and adaptive , which translates into better performance in aging animals . Here , in two separate experiments , we demonstrate for the first time to our knowledge , in humans that increases in cardiovascular fitness results in increased functioning of key aspects of the attentional network of the brain during a cognitively challenging task . Specifically , highly fit ( Study 1 ) or aerobically trained ( Study 2 ) persons show greater task-related activity in regions of the prefrontal and parietal cortices that are involved in spatial selection and inhibitory functioning , when compared with low-fit ( Study 1 ) or nonaerobic control ( Study 2 ) participants . Additionally , in both studies there exist groupwise differences in activation of the anterior cingulate cortex , which is thought to monitor for conflict in the attentional system , and signal the need for adaptation in the attentional network . These data suggest that increased cardiovascular fitness can affect improvements in the plasticity of the aging human brain , and may serve to reduce both biological and cognitive senescence in humans BACKGROUND Several reports suggest beneficial impacts of either physical or mental activity on cognitive function in old age . However , the differential effects of complex mental and physical activities on cognitive performance in humans remain to be clarified . METHODS This r and omized controlled trial evaluates a cognitive and a physical st and ardized 6-month activity intervention ( 3 x 1.5 h/wk ) conducted in Berlin ( Germany ) . Two hundred fifty nine healthy women aged 70 - 93 years were r and omized to a computer course ( n = 92 ) , an exercise course ( n = 91 ) , or a control group ( n = 76 ) , of whom 230 completed the 6-month assessment . Group differences in change over a period of 6 months in episodic memory ( story recall , possible range , 0 - 21 ; word recall , possible range , 0 - 16 ) , executive control ( working memory , ie , time quotient of Trail Making Tests B/A ) , and verbal fluency were evaluated by analyses of covariance ( intention to treat ) adjusting for baseline , fluid intelligence , and educational level . RESULTS In contrast to the control group , both the exercise group , DeltaM ( SD ) = 2.09 ( 2.66 ) , p < .001 , and the computer group , DeltaM ( SD ) = 1.89 ( 2.88 ) , p < .001 , showed improved delayed story recall . They maintained performance in delayed word recall and working memory ( time measure ) as opposed to the control group that showed a decline , DeltaM ( SD ) = -0.91 ( 2.15 ) , p = .001 , and DeltaM ( SD ) = 0.24 ( 0.68 ) , p = .04 , respectively . CONCLUSIONS In healthy older women , participation in new stimulating activities contributes to cognitive fitness and might delay cognitive decline . Exercise and computer classes seem to generate equivalent beneficial effects This study examined the effects of a 12-week aerobic exercise program on psychological well-being and cognitive functioning in a group of ethnically diverse older adults living in an urban community . Forty-eight older men and women ( mean age = 72 + /- 6 ) were r and omly assigned to one of three groups : an aerobic exercise training group , a social activity control group , or a waiting list group . Results indicated little change in psychological well-being and provided limited support for the association of physiological improvement with enhanced mastery and cognitive functioning This study examined the effects of two short physical training programs on various parameters of heart rate variability ( HRV ) and on executive performance in older people . Twenty-four sedentary men and women aged 65–78 years were r and omly assigned to an aerobic exercise program or a stretching program three times a week for 12 weeks . Resting HRV was measured in time and frequency domains in each participant before and after the 12-week programs . Executive performance was measured with the Wisconsin card sorting test ( WCST ) . Significant group – session interactions emerged for the st and ard deviation of normal beat-to-beat ( R – R ) intervals , the root-mean-square of successive R – R , and high frequency power . Only the aerobic training group increased vagal-mediated HRV parameters . Moreover , only the participants in the aerobic training group improved their performance on the WCST . These results highlight the role of aerobic exercise as an important cardiac and brain protective factor , and suggest a direct link between exercise , HRV , and cognition in the aged population OBJECTIVE To compare the effects of Tai Chi ( TC , n = 37 ) and Western exercise ( WE , n = 39 ) with an attention-control group ( C , n = 56 ) on physical and cognitive functioning in healthy adults age 69 + /- 5.8 yr , in a 2-phase r and omized trial . METHODS TC and WE involved combined class and home-based protocol s. Physical functioning included balance , strength , flexibility , and cardiorespiratory endurance . Cognitive functioning included semantic fluency and digit-span tests . Data were analyzed using intention-to-treat analysis . RESULTS At 6 mo , WE had greater improvements in upper body flexibility ( F = 4.67 , p = .01 ) than TC and C. TC had greater improvements in balance ( F = 3.36 , p = .04 ) and a cognitive-function measure ( F = 7.75 , p < .001 ) than WE and C. The differential cognitive-function improvements observed in TC were maintained through 12 mo . CONCLUSION The TC and WE interventions result ed in differential improvements in physical functioning among generally healthy older adults . TC led to improvement in an indicator of cognitive functioning that was maintained through 12 mo BACKGROUND Physical and cognitive activity seems to be an effective strategy by which to promote age-sensitive fluid cognitive abilities in older adults . METHOD In this r and omized controlled trial , 70 healthy senior citizens ( age 60 - 75 ) were allocated to a physical , cognitive , combined physical plus cognitive , and waiting control group . The trial assessed information processing speed , short-term memory , spatial relations , concentration , reasoning , and cognitive speed . RESULTS In contrast to the control group , the physical , cognitive , and combined training groups enhanced their concentration immediately after intervention . Only the physical training group showed improved concentration 3 months later . The combined training group displayed improved cognitive speed both immediately and three months after intervention . The cognitive training group displayed improved cognitive speed 3 months after intervention . CONCLUSIONS Physical , cognitive , and combined physical plus cognitive activity can be seen as cognition-enrichment behaviors in healthy older adults that show different rather than equal intervention effects Objective : To determine the effect of a general group-based exercise programme on cognitive performance and mood among seniors without dementia living in retirement villages . Design : R and omised controlled trial . Setting : Four intermediate care and four self-care retirement village sites in Sydney , Australia . Participants : 154 seniors ( 19 men , 135 women ; age range 62 to 95 years ) , who were residents of intermediate care and self-care retirement facilities . Intervention : Participants were r and omised to one of three experimental groups : ( 1 ) a general group-based exercise ( GE ) programme composed of resistance training and balance training exercises ; ( 2 ) a flexibility exercise and relaxation technique ( FR ) programme ; or ( 3 ) no-exercise control ( NEC ) . The intervention groups ( GE and FR ) participated in 1-hour exercise classes twice a week for a total period of 6 months . Main outcome measures : Using st and ard neuropsychological tests , we assessed cognitive performance at baseline and at 6-month re-test in three domains : ( 1 ) fluid intelligence ; ( 2 ) visual , verbal and working memory ; and ( 3 ) executive functioning . We also assessed mood using the Geriatric Depression Scale ( GDS ) and the Positive and Negative Affect Schedule ( PANAS ) . Results : The GE programme significantly improved cognitive performance of fluid intelligence compared with FR or NEC . There were also significant improvements in the positive PANAS scale within both the GE and FR groups and an indication that the two exercise programmes reduced depression in those with initially high GDS scores . Conclusions : Our GE programme significantly improved cognitive performance of fluid intelligence in seniors residing in retirement villages compared with our FR programme and the NEC group . Furthermore , both group-based exercise programmes were beneficial for certain aspects of mood within the 6-month intervention period IMPORTANCE The prevalence of cognitive impairment and dementia are projected to rise dramatically during the next 40 years , and strategies for maintaining cognitive function with age are critically needed . Physical or mental activity alone result in relatively small , domain-specific improvements in cognitive function in older adults ; combined interventions may have more global effects . OBJECTIVE To examine the combined effects of physical plus mental activity on cognitive function in older adults . DESIGN R and omized controlled trial with a factorial design . SETTING San Francisco , California . PARTICIPANTS A total of 126 inactive , community-residing older adults with cognitive complaints . INTERVENTIONS All participants engaged in home-based mental activity ( 1 h/d , 3 d/wk ) plus class-based physical activity ( 1 h/d , 3 d/wk ) for 12 weeks and were r and omized to either mental activity intervention ( MA-I ; intensive computer ) or mental activity control ( MA-C ; educational DVDs ) plus exercise intervention ( EX-I ; aerobic ) or exercise control ( EX-C ; stretching and toning ) ; a 2 × 2 factorial design was used so that there were 4 groups : MA-I/EX-I , MA-I/EX-C , MA-C/EX-1 , and MA-C/EX-C. MAIN OUTCOME MEASURES Global cognitive change based on a comprehensive neuropsychological test battery . RESULTS Participants had a mean age of 73.4 years ; 62.7 % were women , and 34.9 % were Hispanic or nonwhite . There were no significant differences between the groups at baseline . Global cognitive scores improved significantly over time ( mean , 0.16 SD ; P < .001 ) but did not differ between groups in the comparison between MA-I and MA-C ( ignoring exercise , P = .17 ) , the comparison between EX-I and EX-C ( ignoring mental activity , P = .74 ) , or across all 4 r and omization groups ( P = .26 ) . CONCLUSIONS AND RELEVANCE In inactive older adults with cognitive complaints , 12 weeks of physical plus mental activity was associated with significant improvements in global cognitive function with no evidence of difference between intervention and active control groups . These findings may reflect practice effects or may suggest that the amount of activity is more important than the type in this subject population . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00522899 Objective : Estrogen plays an important role in cognitive function , including attention , learning , and memory , and affects the structure and function of brain areas . We investigated the effects of combined exercise on memory deficits induced by ovariectomy ( OVX ) in relation to cell proliferation and apoptosis in the hippocampus . Methods : Rats were r and omly divided into four groups : sham , sham and exercise , OVX , and OVX and exercise . Rats in combined exercise groups were subjected to 3 days of resistance training and 3 days of running ( for a total of 6 d/wk ) for eight consecutive weeks . Rats were tested in step-down avoidance task and Morris water maze task to verify the effects of OVX on short-term and spatial working memory . Results : In the present study , the number of BrdU-positive and doublecortin-positive cells and expression of brain-derived neurotrophic factor , TrkB , and Bcl-2 decreased ; expression of Bax and the number of caspase-3–positive and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling – positive cells increased ; and short-term and spatial working memory decreased in the OVX group compared with the sham group . Conversely , when the combined exercise group was compared with the OVX group , the number of BrdU-positive and doublecortin-positive cells and expression of brain-derived neurotrophic factor , TrkB , and Bcl-2 increased ; expression of Bax and the number of caspase-3–positive and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling – positive cells decreased ; and short-term and spatial working memory increased . Conclusions : Combined exercise increases cell proliferation and inhibits apoptosis in the hippocampus and improves cognitive function despite estrogen deficiency OBJECTIVES To assess whether resistance training ( RT ) slows the progression of white matter lesions ( WMLs ) in older women . DESIGN Secondary analysis of a 52-week r and omized controlled trial of RT , the Brain Power Study . SETTING Community center and research center . PARTICIPANTS Of 155 community-dwelling women aged 65 to 75 enrolled in the Brain Power Study , 54 who had evidence of WMLs on magnetic resonance imaging ( MRI ) at baseline were included in this secondary analysis . INTERVENTION Participants were r and omized to once-weekly RT ( 1 × RT ) , twice-weekly RT ( 2 × RT ) , or twice-weekly balance and tone ( BAT ) . Assessors were blinded to participant assignments . MEASUREMENTS WML volume was measured using MRI at baseline and trial completion . RESULTS At trial completion , the 2 × RT group had significantly lower WML volume than the BAT group ( P = .03 ) . There was no significant difference between the BAT group and the 1 × RT group at trial completion ( P = .77 ) . Among participants in the two RT groups , reduced WML progression over 12 months was significantly associated with maintenance of gait speed ( correlation coefficient ( r ) = -0.31 , P = .049 ) but not with executive functions ( r = 0.30 ; P = .06 ) . CONCLUSION Engaging in progressive RT may reduce WML progression Brain-derived neurotrophic factor ( BDNF ) is one of the key molecules modulating brain plasticity . While low circulating levels of BDNF have been suggested to predispose to Alzheimer 's disease , very little data are available on its association with cognitive function in general population . We evaluated the association between plasma BDNF levels and cognition in a representative population sample of ageing men and women . The subjects ( n=1389 ) were participants of the Dose-Responses to Exercise Training ( DR 's EXTRA ) Study and represent a r and om sample of Eastern Finnish people ( 684 men and 705 women ) , 57 - 79 years of age at baseline of the study . Plasma BDNF levels were measured by enzyme-linked immunosorbent assay ( ELISA ) . Cognitive function was evaluated using the Consortium to Establish a Registry for Alzheimer 's Disease ( CERAD ) neuropsychological test battery . Women had a higher mean ( + /-SEM ) plasma BDNF level than men ( 1721+/-55vs . 1495+/-54pg/ml , P<0.001 ) . In women , 1 SD decrease in BDNF increased the risk for a low score in Naming Test by 53 % ( 95 % CI 1.21 - 1.92 , P<0.001 ) , in Mini-Mental State Examination by 63 % ( 95 % CI 1.21 - 2.20 , P=0.001 ) , in Word List Memory by 56 % ( 95 % CI 1.08 - 2.26 , P=0.019 ) , in Word List Recall by 50 % ( 95 % CI 1.10 - 2.05 , P=0.010 ) , in Word List Saving by 49 % ( 95 % CI 1.12 - 1.99 , P=0.007 ) , and in Word List Recognition by 64 % ( 95 % CI 1.19 - 2.25 , P=0.002 ) . Data were adjusted for age , education , depression , impaired glucose metabolism , cardiovascular disease , antihypertensive medication , lipid lowering medication , use of sex hormones , smoking , alcohol consumption , storing time of plasma in the freezer and platelet count . BDNF was not associated with cognition in men . Present data suggest that plasma BDNF is a biomarker of impaired memory and general cognitive function in ageing women The authors examined whether resistance training has an effect on working memory span . Participants included 210 community-residing older adults with at least one disability from the Strong for Life program , a r and omized controlled trial that examined the effects of home-based resistance exercise . Memory was assessed with the WAIS backward digit span at baseline and 3 and 6 months into the intervention . Although there were no differences between the experimental treatment and control groups in average levels of memory change , within the treatment group change in resistance level during the intervention was a significant predictor of memory change , controlling for age , education , sex , and disability level . The results suggest that strength training can benefit memory among older adults , especially when using higher resistance levels Physical activity has been proposed as one of the most effective strategies to prevent cognitive decline . Protein supplementation may exert an additive effect . The effect of resistance-type exercise training with or without protein supplementation on cognitive functioning in frail and pre-frail elderly people was assessed in a secondary analysis . Two 24-week , double-blind , r and omized , placebo-controlled intervention studies were carried out in parallel . Subjects performed a resistance-type exercise program of two sessions per week ( n=62 ) or no exercise program ( n=65 ) . In both studies , subjects were r and omly allocated to either a protein ( 2 × 15 g daily ) or a placebo drink . Cognitive functioning was assessed with a neuropsychological test battery focusing on the cognitive domains episodic memory , attention and working memory , information processing speed , and executive functioning . In frail and pre-frail elderly , resistance-type exercise training in combination with protein supplementation improved information processing speed ( changes in domain score 0.08±0.51 versus -0.23±0.19 in the non-exercise group , p=0.04 ) . Exercise training without protein supplementation was beneficial for attention and working memory ( changes in domain scores 0.35±0.70 versus -0.12±0.69 in the non-exercise group , p=0.02 ) . There were no significant differences among the intervention groups on the other cognitive tests or domain scores IMPORTANCE Epidemiological evidence suggests that physical activity benefits cognition , but results from r and omized trials are limited and mixed . OBJECTIVE To determine whether a 24-month physical activity program results in better cognitive function , lower risk of mild cognitive impairment ( MCI ) or dementia , or both , compared with a health education program . DESIGN , SETTING , AND PARTICIPANTS A r and omized clinical trial , the Lifestyle Interventions and Independence for Elders ( LIFE ) study , enrolled 1635 community-living participants at 8 US centers from February 2010 until December 2011 . Participants were sedentary adults aged 70 to 89 years who were at risk for mobility disability but able to walk 400 m. INTERVENTIONS A structured , moderate-intensity physical activity program ( n = 818 ) that included walking , resistance training , and flexibility exercises or a health education program ( n = 817 ) of educational workshops and upper-extremity stretching . MAIN OUTCOMES AND MEASURES Prespecified secondary outcomes of the LIFE study included cognitive function measured by the Digit Symbol Coding ( DSC ) task subtest of the Wechsler Adult Intelligence Scale ( score range : 0 - 133 ; higher scores indicate better function ) and the revised Hopkins Verbal Learning Test ( HVLT-R ; 12-item word list recall task ) assessed in 1476 participants ( 90.3 % ) . Tertiary outcomes included global and executive cognitive function and incident MCI or dementia at 24 months . RESULTS At 24 months , DSC task and HVLT-R scores ( adjusted for clinic site , sex , and baseline values ) were not different between groups . The mean DSC task scores were 46.26 points for the physical activity group vs 46.28 for the health education group ( mean difference , -0.01 points [ 95 % CI , -0.80 to 0.77 points ] , P = .97 ) . The mean HVLT-R delayed recall scores were 7.22 for the physical activity group vs 7.25 for the health education group ( mean difference , -0.03 words [ 95 % CI , -0.29 to 0.24 words ] , P = .84 ) . No differences for any other cognitive or composite measures were observed . Participants in the physical activity group who were 80 years or older ( n = 307 ) and those with poorer baseline physical performance ( n = 328 ) had better changes in executive function composite scores compared with the health education group ( P = .01 for interaction for both comparisons ) . Incident MCI or dementia occurred in 98 participants ( 13.2 % ) in the physical activity group and 91 participants ( 12.1 % ) in the health education group ( odds ratio , 1.08 [ 95 % CI , 0.80 to 1.46 ] ) . CONCLUSIONS AND RELEVANCE Among sedentary older adults , a 24-month moderate-intensity physical activity program compared with a health education program did not result in improvements in global or domain-specific cognitive function . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01072500 BACKGROUND Cognitive impairment is an important contributor to disability . Limited clinical trial evidence exists regarding the impact of physical exercise on cognitive function ( CF ) . We report results of a pilot study to provide estimates of the relative impact of physical activity ( PA ) on 1-year changes in cognitive outcomes and to characterize relationships between changes in mobility disability and changes in cognition in older adults at increased risk for disability . METHODS Sedentary persons ( 102 ) at increased risk for disability ( aged 70 - 89 years ) were r and omized to moderate-intensity PA or health education . Participants were administered the Digit Symbol Substitution Test ( DSST ) , Rey Auditory Verbal Learning Test ( RAVLT ) , modified Stroop test , and Modified Mini-Mental State Examination at baseline and 1 year . RESULTS Group differences were not significant but improvements in cognitive scores were associated with improvements in physical function . Specifically , the DSST significantly correlated with change in the Short Physical Performance Battery score ( r = .38 , p = .0002 ) , in chair st and score ( r = .26 , p = .012 ) , in balance score ( r = .21 , p = .046 ) , and in 400-m gait speed ( r = .15 , p = .147 ) . Change recall on the RAVLT and in the Stroop test was also positively correlated with changes in chair st and and balance , respectively . CONCLUSIONS These results provide further support for the benefits of exercise on CF in older adults . An adequately powered clinical trial of PA involving older adults at increased risk for cognitive disability is needed to exp and the indications for prescribing exercise for prevention of decline in brain function AIM To compare the effect of multicomponent and resistance training and detraining on cognition and depressive symptoms in oldest-old community-dwelling people . METHODS A total of 69 sedentary older adults aged older than 80 years were assessed and r and omized into three groups ( control , multicomponent and resistance training ) . The multicomponent group performed protocol consisting of aerobic , strength and balance exercises . The resistance group participated in strength exercises using six machines . The control group did not perform any intervention . The training sessions had progressive intensity , lasted 16 weeks and included three sessions per week . The volunteers were assessed at baseline , at the end of the 16-week training sessions and after the 6-week detraining period . The assessment consisted of anamneses , Geriatric Depression Scale and cognition ( Montreal Cognitive Assessment , Clock Drawing Test , verbal fluency and dual task ) . RESULTS There were no significant differences between groups and times in any of variables ; however , the adherence to training was low , mainly in the multicomponent group . CONCLUSIONS R and omized controlled trials using adherence strategies and longer times comparing training variations are required to verify which training protocol s are more effective and consistent on cognition and depression in oldest-old people The greater coronary heart disease morbidity of sedentary as opposed to physically active workers was demonstrated many years ago by J N Morris and his colleagues in a comparison of London bus drivers and conductors . These two groups of transport workers belonged to the same social class and had similar lifestyles . They differed principally in the amount of physical activity in which they engaged when at work . The drivers were confined to a small enclosed driving compartment which rendered them almost completely immobile , whilst the conductors were continuously active , especially as they constantly had to run up and down the stairs of the doubledecker London buses . During the five-year follow-up the drivers had a CHD incidence almost double that of the conductors . The differences between the two groups became greater as their members grew older ( Table IX.1 ) . ' The finding of this untoward accompaniment of physical inactivity has been confirmed by the results of the Framingham study 2 and a 27 cohort based rigorous meta- analysis reported by Jesse Berlin and Graham Colditz . These authors found a relative risk of death from coronary heart disease of 1.9 ( CL 1.6 - 2.2 ) for sedentary as opposed to high physical activity groups , and the benefits were shown to be greater in the studies that the authors judged to be method ologically stronger.3 Conversely , in the Whitehall study of British civil servants leisure-time physical activity has been found to have cardiovascular health benefits similar to those apparently conferred on the London bus conductors by their workaday exertions . Vigorous weekend exercise apparently protected the middle-aged men from fatal heart attacks and non-fatal first episodes of coronary heart disease.4 It is probable that a r and omized and controlled prospect i ve study of the cardiovascular consequences of prolonged inactivity will never be undertaken . It would be both unethical and impractical to enforce a long-term sedentary lifestyle on a control group . However , the physiological means by which regular exercise has cardioprotective effects are now well defined . Animal studies have shown that the coronary arterial capacity becomes greater relative to the cardiac muscle mass and an increase in coronary artery diameter has been demonstrated angiographically . Capillary growth is induced and increase in coronary blood flow in response to |
13,795 | 28,348,736 | Conclusion : High-intensity training is promising as a time-efficient exercise strategy in cardiovascular rehabilitation , but data on endothelial effects in cerebrovascular rehabilitation are warranted . | Objectives : Exercise improves endothelial dysfunction , the key manifestation of cardiovascular and cerebrovascular disease , and is recommended in both cardiovascular and cerebrovascular rehabilitation .
Disagreement remains , however , on the role of intensity of exercise .
The purpose of this review was to gather current knowledge on the effects of high-intensity training versus moderate-intensity continuous exercise on endothelial function in cardiovascular and cerebrovascular patients . | Background and Purpose — A new gait training strategy for patients with stroke seeks to increase walking speed through treadmill training . This study compares the effects of structured speed-dependent treadmill training ( STT ) ( with the use of an interval paradigm to increase the treadmill speed stepwise according to principles of sport physiology ) with limited progressive treadmill training ( LTT ) and conventional gait training ( CGT ) on clinical outcome measures for patients with hemiparesis . Methods — Sixty ambulatory poststroke patients were each r and omly selected to receive 1 of the 3 different gait therapies : 20 subjects were treated with STT , 20 subjects were trained to walk on a treadmill with a 20 % increase of belt speed over the treatment period ( LTT ) , and 20 subjects were treated with CGT . Treatment outcomes were assessed on the basis of overground walking speed , cadence , stride length , and Functional Ambulation Category scores . Results — After a 4-week training period , the STT group scored significantly higher than the LTT and CGT groups for overground walking speed ( STT versus LTT , P < 0.001 ; STT versus CGT , P < 0.001 ) , cadence ( STT versus LTT , P = 0.007 ; STT versus CGT , P < 0.001 ) , stride length ( STT versus LTT , P < 0.001 ; STT versus CGT , P < 0.001 ) , and Functional Ambulation Category scores ( STT versus LTT , P = 0.007 ; STT versus CGT , P < 0.001 ) . Conclusions — Structured STT in poststroke patients result ed in better walking abilities than LTT or CGT . This gait training strategy provides a dynamic and integrative approach for the treatment of gait dysfunction after stroke OBJECTIVE To compare the effects of speed-dependent treadmill training on gait and balance performance in patients with sub-acute stroke . DESIGN Single-blinded r and omized controlled trial . SUBJECTS A total of 26 patients with sub-acute stroke were r and omly assigned to experimental ( n = 13 ) and control ( n = 13 ) groups . METHODS Subjects in the experimental group underwent short interval walking trials with stepwise increases in treadmill speed ( speed-dependent treadmill training ) , following the principles of sprint training . Control subjects received gait training on the treadmill at a steady speed . Gait speed , stride length , cadence , and Berg 's Balance Score were recorded and analysed before and after the 10 training sessions . RESULTS Results of 2-way repeated measures analysis of variance showed significant group × time interactions for gait speed and stride length ( p < 0.05 ) . Within each subject group there were improvements in all gait parameters and Berg ’s Balance Score after the training programme . In addition , the experimental group showed significantly larger increases in gait speed ( mean 0.15 m/s , 95 % confidence interval 0.04–0.26 ) and stride length ( mean 0.16 m , 95 % confidence interval 0.02–0.30 ) than the control subjects . CONCLUSION Speed-dependent treadmill training in patients with sub-acute stroke result ed in larger gains in gait speed and stride length compared with steady speed . The positive findings provide evidence for clinical practice of speed-dependent treadmill training in enhancing gait function after stroke Background — Exercise training reduces the symptoms of chronic heart failure . Which exercise intensity yields maximal beneficial adaptations is controversial . Furthermore , the incidence of chronic heart failure increases with advanced age ; it has been reported that 88 % and 49 % of patients with a first diagnosis of chronic heart failure are > 65 and > 80 years old , respectively . Despite this , most previous studies have excluded patients with an age > 70 years . Our objective was to compare training programs with moderate versus high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with postinfa rct ion heart failure . Methods and Results — Twenty-seven patients with stable postinfa rct ion heart failure who were undergoing optimal medical treatment , including & bgr;-blockers and angiotensin-converting enzyme inhibitors ( aged 75.5±11.1 years ; left ventricular [ LV ] ejection fraction 29 % ; & OV0312;o2peak 13 mL · kg−1 · min−1 ) were r and omized to either moderate continuous training ( 70 % of highest measured heart rate , ie , peak heart rate ) or aerobic interval training ( 95 % of peak heart rate ) 3 times per week for 12 weeks or to a control group that received st and ard advice regarding physical activity . & OV0312;o2peak increased more with aerobic interval training than moderate continuous training ( 46 % versus 14 % , P<0.001 ) and was associated with reverse LV remodeling . LV end-diastolic and end-systolic volumes declined with aerobic interval training only , by 18 % and 25 % , respectively ; LV ejection fraction increased 35 % , and pro-brain natriuretic peptide decreased 40 % . Improvement in brachial artery flow-mediated dilation ( endothelial function ) was greater with aerobic interval training , and mitochondrial function in lateral vastus muscle increased with aerobic interval training only . The MacNew global score for quality of life in cardiovascular disease increased in both exercise groups . No changes occurred in the control group . Conclusions — Exercise intensity was an important factor for reversing LV remodeling and improving aerobic capacity , endothelial function , and quality of life in patients with postinfa rct ion heart failure . These findings may have important implication s for exercise training in rehabilitation programs and future studies Low-volume sprint interval training ( SIT ) , or repeated sessions of brief , intense intermittent exercise , elicits metabolic adaptations that resemble traditional high-volume endurance training ( ET ) . The effects of these different forms of exercise training on vascular structure and function remain largely unexplored . To test the hypothesis that SIT and ET would similarly improve peripheral artery distensibility and endothelial function and central artery distensibility , we recruited 20 healthy untrained subjects ( age : 23.3 + /- 2.8 yr ) and had them perform 6 wk of SIT or ET ( n = 5 men and 5 women per group ) . The SIT group completed four to six 30-s " all-out " Wingate tests separated by 4.5 min of recovery 3 days/wk . The ET group completed 40 - 60 min of cycling at 65 % of their peak oxygen uptake ( Vo2peak ) 5 days/wk . Popliteal endothelial function , both relative and normalized to shear stimulus , was improved after training in both groups ( main effect for time , P < 0.05 ) . Carotid artery distensibility was not statistically altered by training ( P = 0.29 ) in either group ; however , popliteal artery distensibility was improved in both groups to the same degree ( main effect , P < 0.05 ) . We conclude that SIT is a time-efficient strategy to elicit improvements in peripheral vascular structure and function that are comparable to ET . However , alterations in central artery distensibility may require a longer training stimuli and /or greater initial vascular stiffness than observed in this group of healthy subjects In this large multicenter trial , we aim ed to assess the effect of aerobic exercise training in stable coronary artery disease ( CAD ) patients on cellular markers of endothelial integrity and to examine their relation with improvement of endothelial function . Two-hundred CAD patients ( left ventricular ejection fraction > 40 % , 90 % male , mean age 58.4 ± 9.1 yr ) were r and omized on a 1:1 base to a supervised 12-wk rehabilitation program of either aerobic interval training or aerobic continuous training on a bicycle . At baseline and after 12 wk , numbers of circulating CD34(+)/KDR(+)/CD45dim endothelial progenitor cells ( EPCs ) , CD31(+)/CD3(+)/CXCR4(+ ) angiogenic T cells , and CD31(+)/CD42b(- ) endothelial microparticles ( EMPs ) were analyzed by flow cytometry . Endothelial function was assessed by flow-mediated dilation ( FMD ) of the brachial artery . After 12 wk of aerobic interval training or aerobic continuous training , numbers of circulating EPCs , angiogenic T cells , and EMPs were comparable with baseline levels . Whereas improvement in peak oxygen consumption was correlated to improvement in FMD ( Pearson r = 0.17 , P = 0.035 ) , a direct correlation of baseline or posttraining EPCs , angiogenic T cells , and EMP levels with FMD was absent . Baseline EMPs related inversely to the magnitude of the increases in peak oxygen consumption ( Spearman rho = -0.245 , P = 0.027 ) and FMD ( Spearman rho = -0.374 , P = 0.001 ) following exercise training . In conclusion , endothelial function improvement in response to exercise training in patients with CAD did not relate to altered levels of EPCs and angiogenic T cells and /or a diminished shedding of EMPs into the circulation . EMP flow cytometry may be predictive of the increase in aerobic capacity and endothelial function Background —In stable coronary artery disease ( CAD ) , exercise training has well-documented positive effects on arterial endothelial function . NO derived from endothelial NO synthase ( eNOS ) is regarded as a protective factor against atherosclerosis . The aim of the present study was to investigate the effects of exercise training on the endothelial function in relation to the expression of eNOS and Akt-dependent eNOS phosphorylation in the left internal mammary artery ( LIMA ) of patients with stable CAD . Methods and Results —In 17 training patients ( T ) and 18 control patients ( C ) , endothelium-dependent vasodilation and average peak flow velocity ( APV ) in response to acetylcholine were measured invasively at study beginning and after 4 weeks in the LIMA . In LIMA tissue sample d during bypass surgery , eNOS expression and content of pospho-eNOS-Ser1177 , Akt , and phospho-Akt were determined by Western blot and quantitative reverse transcriptase – polymerase chain reaction . After exercise training , LIMA APV in response to acetylcholine was increased by 56±8 % ( from + 48±8 % at beginning to + 104±11 % after 4 weeks , P < 0.001 ) . Patients in T had a 2-fold higher eNOS protein expression ( T 1.0±0.7 versus C 0.5±0.3 arbitrary units , P < 0.05 ) and 4-fold higher eNOS Ser1177-phosphorylation levels in LIMA-endothelium ( 1.2±0.9 versus 0.3±0.2 arbitrary units , P < 0.01 ) . A linear correlation was confirmed between Akt phosphorylation and phospho-eNOS levels ( R = 0.80 , P < 0.05 ) and between phospho-eNOS and & Dgr ; APV ( R = 0.59 , P < 0.05 ) . Conclusions —Exercise training in stable CAD leads to an improved agonist-mediated endothelium-dependent vasodilatory capacity . The change in acetylcholine-induced vasodilatation was closely related to a shear stress – induced/Akt-dependent phosphorylation of eNOS on Ser1177 Background Despite the cardiovascular etiology of stroke , exercise and risk factor modification programs akin to cardiac rehabilitation ( CR ) are not available . This study aim ed to establish the feasibility of adapting a CR model for individuals with mild to moderate stroke disability . A secondary objective was to determine the program 's effects on aerobic and walking capacity , and stroke risk factors . Methods A repeated measures design was used with a 3-month baseline period and 6-month adapted CR intervention ( n = 43 , mean ± SD age 65 ± 12 years , 30 ± 28 months post stroke ) . Feasibility was determined by the number of participants who completed the study , occurrence of adverse events and frequency , duration and intensity of exercise performed . To determine effectiveness of the program , outcomes measured included aerobic capacity ( VO2peak , ventilatory threshold ) , 6-Minute Walk Test ( 6MWT ) distance , and risk factors . Descriptive statistics characterized the classes attended and number and intensity of exercise sessions . Paired t-tests , one-factor repeated measures analyses of variance contrasts and chi-square analyses were used to compare changes over time . Results Two participants withdrew during the baseline period . Of the remaining 41 participants who commenced the program , 38 ( 93 % ) completed all aspects . No serious adverse effects occurred . Post-intervention , VO2peak improved relative to the stable baseline period ( P = 0.046 ) and the increase in ventilatory threshold approached significance ( P = 0.062 ) . Conclusions CR is feasible after stroke and may be adapted to accommo date for those with a range of post-stroke disability . It is effective in increasing aerobic capacity . CR may be an untapped opportunity for stroke survivors to access programs of exercise and risk factor modification to lower future event risk . Trial registration Clinical Trials.gov registration number : Objective : To evaluate risk factor reduction and health-related quality of life following a 10-week cardiac rehabilitation programme in non-acute ischaemic stroke subjects . Design : Single-blinded r and omized control trial . Setting : Outpatient rehabilitation . Subjects : Forty-eight community-dwelling ischaemic stroke patients ( 38 independently mobile , 9 requiring assistance , 1 non-ambulatory ) were r and omly assigned to intervention or control groups by concealed allocation . Intervention : The trial consisted of a 10-week schedule with measures taken at weeks 1 and 10 . Both groups continued usual care ( excluding aerobic exercise ) ; intervention subjects attended 16 cycle ergometry sessions of aerobic-training intensity and two stress-management classes . Main outcome measures : Cardiac risk score ( CRS ) ; VO2 ( mL O2/kg per minute ) and Borg Rate of Perceived Exertion ( RPE ) assessed during a st and ardized ergometry test ; Hospital Anxiety and Depression Scale ( HADS ) ; Frenchay Activity Index ; Fasting Lipid Profiles and Resting Blood Pressure . Results : Group comparison with independent t-tests showed significantly greater improvement at follow-up by intervention subjects than controls in VO2 ( intervention 10.6 ±1.6 to 12.0 ± 2.2 , control 11.1 ±1.8 to 11.1 ±1.9 t=4.734 , P<0.001 ) and CRS ( intervention 13.4 ±10.1 to 12.4 ±10.5 , control 9.4 ±6.7 to 15.0 ±6.1 t=-2.537 , P<0.05 ) . RPE rating decreased in intervention subjects ( 13.4 ±12.2 to 12.4 ±2.0 ) and increased in controls ( 13.8 ±1.8 to 14.4 ±1.6 ) ; Mann — Whitney U ( U = 173.5 , P<0.05 ) . Within-group comparison showed significant decrease in the HADS depression subscale in the intervention group alone ( 5.1 ±3.4 to 3.0 ±2.8 ) ( Wilcoxon signed ranks test Z=-3.278 , P<0.001 ) . Conclusion : Preliminary findings suggest non-acute ischaemic stroke patients can improve their cardiovascular fitness and reduce their CRS with a cardiac rehabilitation programme . The intervention was associated with improvement in self-reported depression Moderate-intensity endurance exercise training improves vascular endothelial vasomotor function ; however , the impact of high-intensity exercise training has been equivocal . Thus , the effect of the physiological stress of the exercise remains poorly understood . Furthermore , enhanced vascular repair mediated by circulating progenitor cells may also be improved . To address whether the physiological stress of exercise training is an important factor contributing to these adaptations , 20 healthy participants trained for 6 weeks . Training involved either moderate ( MSIT ; n= 9 ) or heavy metabolic stress ( HSIT ; n= 11 ) interval exercise training programmes matched for total work and duration of exercise . Before and after training , flow-mediated dilatation , low-flow-mediated constriction and total vessel reactivity were measured at the brachial artery using Doppler ultrasound . Circulating progenitor cells ( CD34 + , CD133 + and CD309/KDR+ ) were measured by flow cytometry ( means ± SD ) . Relative ( MSIT pre- 5.5 ± 3.4 versus post-training 6.6 ± 2.5 % ; HSIT pre- 6.6 ± 4.1 versus post-training 7.0 ± 3.4 % , P= 0.33 ) and normalized ( P= 0.16 ) flow-mediated dilatation did not increase with either training programme . However , low-flow-mediated constriction was greater after training in both groups ( MSIT pre- −0.5 ± 3.2 versus post-training −1.9 ± 3.1 % ; HSIT pre- −1.0 ± 1.7 versus post-training −2.9 ± 3.0 % , P= 0.04 ) and contributed to greater total vessel reactivity ( MSIT pre- 7.4 ± 3.3 versus post-training 10.1 ± 3.7 % ; HSIT pre- 10.9 ± 5.9 versus post-training 12.7 ± 6.2 % , P= 0.01 ) . Peak reactive hyperaemia and the area under the shear rate curve were not different between groups , either before or after training . Although circulating progenitor cell numbers increased following heavy-intensity interval exercise training , variability was great amongst participants [ MSIT pre- 16 ± 18 versus post-training 14 ± 12 cells ( ml whole blood)−1 ; HSIT pre- 8 ± 6 versus post-training 19 ± 23 cells ( ml whole blood)−1 , P= 0.50 ] . Overall , vasoconstrictor function may be augmented by moderate- and heavy-intensity interval exercise training in young adults . However , circulating progenitor cell numbers were not increased , suggesting that these cells are not likely to be upregulated as a result of training BACKGROUND High-intensity interval training has been shown to be superior to moderate continuous exercise training in improving exercise capacity and endothelial function in patients with coronary artery disease . The objective of this study was to evaluate this training model on in-stent restenosis following percutaneous coronary intervention for stable or unstable angina . METHODS AND RESULTS We prospect ively r and omized 40 patients after percutaneous coronary intervention with implantation of a bare metal stent ( n = 30 ) or drug eluting stent ( n = 32 ) to a 6-month supervised high-intensity interval exercise training program ( n = 20 ) or to a control group ( n = 20 ) . At six months , restenosis , measured as in-segment late luminal loss of the stented coronary area , was smaller in the training group 0.10 ( 0.52 ) mm compared to the control group 0.39 ( 0.38 ) mm ( P = .01 ) . Reduction of late luminal loss in the training group was consistent with both stent types . Peak oxygen uptake increased in the training and control group by 16.8 % and 7.8 % , respectively ( P < .01 ) . Flow-mediated dilation improved 5.2 % ( 7.6 ) in the training group and decreased -0.1 % ( 8.1 ) in the control group ( P = .01 ) . Levels of high-sensitivity C-reactive protein decreased by -0.4 ( 1.1 ) mg/L in the training group and increased by 0.1 ( 1.2 ) mg/L in the control group ( P = .03 for trend ) . CONCLUSIONS Regular high-intensity interval exercise training was associated with a significant reduction in late luminal loss in the stented coronary segment . This effect was associated with increased aerobic capacity , improved endothelium function , and attenuated inflammation BACKGROUND Growing evidence in long-term treatment of heart transplant ( HTx ) recipients indicates effects of high-intensity interval training ( HIIT ) on several parameters , including oxygen uptake , vascular function and psychological distress . In this study we compare the effect of HIIT vs continued moderate training ( CON ) on vascular function , biomarkers and health-related quality of life ( HRQoL ) in HTx recipients . METHODS A r and omized , controlled crossover trial of stable HTx recipients > 12 months after transplantation was done on patients with 12 weeks of HIIT or 12 weeks of CON , followed by a 5-month washout and crossover . Outcomes included endothelial function , arterial stiffness , biomarkers , HRQoL and markers of anxiety and depression . RESULTS Sixteen HTx recipients ( mean age 52 years , 75 % male ) completed the study . HIIT increased VO(2peak ) more than CON ( between-group difference , p < 0.001 ) . The physical component score of the 36-item Short Form ( SF-36 ) was increased significantly in HIIT patients ( p = 0.02 ) and borderline increased in CON patients ( p = 0.07 ) , whereas there was no significant effect of exercise on the mental component . Depression score decreased significantly in HIIT patients ( p = 0.04 ) with no change in CON patients ( p = 0.75 ) , whereas anxiety score decreased significantly in both HIIT ( p < 0.01 ) and CON ( p < 0.05 ) patients . There were no between-group differences in any of the measures ( all p > 0.05 ) . Arterial stiffness and biomarkers were not changed , nor did endothelial function change after HIIT ( p = 0.08 ) or CON ( p = 0.68 ) . CONCLUSIONS HIIT and CON are both well tolerated and induce similar improvements in physical components of HRQoL and in markers of anxiety . Effects of either training modality on vascular function and biomarkers could not be confirmed Objective : Exercise capacity strongly predicts survival and aerobic interval training ( AIT ) increases peak oxygen uptake effectively in cardiac patients . Usual care in Norway provides exercise training at the hospitals following myocardial infa rct ion ( MI ) , but the effect and actual intensity of these rehabilitation programmes are unknown . Design : R and omized controlled trial . Setting : Hospital cardiac rehabilitation . Subjects : One hundred and seven patients , recruited two to 12 weeks after MI , were r and omized to usual care rehabilitation or treadmill AIT . Interventions : Usual care aerobic group exercise training or treadmill AIT as 4 × 4 minutes intervals at 85–95 % of peak heart rate . Twice weekly exercise training for 12 weeks . Main measures : The primary outcome measure was peak oxygen uptake . Secondary outcome measures were endothelial function , blood markers of cardiovascular disease , quality of life , resting heart rate , and heart rate recovery . Results : Eighty-nine patients ( 74 men , 15 women , 57.4 ± 9.5 years ) completed the programme . Peak oxygen uptake increased more ( P = 0.002 ) after AIT ( from 31.6 ± 5.8 to 36.2 ± 8.6 mL·kg−1·min−1 , P < 0.001 ) than after usual care rehabilitation ( from 32.2 ± 6.7 to 34.7 ± 7.9 mL·kg−1·min−1 , P < 0.001 ) . The AIT group exercised with significantly higher intensity in the intervals compared to the highest intensity in the usual care group ( 87.3 ± 3.9 % versus 78.7 ± 7.2 % of peak heart rate , respectively , P < 0.001 ) . Both programmes increased endothelial function , serum adiponectin , and quality of life , and reduced serum ferritin and resting heart rate . High-density lipoprotein cholesterol increased only after AIT . Conclusions : AIT increased peak oxygen uptake more than the usual care rehabilitation provided to MI patients by Norwegian hospitals Abstract Objective : To determine the physiological and functional responses from high aerobic intensity treadmill walking in 4 x 4-minute intervals in people with chronic stroke and to evaluate the feasibility of this mode of training . Method : This was a baseline control trial with 1 year follow-up in an outpatient rehabilitation setting at a university hospital . Eight people with chronic stroke participated in and completed the study . Their mean age was 48.9 ( ± 10.6 ) years . We tested uphill treadmill walking in 4 x 4-minute work periods at an intensity between 85 % and 95 % of peak heart rate from initial maximal treadmill testing . There were 3-minute active breaks between the intervals . The main outcome measures were peak oxygen uptake ( VO2peak ) and walking economy ( Cw ) . Overall compliance and adverse events determine the feasibility . Results : VO2peak increased from 2.32 ( ± 0.44 ) to 2.60 ( ± 0.55 ) L • min–1 post training ( P = .003 ) . Walking economy ( Cw ) improved from 1.12 ( ± 0.15 ) to 1.04 ( ± 0.18 ) L • min–1 ( P = .043 ) . At 1 year follow-up , VO2peak was 2.59 ( ±0.58 ) L • min –1 and was not significantly different from posttraining measurement ( P = 1.00 ) . Cw was 1.19 ( ± 0.15 ) L • min–1 at 1 year follow-up and thus was worse than post training ( P = .023 ) . Functional improvements were found in the 6-minute walk test ( 6MWT ) ( P = .020 ) , 10-meter walk test ( 10MWT ) ( P = .032 ) , and Timed Up and Go test ( TUG ) ( P = .002 ) at post tests . Conclusions : High aerobic intensity interval treadmill walking significantly increased VO2peak and improved Cw in these subjects . The training was feasible and may have important implication s for cardiovascular health and future rehabilitation programs in this population Background and objective . Ambulatory subjects after stroke may benefit from gait-oriented cardiovascular fitness training , but trials to date have not primarily assessed older persons . Methods . Thirty-eight subjects ( age > 60 years ) with residual hemiparetic gait were enrolled > 6 months after stroke . Participants were r and omized to receive 3 months ( 3 × /week ) progressive grade d , high-intensity aerobic treadmill exercise ( TAEX ) or conventional care physiotherapy . Primary outcome measures were peak exercise capacity ( Vo2peak ) and sustained walking capacity in 6-minute walks ( 6MW ) . Secondary measures were gait velocity in 10-m walks , Berg Balance Scale , functional leg strength ( 5 chair-rise ) , self-rated mobility ( Rivermead Mobility Index ) , and quality of life ( SF-12 ) . Results . Thirty-six participants completed the study ( 18 TAEX , 18 controls ) . TAEX but not conventional care improved Vo2peak ( difference 6.4 mL/kg/min , P < .001 ) and 6MW ( 53 m , P < .001 ) . Likewise , maximum walking speed ( 0.13 m/s , P = .01 ) , balance ( P < .05 ) , and the mental subscore of the SF-12 ( P < .01 ) improved more after TAEX . Gains in Vo2peak correlated with the degree at which training intensity could be progressed in the individual participant ( P < .01 ) . Better walking was related to progression in treadmill velocity and training duration ( P < .001 ) . Vo2peak and 6MW performances were still higher 1 year after the end of training when compared with the baseline , although endurance walking ( 6MW ) at 1 year was lower than immediately after training ( P < .01 ) . Conclusion . This trial demonstrates that TAEX effectively improves cardiovascular fitness and gait in persons with chronic stroke UNLABELLED Poststroke hemiparesis often leads to a vicious cycle of limited activity , deconditioning , and poor cardiovascular health . Accumulating evidence suggests that exercise intensity is a critical factor determining gains in aerobic capacity , cardiovascular protection , and functional recovery after stroke . High-intensity interval training ( HIT ) is a strategy that augments exercise intensity using bursts of concentrated effort alternated with recovery periods . However , there was previously no stroke-specific evidence to guide HIT protocol selection . PURPOSE This study aim ed to compare within-session exercise responses among three different HIT protocol s for persons with chronic ( > 6 months after ) stroke . METHODS Nineteen ambulatory persons with chronic stroke performed three different 1-d HIT sessions in a r and omized order , approximately 1 wk apart . HIT involved repeated 30-s bursts of treadmill walking at maximum tolerated speed , alternated with rest periods . The three HIT protocol s were different on the basis of the length of the rest periods , as follows : 30 s ( P30 ) , 60 s ( P60 ) , or 120 s ( P120 ) . Exercise tolerance , oxygen uptake ( V˙O2 ) , HR , peak treadmill speed , and step count were measured . RESULTS P30 achieved the highest mean V˙O2 , HR , and step count but with reduced exercise tolerance and lower treadmill speed than P60 or P120 ( P30 : 70.9 % V˙O2peak , 76.1 % HR reserve ( HRR ) , 1619 steps , 1.03 m·s(-1 ) ; P60 : 63.3 % V˙O2peak , 63.1 % HRR , 1370 steps , 1.13 m·s(-1 ) ; P120 : 47.5 % V˙O2peak , 46.3 % HRR , 1091 steps , 1.10 m·s(-1 ) ) . P60 achieved treadmill speed and exercise tolerance similar to those in P120 , with higher mean V˙O2 , HR , and step count . CONCLUSIONS For treadmill HIT in chronic stroke , a combination of P30 and P60 may optimize aerobic intensity , treadmill speed , and stepping repetition , potentially leading to greater improvements in aerobic capacity and gait outcomes in future studies Heart failure with preserved ejection fraction ( HFpEF ) is a major cause of morbidity and mortality . Exercise training is an established adjuvant therapy in heart failure ; however , the effects of high-intensity interval training ( HIIT ) in HFpEF are unknown . We compared the effects of HIIT vs. moderate-intensity aerobic continuous training ( MI-ACT ) on peak oxygen uptake ( V̇o₂peak ) , left ventricular diastolic dysfunction , and endothelial function in patients with HFpEF . Nineteen patients with HFpEF ( age 70 ± 8.3 yr ) were r and omized to either HIIT ( 4 × 4 min at 85 - 90 % peak heart rate , with 3 min active recovery ) or MI-ACT ( 30 min at 70 % peak heart rate ) . Fifteen patients completed exercise training ( HIIT : n = 9 ; MI-ACT : n = 6 ) . Patients trained 3 days/wk for 4 wk . Before and after training patients underwent a treadmill test for V̇o₂peak determination , 2D-echocardiography for assessment of left ventricular diastolic dysfunction , and brachial artery flow-mediated dilation ( FMD ) for assessment of endothelial function . HIIT improved V̇o₂peak ( pre = 19.2 ± 5.2 ml·kg(-1)·min(-1 ) ; post = 21.0 ± 5.2 ml·kg(-1)·min(-1 ) ; P = 0.04 ) and left ventricular diastolic dysfunction grade ( pre = 2.1 ± 0.3 ; post = 1.3 ± 0.7 ; P = 0.02 ) , but FMD was unchanged ( pre = 6.9 ± 3.7 % ; post = 7.0 ± 4.2 % ) . No changes were observed following MI-ACT . A trend for reduced left atrial volume index was observed following HIIT compared with MI-ACT ( -3.3 ± 6.6 vs. + 5.8 ± 10.7 ml/m(2 ) ; P = 0.06 ) . In HFpEF patients 4 wk of HIIT significantly improved V̇o₂peak and left ventricular diastolic dysfunction . HIIT may provide a more robust stimulus than MI-ACT for early exercise training adaptations in HFpEF OBJECTIVES Poor adherence to regular exercise is a documented challenge among people with heart disease . Identifying key determinants of exercise adherence and distinguishing between the processes driving short- and long-term adherence to regular exercise is a valuable endeavor . The purpose of the present study was to test a model of exercise behavior change , which incorporates motivational orientations and self-efficacy for exercise behavior , in the prediction of short- and long-term exercise adherence . METHOD Male and female patients ( N = 801 ) hospitalized for coronary heart disease were recruited from 3 tertiary care cardiac centers and followed for a period of 1 year after hospital discharge . A prospect i ve , longitudinal design was used to examine the roles of motivation and self-efficacy ( measured at recruitment and at 2 and 6 months after discharge ) in the prediction of exercise behavior at 6 and 12 months . Baseline measures of exercise and clinical and demographic covariates were included in the analyses . RESULTS Structural equation modeling showed that both autonomous motivation and self-efficacy were important determinants of short-term ( 6-month ) exercise behavior regulation , but that only autonomous motivation remained a significant predictor of long-term ( 12-month ) exercise behavior . Self-efficacy partially mediated the relationship between motivation for exercise and 6-month exercise behavior . CONCLUSIONS This research confirmed the roles of autonomous motivation and self-efficacy in the health behavior change process and emphasized the key function of autonomous motivation in exercise maintenance . Theoretical and cardiac rehabilitation program applications of this research are discussed The relationship between endothelial dysfunction and stroke subtypes is unclear . We prospect ively measured brachial flow-mediated vasodilation ( FMD ) in 143 patients with acute ischemic stroke and 40 controls . The overall stroke patients had impaired FMD , but only lacunar infa rct ion had significantly impaired FMD vs the controls . Impaired FMD was an independent predictor for lacunar infa rct ion . Ischemic stroke is associated with endothelial dysfunction , which is more conspicuous in lacunar infa rct ion Aim — The aim of the present study was to assess the impact of the interval exercise training ( IET ) vs. steady state exercise training ( SSET ) on nitric oxide production , through changes of circulating blood markers of endothelial function , including stable end-products of nitric oxide ( NOx ) and S-nitrosothiols ( RSNOs ) in patients with left ventricular dysfunction ( LVD ) . Patients and methods — The impact of the IET vs. SSET on NOx and RSNOs production was assessed in a total of 31 ( 25 male , 6 female ) patients with LVD ( ejection fraction < 40 % ) , who were admitted to our residential rehabilitation centre . Patients were r and omised into an IET group ( n = 18 ; 15 min interval exercise sessions , 2 times daily ) and an SSET group ( n = 13 ; 5 - 10 min steady state exercise sessions , 2 times daily ) , and exercised every day over a period of 3 weeks . The modified Saville-Griess method was used to determine NOx and RSNOs concentrations . Results — A significant increase was observed both for NOx ( P < 0.05 ) and RSNOs ( P < 0.001 ) in the IET group , as well as for RSNOs in the SSET group ( P < 0.001 ) . Both training methods were observed to significantly improve exercise capacity , as demonstrated for increased workload ( P < 0.001 and P < 0.05 for the IET and SSET groups , respectively ) and duration ( P < 0.001 and P < 0.01 for the IET and SSET groups , respectively ) of the exercise stress test at the end of the study . Conclusion — The results of the present study have demonstrated an increased nitric oxide production and improved exercise capacity in patients with left ventricular dysfunction , who were engaged in an interval exercise programme for three weeks , and clearly indicated an advantage of interval compared to steady state training method for cardiovascular rehabilitation BACKGROUND Stroke is a major cause of death and long-term disability across the globe . Previous studies have demonstrated the trainability of stroke survivors and documented beneficial effects of aerobic exercises on cardiovascular fitness and gait ability . AIM The main aim of this study was to compare the effects of a high-intensity treadmill training ( HITT ) against low-intensity treadmill training ( LITT ) on gait ability , quality of life , cardiorespiratory fitness and cost of walking in chronic stroke subjects . DESIGN R and omized , controlled pilot study . SETTING Patients were recruited among Neurorehabilitation Unit outpatient . POPULATION The sample was composed of 16 subjects suffering from chronic stroke . METHODS Subjects were enrolled and r and omly allocated either in the HITT ( N.=8 ) or in the LITT ( N.=8 ) . Both groups performed 3-month training , 3 times per week . Subjects were evaluated before starting the training and after the end of the training by mean of clinical scales ( Six-Minute Walk Test , Ten-Meter Walk Test , Health Survey Question naire SF-36 , Stroke Impact Scale ) and instrumental tests ( gait analysis , VO2peak and walking energy cost ) . RESULTS Fifteen subjects completed the study and no dropouts were observed . One patient in the LITT refused to initiate the training . The HITT group produced greater improvements than LITT group on the Six-Minute Walk Test ( HITT : 64.25 meters , LITT : 6 meters ; p=0.005 ) and Ten-Meter Walk Test performances ( HITT : -1.7 s , LITT : 0.6 s ; P=0.007 ) , stride length ( HITT : 3.3 cm , LITT : 0.4 cm , P=0.003 ) , step length non-paretic side ( HITT : 0.5 cm , LITT : 2.4 cm , P=0.008 ) , step length paretic side ( HITT : 1.8 cm , LITT : 0.7 cm , P=0.004 ) , cadence ( HITT : 1.6 step/min , LITT : 0.6 step/min , P=0.021 ) and symmetry ratio ( HITT : 0.04 cm , LITT : 0.01 cm , P=0.004 ) , VO2peak ( HITT : 4.6 mL/kg/min , LITT : 0.87 mL/kg/min ; P=0.015 ) and walking energy cost at 100 % of self-selected speed ( HITT : -30.8 mL/kg∙km , LITT : -20 5 mL/kg∙km ; P=0.021 ) . Significant changes were found on Six-Minute Walk Test ( P=0.012 ) and Ten-Meter Walk Test ( P=0.042 ) performances , spatio-temporal gait parameters ( stride length P=0.011 , step length paretic side P=0.012 , cadence P=0.037 and symmetry ratio P=0.012 ) , VO2peak ( P=0.025 ) and cost of walking at 100 % of self-selected speed ( P=0.018 ) in the HITT group . In the LITT no significant results were observed . CONCLUSIONS HITT could be considered a feasible training and led to improvement in gait ability and enhanced VO2peak and reduction in cost of walking compared to LITT . CLINICAL REHABILITATION IMPACT Chronic stroke survivors should be encouraged to engage regular aerobic treadmill training at medium/high intensity . HITT is safe and feasible and has positive effects on gait ability , cardiovascular fitness and cost of walking in subjects with stroke in chronic phase Background and Purpose : Many interventions can improve walking ability of individuals with stroke , although the training parameters that maximize recovery are not clear . For example , the contribution of training intensity has not been well established and may contribute to the efficacy of many locomotor interventions . The purpose of this preliminary study was to evaluate the effects of locomotor training intensity on walking outcomes in individuals with gait deficits poststroke . Methods : Using a r and omized cross-over design , 12 participants with chronic stroke ( > 6-month duration ) performed either high-intensity ( 70%-80 % of heart rate reserve ; n = 6 ) or low-intensity ( 30%-40 % heart rate reserve ; n = 6 ) locomotor training for 12 or fewer sessions over 4 to 5 weeks . Four weeks following completion , the alternate training intervention was performed . Training intensity was manipulated by adding loads or applying resistance during walking , with similar speeds , duration s , and amount of stepping practice between conditions . Results : Greater increases in 6-Minute Walk Test performance were observed following high-intensity training compared with low-intensity training . A significant interaction of intensity and order was also observed for 6-Minute Walk Test and peak treadmill speed , with the largest changes in those who performed high-intensity training first . Moderate correlations were observed between locomotor outcomes and measures of training intensity . Conclusion : This study provides the first evidence that the intensity of locomotor practice may be an important independent determinant of walking outcomes poststroke . In the clinical setting , the intensity of locomotor training can be manipulated in many ways , although this represents only 1 parameter to consider . Video Abstract available for more insights from the authors ( see Supplemental Digital Content 1 , http://links.lww.com/JNPT/A90 ) Coronary allograft vasculopathy is a well‐known long‐term complication after cardiac transplantation . Endothelial dysfunction is involved and may be prevented by aerobic exercise . The purpose of this study was to examine whether high intensity aerobic exercise improves peak oxygen uptake ( VO2 peak ) and endothelial function in heart transplant ( HT ) recipients . Twenty‐seven long‐term HT recipients were r and omized to either 8‐weeks high intensity aerobic exercise or no training . Flow mediated dilation of the brachial artery ( FMD ) was measured by ultrasound and VO2 peak by the analysis of expired air . Blood pressure and biomarkers were measured before and after 8 weeks . VO2 peak increased significantly in the exercise group ( VO2 peak 23.9 ± 1.79 to 28.3 ± 1.63 mL/kg/min compared to controls ( VO2 peak 24.6 ± 1.38 to 23.4 ± 1.58 , p < 0.001 exercise vs. control).FMD increased in the exercise group compared to controls ( 8.3 ± 1.1 % to 11.4 ± 1.2 % vs. 5.6 ± 1.0 % to 5.3 ± 1.7 % , p = 0.024 ) . No increase in nitroglycerin‐induced vasodilation was observed . Systolic blood pressure fell in the exercise group ( 142 ±4.2 mmHg to127 ± 3.4 mmHg , p = 0.01 ) and was unchanged in controls ( 141 ± 4.2 mmHg to 142 ±6.4 mmHg , NS ) . High intensity aerobic exercise reduces systolic blood pressure and improves endothelial function in HT recipients Background Aerobic interval training ( AIT ) has been shown to be superior to moderate continuous exercise training in improving exercise capacity and endothelial function in patients with both coronary artery disease and heart failure ( HF ) . The objective of this study was to evaluate this training modality in patients with HF and an implantable cardioverter defibrillator ( ICD ) with regard to feasibility , safety , and effect . Methods We prospect ively included 38 patients with an ICD : 26 patients participated in an AIT programme for 3 months , while 12 patients served as controls . At baseline and 12-week follow up , patients were assessed with a maximal ergospirometry stress test , echocardiography , endothelial function testing , and ICD interrogation . Results No exercise-related adverse events occurred during or soon after the training sessions . ICD interrogation revealed no sustained arrhythmias , antitachycardia pacing , or ICD discharge related to exercise sessions . The AIT programme led to a significant increase in peak oxygen uptake , cycle ergometer workload , and endothelial function compared to the control group . The training programme was safe and not associated with any adverse events or ICD-related complications . Conclusions An AIT programme is feasible and seems safe in a well-treated , stable ICD population . Further , AIT for 3 months results in significantly increased aerobic capacity and endothelial function in this population |
13,796 | 23,087,653 | Our main findings were that NIBS techniques might be effective strategies for down-regulating HPA activity and regulating food , alcohol , and cigarette consumption . | Major depressive disorder ( MDD ) and cardiovascular diseases are intimately associated .
Depression is an independent risk factor for mortality in cardiovascular sample s. Neuroendocrine dysfunctions in MDD are related to an overactive hypothalamus-pituitary-adrenal ( HPA ) axis and increased sympathetic activity .
Novel intervention strategies for MDD include the non-invasive brain stimulation ( NIBS ) techniques such as repetitive transcranial magnetic stimulation ( rTMS ) and transcranial direct current stimulation ( tDCS ) .
In fact , although these techniques have being increasingly used as a treatment for MDD , their cardiovascular effects were not sufficiently investigated , which would be important considering the dyad MDD/cardiovascular disorders . | BACKGROUND The mesolimbic dopaminergic reward system seems to play a crucial role in reinforcing effects of nicotine . Recently , acute high-frequency repetitive transcranial magnetic stimulation ( rTMS ) of frontal brain regions has been shown to efficiently modulate the mesostriatal and mesolimbic dopaminergic system in both animals and humans . For this reason , we investigated whether high-frequency rTMS would be able to influence nicotine-related behavior by study ing rTMS effects on craving and cigarette smoking . METHOD Fourteen treatment-seeking smokers were included in a double-blind crossover trial , conducted in 2002 , comparing single days of active versus sham stimulation . Outcome measures were rTMS effects on number of cigarettes smoked during an ad libitum smoking period and effects on craving after a period of acute abstinence . RESULTS High-frequency ( 20-Hz ) rTMS of left dorsolateral prefrontal cortex reduced cigarette smoking significantly ( p < .01 ) in an active stimulation compared with sham stimulation . Levels of craving did not change significantly . CONCLUSION High-frequency rTMS may be useful for treatment in smoking cessation OBJECTIVE Because neuroimaging studies have shown that cue-provoked smoking craving is associated with changes in the activity of the bilateral dorsolateral prefrontal cortex ( DLPFC ) , we aim ed to investigate whether a powerful technique of noninvasive brain stimulation , transcranial direct current stimulation ( tDCS ) , reduces cue-provoked smoking craving as indexed by a visual analog scale . METHOD We performed a r and omized , sham-controlled crossover study in which 24 subjects received sham and active tDCS ( anodal tDCS of the left and right DLPFC ) in a r and omized order . Craving was induced by cigarette manipulation and exposure to a smoking video . The study ran from January 2006 to October 2006 . RESULTS Smoking craving was significantly increased after exposure to smoking-craving cues ( p < .0001 ) . Stimulation of both left and right DLPFC with active , but not sham , tDCS reduced craving significantly when comparing craving at baseline and after stimulation , without ( p = .007 ) and with ( p = .005 ) smoking-craving cues . There were no significant mood changes in any of the conditions of stimulation . Adverse events were mild and distributed equally across all treatment conditions . CONCLUSIONS Our findings extend the results of a previous study on the use of brain stimulation to reduce craving , showing that cortical stimulation with tDCS is beneficial for reducing cue-provoked craving , and thus support the further exploration of this technique for smoking cessation Background Prefrontal repetitive transcranial magnetic stimulation ( rTMS ) has been used to induce side-specific mood changes in volunteers and patients . To clarify inconsistencies between reports that used different stimulation frequencies , we conducted a controlled study with a low ( 1 Hz ) frequency , comparing left with right-sided stimulation Methods Nineteen healthy volunteers received r and omised left or right prefrontal rTMS at a frequency of 1 Hz and 100 % of motor threshold in two sessions two weeks apart . Results There were significant improvements with TMS for performance in the digit symbol substitution and verbal fluency tests , but no change of mood on a number of measures . There was also a reduction of pulse rate after TMS . The only side-specific TMS-effect was on mean arterial pressure , which decreased pressure after left , but not after right prefrontal TMS . Conclusions Apart from the unexpected and so far unreplicated effect on mean arterial pressure , there were no side-specific effects on mood in volunteers . It is unlikely that a simple laterality model of mood together with the assumed activating effect of higher and ' quenching ' effect of lower stimulation frequency can account for the effects of TMS on mood BACKGROUND Functional neuroimaging studies have shown that specific brain areas are associated with alcohol craving including the dorsolateral prefrontal cortex ( DLPFC ) . We tested whether modulation of DLPFC using transcranial direct current stimulation ( tDCS ) could alter alcohol craving in patients with alcohol dependence while being exposed to alcohol cues . METHODS We performed a r and omized sham-controlled study in which 13 subjects received sham and active bilateral tDCS delivered to DLPFC ( anodal left/cathodal right and anodal right/cathodal left ) . For sham stimulation , the electrodes were placed at the same positions as in active stimulation ; however , the stimulator was turned off after 30s of stimulation . Subjects were presented videos depicting alcohol consumption to increase alcohol craving . RESULTS Our results showed that both anodal left/cathodal right and anodal right/cathodal left significantly decreased alcohol craving compared to sham stimulation ( p<0.0001 ) . In addition , we found that following treatment , craving could not be further increased by alcohol cues . CONCLUSIONS Our findings showed that tDCS treatment to DLPFC can reduce alcohol craving . These findings extend the results of previous studies using noninvasive brain stimulation to reduce craving in humans . Given the relatively rapid suppressive effect of tDCS and the highly fluctuating nature of alcohol craving , this technique may prove to be a valuable treatment strategy within the clinical setting We aim ed to assess whether modulation of the dorsolateral prefrontal cortex ( DLFPC ) with noninvasive brain stimulation , namely transcranial direct current stimulation ( tDCS ) , modifies food craving in healthy subjects . We performed a r and omized sham-controlled cross-over study in which 23 subjects received sham and active tDCS ( anode left/cathode right and anode right/cathode left ) of the DLPFC . Subjects were exposed to food and also watched a movie of food associated with strong craving . Desire for food consumption was evaluated by visual analogue scales ( VAS ) and food consumption before and after treatment . In addition we measured visual attention to food using an eye tracking system . Craving for viewed foods as indexed by VAS was reduced by anode right/cathode left tDCS . After sham stimulation , exposure to real food or food-related movie increased craving ; whereas after anode left/cathode right tDCS , the food-related stimuli did not increase craving levels , as revealed by the VAS scale . Moreover , compared with sham stimulation , subjects fixated food-related pictures less frequently after anode right/cathode left tDCS and consumed less food after both active stimulation conditions . These changes were not related to mood changes after any type of tDCS treatment . The effects of tDCS on food craving might be related to a modulation of neural circuits associated with reward and decision-making This study examined whether a single session of repetitive transcranial magnetic stimulation ( rTMS ) of the left prefrontal cortex ( PFC ) would inhibit food cravings in healthy women who endorsed frequent food cravings . Ten participants viewed images of food and completed ratings for food cravings before and after receiving either real or sham rTMS over the left PFC ( 10 Hz , 100 % resting motor threshold , 10 s-on , 20 s-off for 15 min ; 3000 pulses ) . Sham-TMS was matched with real TMS with respect to perceived painfulness of the stimulation . Each participant received both real and sham rTMS in r and om order and were blind to the condition in a within-subject cross-over design . With an improved sham control condition , prefrontal rTMS inhibited food cravings no better than sham rTMS . The mild pain from the real and sham rTMS may distract or inhibit food craving , and the decreased craving may not be caused by the effect of rTMS itself . Further studies are needed to eluci date whether rTMS has any true effects on food craving and whether painful stimuli inhibit food or other cravings . A sham condition which matches the painfulness is important to underst and the true effects of TMS on behaviors and diseases CONTEXT Depressive symptoms predict adverse cardiovascular outcomes in patients with coronary heart disease , but the mechanisms responsible for this association are unknown . OBJECTIVE To determine why depressive symptoms are associated with an increased risk of cardiovascular events . DESIGN AND PARTICIPANTS The Heart and Soul Study is a prospect i ve cohort study of 1017 out patients with stable coronary heart disease followed up for a mean ( SD ) of 4.8 ( 1.4 ) years . SETTING Participants were recruited between September 11 , 2000 , and December 20 , 2002 , from 12 outpatient clinics in the San Francisco Bay Area and were followed up to January 12 , 2008 . MAIN OUTCOME MEASURES Baseline depressive symptoms were assessed using the Patient Health Question naire ( PHQ ) . We used proportional hazards models to evaluate the extent to which the association of depressive symptoms with subsequent cardiovascular events ( heart failure , myocardial infa rct ion , stroke , transient ischemic attack , or death ) was explained by baseline disease severity and potential biological or behavioral mediators . RESULTS A total of 341 cardiovascular events occurred during 4876 person-years of follow-up . The age-adjusted annual rate of cardiovascular events was 10.0 % among the 199 participants with depressive symptoms ( PHQ score > or = 10 ) and 6.7 % among the 818 participants without depressive symptoms ( hazard ratio [ HR ] , 1.50 ; 95 % confidence interval , [ CI ] , 1.16 - 1.95 ; P = .002 ) . After adjustment for comorbid conditions and disease severity , depressive symptoms were associated with a 31 % higher rate of cardiovascular events ( HR , 1.31 ; 95 % CI , 1.00 - 1.71 ; P = .04 ) . Additional adjustment for potential biological mediators attenuated this association ( HR , 1.24 ; 95 % CI , 0.94 - 1.63 ; P = .12 ) . After further adjustment for potential behavioral mediators , including physical inactivity , there was no significant association ( HR , 1.05 ; 95 % CI , 0.79 - 1.40 ; P = .75 ) . CONCLUSION In this sample of out patients with coronary heart disease , the association between depressive symptoms and adverse cardiovascular events was largely explained by behavioral factors , particularly physical inactivity Previous studies in healthy volunteers reported a possible impact of high frequency repetitive transcranial magnetic stimulation ( HF-rTMS ) on stress hormones , like cortisol . In this sham-controlled , “ single blind ” , crossover study , we examined whether HF-rTMS had an effect on the hypothalamic-pituitary-adrenal ( HPA ) axis , by analysing salivary cortisol levels . Two studies were conducted . First , HF-rTMS on the left dorsolateral prefrontal cortex ( DLPFC ) was performed in 28 young healthy female volunteers . Second , in a comparable , but different group of 26 healthy females , HF-rTMS was performed on the right DLPFC . Salivary cortisol levels were assessed before , immediately after and 30 min after real and sham HF-rTMS . We found no support for the hypothesis that one single session of HF-rTMS on the left or the right DLPFC has an immediate or delayed impact on the HPA – axis , as measured by salivary cortisol . Although we controlled for several method ological problems in HF-rTMS research , the hypothesis that one single session of HF-rTMS on the left or on the right DLPFC can influence the HPA-axis in healthy volunteers was not supported Abstract Objectives . Neuroimaging studies have found that alcohol dependent patients display dopaminergic dysfunction in the ventral striatum , which is associated with alcohol craving . Repetitive transcranial magnetic stimulation ( rTMS ) was introduced as a promising new treatment option for depression , and among other neurobiological mechanisms , it is able to stimulate the striatal dopaminergic system . The aim of our study was to investigate the effect of high frequency rTMS of the left dorsolateral prefrontal cortex compared to sham stimulation on craving and mood in alcohol dependent women . Furthermore , the impact on an attentional blink ( AB ) paradigm to pictures with neutral , emotional and alcohol-related contents was proofed . Methods . Nineteen female detoxified patients were r and omized either to a high frequency rTMS ( 20 Hz ) over the left DLPFC ( n = 10 ) or a sham stimulations ( n = 9 ) at 10 days . Alcohol craving was determined with the Obsessive Compulsive Drinking Scale , depressive symptoms were registered by means of Hamilton Depression Rating Scale and Beck ’ Depression Inventory . For the AB paradigm an age-matched control group was investigated . Results . There were no significantly differences between both groups regarding alcohol craving or mood . In the AB paradigm , real stimulated patients detected alcohol related T2 targets incorrectly in comparison to the sham stimulated and control subjects . Summary . Although there were no differences in clinical parameters such as craving or mood after real high frequency rTMS compared to sham stimulation , we found an interesting difference between the real and the sham stimulated group and controls in the AB paradigm indicating an increase of the AB effect to alcohol-related pictures after real stimulation . Further studies are needed to replicate these findings and correlate them to clinical and neurophysiological data BACKGROUND Prior research in substance dependence has suggested potential anti-craving effects of repetitive transcranial magnetic stimulation ( rTMS ) when applied to the dorsolateral prefrontal cortex ( DLPFC ) . However , no single sham-controlled session studies applied to the right DLPFC have been carried-out in recently detoxified alcohol-dependent patients . Furthermore , no studies examined the effect of a single HF-rTMS session on craving in these patients ' natural habitat . METHODS To further investigate the effect of high-frequency (HF)-rTMS of the right DLPFC on alcohol craving , we performed a prospect i ve , single-blind , sham-controlled study involving 36 hospitalized patients with alcohol dependence syndrome . After successful detoxification , patients were allocated receiving one active or one sham HF-rTMS session . The obsessive-compulsive drinking scale ( OCDS ) was administered to evaluate the extent of craving just before and after the HF-rTMS session ( on Friday ) , on Saturday and Sunday during the weekend at home , and on Monday when the patient returned to the hospital . RESULTS One single blind sham-controlled HF-rTMS session applied to the right DLPFC did not result in changes in craving ( neither immediately after the stimulation session , nor in patients ' natural environment during the weekend ) . CONCLUSIONS One HF-rTMS stimulation session applied to the right DLPFC had no significant effects on alcohol craving in alcohol dependent patients . One such session could have been too short to alter alcohol craving in a sample of alcohol dependent patients Low-frequency ( LF ) rTMS shows beneficial effects in patients with depression and anxiety disorders . To explore its anxiolytic properties we investigated the effects of rTMS on experimentally induced panic attacks . Eleven healthy subjects underwent 1 Hz rTMS or sham rTMS over the right dorsolateral prefrontal cortex in a r and omized cross-over protocol . Panic induction with 50 mug CCK-4 was carried out immediately after rTMS . Response to CCK-4 was assessed using the Acute Panic Inventory and the Panic Symptom Scale and measurements of heart rate , plasma ACTH and cortisol . All subjects reported a marked panic response following CCK-4 administration after both real and sham rTMS . Moreover , injection of CCK-4 induced a marked increase in heart rate , cortisol and ACTH concentrations . However , ANOVA showed no significant differences in any of the measures between both conditions . In contrast to the effects of pretreatment with alprazolam on CCK-4-induced panic in healthy subjects LF rTMS does not affect CCK-4-induced panic and cortisol or ACTH release We assessed the safety of repeated short trains ( 4 stimuli ) of rapid-rate transcranial magnetic stimulation ( rrTMS ) over the left motor cortex in 6 healthy normal subjects . rrTMS involved two separate blocks of 50 consecutive trains of 4 stimuli at a frequency of 20 Hz and an intensity of 5 - 10 % above active motor threshold . We monitored EEG , and assessed aspects of neurological ( balance , gait , two-point discrimination , blood pressure , pulse rate ) , cognitive ( attention , memory , executive function ) and motor function ( speed of movement initiation and execution and manual dexterity ) before and after the two blocks of rrTMS . EMG was also recorded from a number of h and , forearm and arm muscles contralateral to the site of stimulation . Two blocks of repeated rrTMS at 20 Hz and 5 - 10 % above active motor threshold did not produce any adverse effects . Measures of neurological , cognitive and motor function showed no change following rrTMS . From the EMG recording there was evidence of increase in the amplitude of the motor evoked potentials ( MEPs ) recorded from the biceps in one subject during the first block of rrTMS , but this did not occur in the second block . A similar magnification of MEPs was also observed in another subject only during the second block of stimulation . When applied using parameters falling within published guidelines ( Pascual-Leone et al. , 1993 ; Pascual-Leone et al. , 1994 ) , repeated rrTMS is a relatively safe technique in healthy normal subjects . As rrTMS allows disruption of cortical function for a longer period , it has the potential of becoming a particularly useful tool for the study of cognitive function as well as sensory or motor function Frontal lobe dysfunction is a hallmark of alcohol dependence . Recent studies have shown that a simple but powerful technique of cortical modulation -- transcranial direct current stimulation (tDCS)--can induce significant cognitive changes . We therefore aim ed to assess the clinical and electrophysiological ( as indexed by P3 ) effects of tDCS of left dorsolateral prefrontal cortex ( DLPFC ) in different types of alcoholic patients according to Lesch 's typology . We enrolled 49 alcoholic subjects , aged between 18 and 75 yr , during the subacute abstinence period to participate in this study . Subjects underwent event-related potential ( ERP ) registration of alcohol-related and neutral sounds before , during and after active tDCS ( 1 mA , 35 cm² , during 10 min ) or sham procedure in a counterbalanced and r and omized order . Frontal assessment battery ( FAB ) and five items of the Obsessive Compulsive Drinking Scale were applied at the beginning and at the end of each experimental session . ERP analysis showed an increase in the mean amplitude of P3 associated with alcohol-related sounds after tDCS . This effect was not seen for neutral sounds . This change was more pronounced in Lesch IV alcoholics . Secondary exploratory analysis showed a significant improvement of FAB performance after active tDCS compared to sham tDCS in Lesch IV alcoholics only . We showed clinical and electrophysiological evidence of tDCS-induced frontal activity enhancement that was specific for Lesch IV alcoholics . Given that frontal dysfunction may contribute to the loss of control over drinking behaviour , local increase in frontal activity induced by tDCS might have a beneficial clinical impact in the future OBJECTIVE The H-coils are a new development in transcranial magnetic stimulation ( TMS ) research , allowing direct stimulation of deeper neuronal pathways than does st and ard TMS . This study assessed possible health risks , and some cognitive and emotional effects , of two H-coil versions design ed to stimulate deep portions of the prefrontal cortex , using several stimulation frequencies . METHODS Healthy volunteers ( n=32 ) were r and omly assigned to one of four groups : each of two H-coil design s ( H1/H2 ) , st and ard figure-8 coil , and sham-coil control . Subjects were tested in a pre-post design , during three increasing ( single pulses , 10 Hz , and 20 Hz ) stimulation sessions , as well as 24 - 36 h after the last stimulation . RESULTS The major finding of the present study is that stimulation with the novel H-coils was well tolerated , with no adverse physical or neurological outcomes . Computerized cognitive tests found no deterioration in cognitive functions , except for a transient short-term effect of the H1-coil on spatial recognition memory on the first day of rTMS ( but not in the following treatment days ) . On the other h and , spatial working memory was transiently improved by the H2-coil treatment . Finally , the question naires showed no significant emotional or mood alterations , except for reports on ' detachment ' experienced by subjects treated with the H1-coil . CONCLUSIONS This study provides additional evidence for the feasibility and safety of the two H-coil design s ( H1/H2 ) . SIGNIFICANCE The H-coils offer a safe new tool with potential for both research and clinical applications for psychiatric and neurological disorders associated with dysfunctions of deep brain regions Recent evidence has supported the notion that the hypothalamic-pituitary-adrenal ( HPA ) and the sympatho-adreno-medullary ( SAM ) systems are modulated by cortical structures such as the prefrontal cortex . This top-down modulation may play a major role in the neuroendocrine changes associated with stressful events . We aim ed to investigate further this hypothesis by modulating directly prefrontal cortex excitability using transcranial direct current stimulation ( tDCS ) - a non-invasive , neuromodulatory tool that induces polarity-dependent changes in cortical excitability - and measuring effects on salivary cortisol and heart rate variability as proxies of the HPA and SAM systems . Twenty healthy participants with no clinical and neuropsychiatric conditions were r and omized to receive bifrontal tDCS ( left anodal/right cathodal or left cathodal/right anodal ) or sham stimulation , in a within-subject design . During each stimulation session , after a resting period , subjects were shown images with neutral or negative valence . Our findings showed that excitability enhancing left anodal tDCS induced a decrease in cortisol levels . This effect is more pronounced during emotional negative stimuli . Moreover , vagal activity was higher during left anodal tDCS and emotional negative stimuli , as compared to sham stimulation and neutral images . We also observed an association between higher mood scores , higher vagal activation and lower cortisol levels for anodal stimulation . Subjective mood and anxiety evaluation revealed no specific changes after stimulation . Our findings suggest that tDCS induced transient , polarity specific modulatory top-down effects with anodal tDCS leading to a down-regulation of HPA and SAM systems . Further research using tDCS and neuroendocrine markers should explore the mechanisms of stress regulation in healthy and clinical sample BACKGROUND Depression after myocardial infa rct ion ( MI ) is associated with higher morbidity and mortality . Although antidepressants are effective in reducing depression , their use in patients with cardiovascular disease remains controversial . OBJECTIVE To undertake a secondary analysis to determine the effects of using antidepressants on morbidity and mortality in post-MI patients who participated in the Enhancing Recovery in Coronary Heart Disease study . DESIGN Observational secondary analysis . SETTING Eight academic sites . PATIENTS The Enhancing Recovery in Coronary Heart Disease clinical trial r and omized 2481 depressed and /or socially isolated patients from October 1 , 1996 , to October 31 , 1999 . Depression was diagnosed using a structured clinical interview . This analysis was conducted on the 1834 patients enrolled with depression ( 849 women and 985 men ) . INTERVENTION Use of antidepressant medication . MAIN OUTCOME MEASURES Event-free survival was defined as the absence of death or recurrent MI . All-cause mortality was also examined . To relate exposure to antidepressants to subsequent morbidity and mortality , the data were analyzed using a time-dependent covariate model . RESULTS During a mean follow-up of 29 months , 457 fatal and nonfatal cardiovascular events occurred . The risk of death or recurrent MI was significantly lower in patients taking selective serotonin reuptake inhibitors ( adjusted hazard ratio [ HR ] , 0.57 ; 95 % confidence interval [ CI ] , 0.38 - 0.84 ) , as were the risk of all-cause mortality ( adjusted HR , 0.59 ; 95 % CI , 0.37 - 0.96 ) and recurrent MI ( adjusted HR , 0.53 ; 95 % CI , 0.32 - 0.90 ) , compared with patients who did not use selective serotonin reuptake inhibitors . For patients taking non-selective serotonin reuptake inhibitor antidepressants , the comparable HRs ( 95 % CIs ) were 0.72 ( 0.44 - 1.18 ) , 0.64 ( 0.34 - 1.22 ) , and 0.73 ( 0.38 - 1.38 ) for risk of death or recurrent MI , all-cause mortality , or recurrent MI , respectively , compared with nonusers . CONCLUSIONS Use of selective serotonin reuptake inhibitors in depressed patients who experience an acute MI might reduce subsequent cardiovascular morbidity and mortality . A controlled trial is needed to examine this important issue AIMS To evaluate the effect of repeated high-frequency transcranial magnetic stimulation ( rTMS ) of the left dorsolateral prefrontal cortex ( DLPFC ) , combined with either smoking or neutral cues , on cigarette consumption , dependence and craving . DESIGN Participants were divided r and omly to real and sham stimulation groups . Each group was subdivided r and omly into two subgroups presented with either smoking-related or neutral pictures just before the daily TMS intervention . Ten daily rTMS sessions were applied every week-day and then a maintenance phase was conducted in which rTMS sessions were less frequent . SETTING Single-site , out-patient , r and omized , double-blind , sham-controlled . PARTICIPANTS Forty-eight chronic smokers who smoked at least 20 cigarettes per day and were motivated to quit smoking . Healthy males and females were recruited from the general population using advertisements in newspapers and on internet websites . INTERVENTION Ten daily rTMS sessions were administered using a st and ard figure-8 coil over the DLPFC . Stimulation included 20 trains/day at 100 % of motor threshold . Each train consisted of 50 pulses at 10 Hz with an inter-train interval of 15 seconds . MEASUREMENTS Cigarette consumption was evaluated objective ly by measuring cotinine levels in urine sample s and subjectively by participants ' self-reports . Dependence and craving were evaluated by st and ard question naires . FINDINGS Ten daily rTMS sessions over the DLPFC reduced cigarette consumption and nicotine dependence . Furthermore , treatment blocked the craving induced by daily presentation of smoking-related pictures . However , these effects tended to dissipate over time . CONCLUSIONS Multiple high-frequency rTMS of the DLPFC can attenuate nicotine craving BACKGROUND Dysfunction of the prefrontal cortex is implicated in craving for drugs and food . This study explores the effect of prefrontal cortex stimulation on food craving . METHODS In a r and omized double-blind parallel group study , 28 women , who reported frequent cravings for food were exposed to foods that typically elicit strong cravings before and after a single session of real or sham 10-Hz repetitive transcranial magnetic stimulation to the left dorsolateral prefrontal cortex at an intensity of 110 % individual motor threshold . RESULTS Self-reported food craving during exposure to the experimental foods remained stable before and after real stimulation compared with sham stimulation in which cravings increased over the experimental session . Consumption of snack foods within a 5-min period after stimulation did not differ between groups . CONCLUSIONS Prefrontal stimulation inhibits the development of craving . A longer period of observation is necessary to establish whether there is an effect on food consumption Although negative results have been reported , an important aspect of the physiology of repetitive transcranial magnetic stimulation ( rTMS ) could be related to the endocrinological response of the hypothalamic-pituitary-adrenal ( HPA ) axis , such as cortisol secretion . Because endocrinological responses are influenced by anxiety states , this could influence the effect of rTMS in healthy individuals . In this sham-controlled , " single blind " crossover study , we examined whether one session of HF-rTMS could affect the HPA-system , when taking into account individual state anxiety scores based on the State-Trait Anxiety Inventory ( STAI ) . Twenty-four healthy rTMS naïve females received one sham-controlled high frequency (HF)-rTMS session delivered on the right dorsolateral prefrontal cortex ( DLPFC ) . The Profile of Mood States ( POMS ) question naire , together with salivary cortisol sample s , was collected before , just after and 30 min post HF-rTMS . To examine whether state anxiety could influence endocrinological outcome measurements , we administered the STAI-state just before each HF-rTMS experiment started . Based on the POMS question naire , no mood changes were observed . Without taking individual state anxiety scores into account , one sham-controlled right-sided HF-rTMS session did not influence the HPA-system . When taking into account individual STAI-state scores , we found that healthy women scoring higher on the STAI-state displayed a significantly more sensitive HPA-system , result ing in salivary cortisol concentration increases after real HF-rTMS , compared to those scoring lower on this anxiety scale . Our results indicate that healthy women scoring high on state anxiety display a more sensitive HPA-system when receiving one right-sided HF-rTMS session . Our findings suggest that the incorporation of individual anxiety states in experimental rTMS research could add further information about its neurobiological influences on the HPA-system Purpose Electromagnetic fields have been administered , with mixed success , in order to treat a variety of ailments . Transcranial magnetic stimulation ( TMS ) elicits brief changes in peripheral sympathetic nervous system ( SNS ) activity . The purpose of this study was to explore the utility of repetitive trans-spinal magnetic stimulation ( rTSMS ) for acute and prolonged modulation of SNS in adult humans . Methods 23 healthy men and women were r and omly assigned to receive either rTSMS ( figure-eight coil aligned with the sixth and seventh cervical vertebrae ; 10 Hz ; n = 14 , at 100 % intensity of stimulator output ) or sham stimulation ( n = 13 ) . Results Compared with sham , rTSMS did not affect skeletal muscle SNS activity ( via microneurography ) during the 60-s or 10-min period following stimulation . rTSMS also had no effect on R-to-R interval ( RRint ) and st and ard deviation of RRint ( a marker of heart rate variability ) , blood pressure or plasma concentrations of norepinephrine , epinephrine , insulin and glucose ( condition/time interaction , all P > 0.10 ) . Conclusion These data suggest that rTSMS does not influence SNS in adults . While rTSMS represents a novel application of TMS technology , further study and perhaps modification of the technique is required before use in clinical studies of peripheral SNS function We examined whether repetitive transcranial magnetic stimulation ( rTMS ) at a low rate could influence autonomic function , specially heart rate variability ( HRV ) by power spectrum analysis . We studied 16 healthy male volunteers as a stimulation group and 16 others as a sham group . The stimulation group received magnetic stimulations from a circular coil over Cz at a frequency of 0.2 Hz and an intensity presenting 90 % of the motor threshold . Experiments in both groups included four daily sessions ; at each , a train of 70 stimuli was delivered over 350 s. HRV of low-frequency power ( LF ) in a st and ing position and high-frequency power ( HF ) in a supine position were measured before and after each session . After stimulation , HF and LF powers were significantly increased . After sham stimulation , the power of HF but not that of LF significantly increased . Neither actual nor sham stimulation produced a long-term effect detectable on day 5 . The finding of transiently increased LF power following actual but not sham stimulation suggests that rTMS may activate the sympathetic nervous system OBJECTIVE To study the anticraving efficacy of high-frequency repetitive transcranial magnetic stimulation ( rTMS ) of the right dorsolateral pre-frontal cortex ( DLPFC ) in patients with alcohol dependence . METHODS We performed a prospect i ve , single-blind , sham-controlled study involving 45 patients with alcohol dependence syndrome ( according to ICD-10 DCR ) , with Clinical Institute of Withdrawal Assessment in Alcohol Withdrawal ( CIWA-Ar ) scores < or=10 . Patients were allocated to active and sham rTMS in a 2 : 1 ratio , such that 30 patients received active and 15 patients sham rTMS to the right DLPFC ( 10 Hz frequency , 4.9 seconds per train , inter-train interval of 30 seconds , 20 trains per session , total 10 sessions ) . The Alcohol Craving Question naire ( ACQ-NOW ) was administered to measure the severity of alcohol craving at baseline , after the last rTMS session and after 1 month of the last rTMS session . RESULTS Two-way repeated- measures analysis of variance ( ANOVA ) showed significant reduction in the post-rTMS ACQ-NOW total score and factor scores in the group allocated active rTMS compared to the sham stimulation . The effect size for treatment with time interaction was moderate ( eta(2 ) = 0.401 ) . CONCLUSIONS Right dorsolateral pre-frontal high-frequency rTMS was found to have significant anticraving effects in alcohol dependence . The results highlight the potential of rTMS which , combined with other anticraving drugs , can act as an effective strategy in reducing craving and subsequent relapse in alcohol dependence BACKGROUND Previous functional magnetic resonance imaging studies have shown strong correlations between cue-elicited craving for cigarettes and activation of the superior frontal gyrus ( SFG ) . Repetitive transcranial magnetic stimulation ( rTMS ) offers a noninvasive means to reversibly affect brain cortical activity , which can be applied to testing hypotheses about the causal role of SFG in modulating craving . METHODS Fifteen volunteer smokers were recruited to investigate the effects of rTMS on subjective responses to smoking versus neutral cues and to controlled presentations of cigarette smoke . On different days , participants were exposed to three conditions : 1 ) high-frequency ( 10 Hz ) rTMS directed at the SFG ; 2 ) low-frequency ( 1 Hz ) rTMS directed at the SFG ; and 3 ) low-frequency ( 1 Hz ) rTMS directed at the motor cortex ( control condition ) . RESULTS Craving ratings in response to smoking versus neutral cues were differentially affected by the 10-Hz versus 1-Hz SFG condition . Craving after smoking cue presentations was elevated in the 10-Hz SFG condition , whereas craving after neutral cue presentations was reduced . Upon smoking in the 10-Hz SFG condition , ratings of immediate craving reduction as well as the intensity of interoceptive airway sensations were also attenuated . CONCLUSIONS These results support the view that the SFG plays a role in modulating craving reactivity ; moreover , the results suggest that the SFG plays a role in both excitatory and inhibitory influences on craving , consistent with prior research demonstrating the role of the prefrontal cortex in the elicitation as well as inhibition of drug-seeking behaviors BACKGROUND In people with bulimic eating disorders , exposure to high-calorie foods can result in increases in food craving , raised subjective stress and salivary cortisol concentrations . This cue-induced food craving can be reduced by repetitive transcranial magnetic stimulation ( rTMS ) . We investigated whether rTMS has a similar effect on salivary cortisol concentrations , a measure of hypothalamic-pituitary-adrenal axis ( HPAA ) activity . METHOD We enrolled twenty-two female participants who took part in a double-blind r and omized sham-controlled trial on the effects of rTMS on food craving . Per group , eleven participants were r and omized to the real or sham rTMS condition . The intervention consisted of one session of high-frequency rTMS delivered to the left dorsolateral prefrontal cortex ( DLPFC ) . Salivary cortisol concentrations were assessed at four time points throughout the 90-min trial . To investigate differences in post-rTMS concentrations between the real and sham rTMS groups , a r and om-effects model including the pre-rTMS cortisol concentrations as covariates was used . RESULTS Salivary cortisol concentrations following real rTMS were significantly lower compared with those following sham rTMS . In this sample , there was also a trend for real rTMS to reduce food craving more than sham rTMS . CONCLUSIONS These results suggest that rTMS applied to the left DLPFC alters HPAA activity in people with a bulimic disorder Smoking cue-provoked craving is an intricate behavior associated with strong changes in neural networks . Craving is one of the main reasons subjects continue to smoke ; therefore interventions that can modify activity in neural networks associated with craving can be useful tools in future research investigating novel treatments for smoking cessation . The goal of this study was to use a neuromodulatory technique associated with a powerful effect on spontaneous neuronal firing - transcranial direct current stimulation ( tDCS ) - to modify cue-provoked smoking craving . Based on preliminary data showing that craving can be modified after a single tDCS session , here we investigated the effects of repeated tDCS sessions on craving behavior . Twenty-seven subjects were r and omized to receive sham or active tDCS ( anodal tDCS of the left DLPFC ) . Our results show a significant cumulative effect of tDCS on modifying smoking cue-provoked craving . In fact , in the group of active stimulation , smoking cues had an opposite effect on craving after stimulation - it decreased craving - as compared to sham stimulation in which there was a small decrease or increase on craving . In addition , during these 5 days of stimulation there was a small but significant decrease in the number of cigarettes smoked in the active as compared to sham tDCS group . Our findings extend the results of our previous study as they confirm the notion that tDCS has a specific effect on craving behavior and that the effects of several sessions can increase the magnitude of its effect . These results open avenues for the exploration of this method as a therapeutic alternative for smoking cessation and also as a mean to change stimulus-induced behavior BACKGROUND Hypothalamic-pituitary-adrenocortical ( HPA ) dysregulation assessed by the combined dexamethasone corticotropin releasing hormone test ( DEX/CRH test ) has been demonstrated to normalize after successful antidepressant pharmacotherapy . Here , we investigated whether repetitive transcranial magnetic stimulation ( rTMS ) also leads to a normalization of HPA system activity in depressed patients . METHODS Thirty-seven medication free patients suffering from a major depressive episode ( DSM-IV ) underwent a DEX/CRH test before and after 13 daily sessions of left prefrontal rTMS in an open trial . RESULTS There was an overshoot of CRH-induced cortisol release that was not affected by rTMS treatment . Postdexamethasone cortisol levels prior to CRH challenge decreased in responders after rTMS treatment , whereas no change of CRH-induced adrenocorticotropic hormone ( ACTH ) and cortisol release in responders or nonresponders was observed . CONCLUSIONS The persisting HPA system hyperactivity after rTMS suggests a high risk for relapse and therefore argues for an immediate maintenance therapy in patients responding to this treatment This study examined whether a 20-min session of prefrontal transcranial direct current stimulation ( tDCS ) ( anode over the right prefrontal cortex and cathode over the left prefrontal cortex ) would reduce food cravings and increase the self-reported ability to resist foods in 19 healthy individuals who reported frequent food cravings . Participants viewed computerized images of food and used computerized visual analogue scales to rate food cravings and inability to resist foods before , during , and after receiving either real or sham tDCS . This study employed a r and omized within-subject crossover design ; participants received both real and sham tDCS and were blind to the condition . Food cravings ratings were reduced in both conditions , however , the percent change in cravings ratings from pre- to post-stimulation was significantly greater for real stimulation than for sham . The percent change in inability to resist food from pre- to post-stimulation also showed a greater decrease in the real condition than for sham . Post hoc analyses suggest that active prefrontal tDCS acutely and significantly decreased food cravings ratings for sweet foods and carbohydrates more so than sham tDCS . No significant differences were seen in the amount of food ingested between real and sham tDCS . These findings in healthy subjects indicate that tDCS is able to temporarily reduce food cravings and improve the self-reported ability to resist foods Dysfunctions of the autonomic nervous system ( ANS ) are common in Parkinson ’s disease ( PD ) . Regarding motor disability , deep brain stimulation of the subthalamic nucleus ( STN ) is an effective treatment option in long lasting PD . The aims of this study were to examine whether STN stimulation has an influence on functions of the ANS and to compare these effects to those induced by levodopa . Blood pressure ( BP ) and heart rate ( HR ) during rest and orthostatic conditions , HR variability ( HRV ) and breathing-induced cutaneous sympathetic vasoconstriction ( CVC ) were tested in 14 PD patients treated with STN stimulation during “ ON ” and “ OFF ” condition of the stimulator . The effects of a single dose of levodopa on ANS were tested in 15 PD patients without DBS . STN stimulation had no influence on cardiovascular ANS functions , whereas CVC was significantly increased . In contrast , levodopa significantly lowered BP and HR at rest and enhanced orthostatic hypotension . Further , HRV , skin perfusion and temperature increased after administration of levodopa . Our results suggest that in contrast to levodopa , STN stimulation has only minor effects on autonomic functions . Since less pharmacotherapy is needed after STN stimulation , reduced levodopa intake results in relative improvement of autonomic function in deep brain stimulated PD patients BACKGROUND Repetitive transcranial magnetic stimulation ( rTMS ) is a new therapeutic tool in the treatment of affective disorders but only few studies on its safety exist . We aim ed to determine the impact of rTMS on (neuro)endocrinological serum levels by a placebo-controlled cross-over study . METHODS 23 healthy subjects were stimulated by rTMS in a typical paradigm used in the treatment of depression ( coil placed over left dorsolateral prefrontal cortex , 10 and 20 Hz stimulation ) . Placebo , infrathreshold , and suprathreshold stimulation were applied in r and om order . The serum levels of cortisol , prolactin , FSH , and TSH were measured before and after stimulation . RESULTS After infrathreshold stimulation , cortisol and TSH serum levels decreased mildly but significantly . All other stimulations had no significant impact on hormone levels . In female , but not in male , subjects placebo stimulation yielded a significant increase of prolactin . CONCLUSIONS rTMS as applied for the treatment of depression leads to only very mild and safe changes of hormones . These changes , in particular the decrease of cortisol levels , might explain in part the efficacy of rTMS BACKGROUND Repetitive transcranial magnetic stimulation ( rTMS ) is increasingly used in research . However , cardiac safety is not routinely assessed . OBJECTIVE This study aims to investigate cardiac safety of rTMS in people with a bulimic eating disorder . METHODS Thirty-eight people with a bulimic disorder were enrolled in a r and omized sham-controlled trial . High frequency rTMS was delivered to the left dorsolateral prefrontal cortex . RESULTS rTMS did not alter blood pressure or heart rate . CONCLUSIONS Our findings indicated that this rTMS paradigm has no cardiac complications as assessed by blood pressure and heart rate . This adds to the emerging literature on the cardiac safety of rTMS BACKGROUND Craving or the " urge to consume " is a characteristic of bulimic eating disorders and addictions . Dysfunction of the dorsolateral prefrontal cortex ( DLPFC ) is associated with craving . We investigated whether stimulation of the DLPFC reduces food craving in people with a bulimic-type eating disorder . METHODS Thirty-eight people with bulimic-type eating disorders were r and omly allocated to receive one session of real or sham high-frequency repetitive transcranial magnetic stimulation ( rTMS ) to the left DLPFC in a double-blind procedure . Outcome measures included self-reported food craving immediately after the stimulation session and frequency of bingeing over a 24-hour follow-up period . RESULTS Compared with sham control , real rTMS was associated with decreased self-reported urge to eat and fewer binge-eating episodes over the 24 hours following stimulation . CONCLUSIONS High-frequency rTMS of the left DLPFC lowers cue-induced food cravings in people with a bulimic eating disorder and may reduce binge eating . These results provide a rationale for exploring rTMS as a treatment for bulimic eating disorders One of the major goals of antidepressant treatment is a sustained response and remission of depressive symptoms . Some of the previous studies of vagus nerve stimulation ( VNS ) have suggested antidepressant effects . Our naturalistic study assessed the efficacy and the safety of VNS in 74 European patients with therapy-resistant major depressive disorder . Psychometric measures were obtained after 3 , 12 , and 24 months of VNS . Mixed-model repeated- measures analysis of variance revealed a significant reduction ( P ≤ 0.05 ) at all the 3 time points in the 28-item Hamilton Rating Scale for Depression ( HRSD28 ) score , the primary outcome measure . After 2 years , 53.1 % ( 26/49 ) of the patients fulfilled the response criteria ( ≥50 % reduction in the HRSD28 scores from baseline ) and 38.9 % ( 19/49 ) fulfilled the remission criteria ( HRSD28 scores ≤ 10 ) . The proportion of patients who fulfilled the remission criteria remained constant as the duration of VNS treatment increased . Voice alteration , cough , and pain were the most frequently reported adverse effects . Two patients committed suicide during the study ; no other deaths were reported . No statistically significant differences were seen in the number of concomitant antidepressant medications . The results of this 2-year open-label trial suggest a clinical response and a comparatively benign adverse effect profile among patients with treatment-resistant depression |
13,797 | 25,198,064 | AUTHORS ' CONCLUSIONS There is no high quality evidence examining the effectiveness of surgery for femoroacetabular impingement . | BACKGROUND Surgery is sometimes recommended for femoroacetabular impingement where non-operative interventions have failed .
OBJECTIVES To determine the benefits and safety of surgery for femoroacetabular impingement . | OBJECTIVES Femoroacetabular impingement is proposed to cause early osteoarthritis ( OA ) in the non-dysplastic hip . We previously reported on the prevalence of femoral deformities in a young asymptomatic male population . The aim of this study was to determine the prevalence of both femoral and acetabular types of impingement in young females . METHODS We conducted a population -based cross-sectional study of asymptomatic young females . All participants completed a set of question naires and underwent clinical examination of the hip . A r and om sample was subsequently invited to obtain magnetic resonance images ( MRI ) of the hip . All MRIs were read for cam-type deformities , increased acetabular depths , labral lesions , and impingement pits . Prevalence estimates of cam-type deformities and increased acetabular depths were estimated , and relationships between deformities and signs of joint damage were examined using logistic regression models . RESULTS The study included 283 subjects , and 80 asymptomatic females with a mean age of 19.3 years attended MRI . Fifteen showed some evidence of cam-type deformities , but none were scored to be definite . The overall prevalence was therefore 0 % [ 95 % confidence interval ( 95 % CI ) 0 - 5 % ] . The prevalence of increased acetabular depth was 10 % ( 95 % CI 5 - 19 ) . No association was found between increased acetabular depth and decreased internal rotation of the hip . Increased acetabular depth was not associated with signs of labral damage . CONCLUSIONS Definite cam-type deformities in women are rare compared to men , whereas the prevalence of increased acetabular depth is higher , suggesting that femoroacetabular impingement has different gender-related biomechanical mechanisms BACKGROUND The conduct of r and omized , controlled trials of nonpharmacologic treatments presents specific challenges that are not adequately addressed in trial reports . OBJECTIVE To develop an extension of the CONSORT ( Consoli date d St and ards of Reporting Trials ) Statement for trials of nonpharmacologic treatments . DESIGN A consensus meeting was organized to develop an extension of the CONSORT Statement that addresses r and omized trials of nonpharmacologic treatments . To prepare for the meeting , a survey was conducted to identify the specific issues for discussion . SETTING Consensus meeting in Paris , France . PARTICIPANTS A total of 33 experts attended the meeting . The experts were method ologists ( n = 17 ) ; surgeons ( n = 6 ) ; editors ( n = 5 ) ; and clinicians involved in rehabilitation ( n = 1 ) , psychotherapy ( n = 2 ) , education ( n = 1 ) , and implantable devices ( n = 1 ) . MEASUREMENTS Experts indicated which of the 22 items on the CONSORT checklist should be modified or which additional items should be added specifically for nonpharmacologic treatments . During a 3-day consensus meeting , all items were discussed and additional method ological issues related to nonpharmacologic research were identified . RESULTS The consensus was that 11 items on the CONSORT checklist needed some modifications for nonpharmacologic trials : item 1 ( title and abstract ) , item 3 ( participants ) , item 4 ( interventions ) , item 7 ( sample size ) , item 8 ( r and omization ) , item 11 ( blinding ) , item 12 ( statistical methods ) , item 13 ( participant flow ) , item 15 ( baseline data ) , item 20 ( discussion : interpretation ) , and item 21 ( generalizability ) . In addition , the meeting participants added 1 item related to implementation of the intervention . LIMITATION Evidence was not always available to support the inclusion of each checklist item . CONCLUSION The methods and processes used to develop this extension could be used for other reporting guidelines . The use of this extension to the CONSORT Statement should improve the quality of reporting r and omized , controlled trials assessing nonpharmacologic treatments Background Surgical placebos are controversial . This in-depth study explored the design , acceptability , and feasibility issues relevant to design ing a surgical placebo-controlled trial for the evaluation of the clinical and cost effectiveness of arthroscopic lavage for the management of people with osteoarthritis of the knee in the UK . Methods Two surgeon focus groups at a UK national meeting for orthopaedic surgeons and one regional surgeon focus group ( 41 surgeons ) ; plenary discussion at a UK national meeting for orthopaedic anaesthetists ( 130 anaesthetists ) ; three focus groups with anaesthetists ( one national , two regional ; 58 anaesthetists ) ; two focus groups with members of the patient organisation Arthritis Care ( 7 participants ) ; telephone interviews with people on consultant waiting lists from two UK regional centres ( 15 participants ) ; interviews with Chairs of UK ethics committees ( 6 individuals ) ; postal surveys of members of the British Association of Surgeons of the Knee ( 382 surgeons ) and members of the British Society of Orthopaedic Anaesthetists ( 398 anaesthetists ) ; two centre pilot ( 49 patients assessed ) . Results There was widespread acceptance that evaluation of arthroscopic lavage had to be conducted with a placebo control if scientific rigour was not to be compromised . The choice of placebo surgical procedure ( three small incisions ) proved easier than the method of anaesthesia ( general anaesthesia ) . General anaesthesia , while an excellent mimic , was more intrusive and raised concerns among some stakeholders and caused extensive discussion with local decision-makers when seeking formal approval for the pilot . Patients were willing to participate in a pilot with a placebo arm ; although some patients when allocated to surgery became apprehensive about the possibility of receiving placebo , and withdrew . Placebo surgery was undertaken successfully . Conclusions Our study illustrated the opposing and often strongly held opinions about surgical placebos , the ethical issues underpinning this controversy , and the challenges that exist even when ethics committee approval has been granted . It showed that a placebo-controlled trial could be conducted in principle , albeit with difficulty . It also highlighted that not only does a placebo-controlled trial in surgery have to be ethically and scientifically acceptable but that it also must be a feasible course of action . The place of placebo-controlled surgical trials more generally is likely to be limited and require specific circumstances to be met . Suggested criteria are presented . Trial registration numberThe trial was assigned IS RCT N02328576 through http://controlled-trials.com/ in June 2006 . The first patient was r and omised to the pilot in July 2007 The benefit of arthroscopy of the hip in the treatment of femoroacetabular impingement ( FAI ) in terms of quality of life ( QoL ) has not been reported . We prospect ively collected data on 612 patients ( 257 women ( 42 % ) and 355 men ( 58 % ) ) with a mean age at the time of surgery of 36.7 years ( 14 to 75 ) who underwent arthroscopy of the hip for FAI under the care of a single surgeon . The minimum follow-up was one year ( mean 3.2 years ( 1 to 7 ) ) . The responses to the modified Harris hip score were translated using the Rosser Index Matrix in order to provide a QoL score . The mean QoL score increased from 0.946 ( -1.486 to 0.995 ) to 0.974 ( 0.7 to 1 ) at one year after surgery ( p < 0.001 ) . The mean QoL score in men was significantly higher than in women , both before and one year after surgery ( both p < 0.001 ) . However , the mean change in the QoL score was not statistically different between men and women ( 0.02 ( -0.21 to 0.27 ) and 0.04 ( -0.16 to 0.87 ) , respectively ; p = 0.12 ) . Linear regression analysis revealed that the significant predictors of a change in QoL score were pre-operative QoL score ( p < 0.001 ) and gender ( p = 0.04 ) . The lower the pre-operative score , the higher the gain in QoL post-operatively ( ρ = -0.66 ; p < 0.001 ) . One year after surgery the QoL scores in the 612 patients had improved in 469 ( 76.6 % ) , remained unchanged in 88 ( 14.4 % ) and had deteriorated in 55 ( 9.0 % ) Objectives The number of surgical procedures performed each year to treat femoroacetabular impingement ( FAI ) continues to rise . Although there is evidence that surgery can improve symptoms in the short-term , there is no evidence that it slows the development of osteoarthritis ( OA ) . We performed a feasibility study to determine whether patient and surgeon opinion was permissive for a R and omised Controlled Trial ( RCT ) comparing operative with non-operative treatment for FAI . Methods Surgeon opinion was obtained using vali date d question naires at a Specialist Hip Meeting ( n = 61 , 30 of whom stated that they routinely performed FAI surgery ) and patient opinion was obtained from clinical patients with a new diagnosis of FAI ( n = 31 ) . Results Clinical equipoise was demonstrated when surgeons were given clinical scenarios and asked whether they would manage a patient operatively or non-operatively . A total of 23 surgeons ( 77 % ) who routinely perform FAI surgery were willing to recruit patients into a RCT , and 28 patients ( 90 % ) were willing to participate . 75 % of responding surgeons believed it was appropriate to r and omise patients to non-operative treatment for ≥ 12 months . Conversely , only eight patients ( 26 % ) felt this was acceptable , although 29 ( 94 % ) were willing to continue non-operative treatment for six months . More patients were concerned about their risk of developing OA than their current symptoms , although most patients felt that the two were of equal importance . Conclusions We conclude that a RCT comparing operative and non-operative management of FAI is feasible and should be considered a research priority . An important finding for orthopaedic surgical trials is that patients without life-threatening pathology appear willing to trial a treatment for six months without improvement in their symptoms OBJECTIVES To ascertain the acceptability of a r and omised controlled trial comparing arthroscopic lavage with a placebo-surgical procedure for the management of osteoarthritis of the knee ; and to assess the practical feasibility of mounting such a multicentre placebo-controlled trial . DESIGN Mixed methods study including : focus groups with surgeons and anaesthetists ; focus groups and interviews with potential participants ; interviews with chairpersons of UK Multicentre Research Ethics Committees ( MRECs ) ; surveys of surgeons and anaesthetists ; and a two-centre , three-arm pilot . SETTING UK secondary care . PARTICIPANTS Members of the British Association of Surgeons of the Knee and members of the British Society of Orthopaedic Anaesthetists took part in the focus groups and surveys . Surgeons and anaesthetists from two regional centres in the UK also contributed to focus groups , as did patients from consultant lists in two UK regional centres , and members of Arthritis Care . Chairpersons of six UK MRECs were interviewed . Participants were eligible for the pilot if they were adults ( 18 years or older ) with radiological evidence of osteoarthritis of the knee who might be considered for arthroscopic lavage , and were fit for general anaesthetic ( defined by the American Society of Anaesthesiologists grade s 1 and 2 ) , and able to give informed consent . INTERVENTIONS Participants in the pilot study were r and omised to arthrosocopic lavage ( with or without debridement at the clinical discretion of the surgeon ) ; placebo surgery ; or non-operative management with specialist re assessment . MAIN OUTCOME MEASURES The acceptability and feasibility of mounting a placebo-controlled trial for the evaluation of knee arthroscopic lavage . RESULTS There was broad acceptance across all stakeholder groups of the need to find out more about the effectiveness of arthroscopic lavage . Despite this there was variation in opinion within all the groups about how research ers should approach this and whether or not it would be acceptable to investigate using placebo surgery . Within the health professional groups , there tended to be a split between those who were strongly opposed to the inclusion of a placebo surgery arm and those who were more in favour . For prospect i ve trial participants who had osteoarthritis of the knee , the acceptability of the trial was discussed from a more individual perspective - reflecting on their personal reasons for or against participating . The majority of this group said they would consider taking part . The pilot study showed that , in principle , a placebo-controlled trial could be conducted . It showed that patients were willing to participate in a trial which would involve a placebo-surgical arm and that it was possible to undertake placebo surgery successfully and to blind patients to their allocation - although once patients knew their allocation , some patients allocated to surgery became more concerned about the possibility of undergoing placebo surgery , and withdrew . The experience of the pilot , however , showed that , despite full MREC approval , the study required major discussion and negotiation before local clinical approvals could be obtained . The fact that ethics approval had been granted did not mean that clinicians would automatically accept that the process was ethical . CONCLUSIONS The study showed that , in principle , a placebo-controlled trial of arthroscopic lavage could be conducted in the UK , albeit with difficulty . Against the background of falling use of arthroscopic lavage the decision was , therefore , taken not to proceed to full-scale trial for this procedure . The study showed that for some health professionals the use of placebo surgery can never be justified . It highlighted the importance of the surgeon-anaesthetist relationship in this context and how acceptance of the trial design by both parties is essential to successful participation . It also highlighted the importance of informed consent for trial participants and the strength and influence of individuals ' ethical perspectives in addition to collective ethics provided by MRECs . TRIAL REGISTRATION Current Controlled Trials IS RCT N02328576 OBJECTIVES To study responsiveness and establish the minimal clinical ly important differences ( MCID ) and minimal detectable change ( MDC ) in patients undergoing total hip replacement ( THR ) using the Short Form 36 ( SF-36 ) and the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) . METHODS We conducted a prospect i ve observational study in three public hospitals of all consecutive patients with a diagnosis of hip osteoarthritis ( OA ) on waiting lists to undergo THR . Patients completed the SF-36 and the WOMAC ( subscales transformed to 0 to 100 ) , which measured the health-related quality of life ( HRQoL ) , before intervention and 6 months and 2 years later , and additional transitional questions , which measured the changes in the joint 6 months postoperatively . RESULTS Improvements at 6 months after a THR were between 37 ( stiffness ) and 39 points ( pain ) , depending on the WOMAC domain . The SF-36 domains also showed improvements : physical function ( 31.91 ) , physical role ( 33.71 ) , and bodily pain ( 29.77 ) . From 6 months to 2 years , improvements ranged from 2 to 5 points , except for role physical ( 13.25 ) . A ceiling effect was detected on some WOMAC domains as well as a floor effect on the SF-36 . The MCID ranged from 25.91 ( stiffness ) to 29.26 ( pain ) on the WOMAC and from 10.78 ( physical role ) to 20.40 ( physical function ) on the SF-36 . The MDC ranged from 21.38 ( pain ) to 27.98 ( stiffness ) on the WOMAC and from 18.99 ( physical function ) to 42.05 ( social function ) on the SF-36 . CONCLUSIONS These values indicate expected gains after THR . However , the MCID and MDC values must be viewed cautiously due to the uncertainty of these estimators and should not be considered as absolute thresholds PURPOSE The purpose of this study was to develop a self-administered evaluative tool to measure health-related quality of life in young , active patients with hip disorders . METHODS This outcome measure was developed for active patients ( aged 18 to 60 years , Tegner activity level ≥ 4 ) presenting with a variety of symptomatic hip conditions . This multicenter study recruited patients from international hip arthroscopy and arthroplasty surgeon practice s. The outcome was created using a process of item generation ( 51 patients ) , item reduction ( 150 patients ) , and pretesting ( 31 patients ) . The question naire was tested for test-retest reliability ( 123 patients ) ; face , content , and construct validity ( 51 patients ) ; and responsiveness over a 6-month period in post-arthroscopy patients ( 27 patients ) . RESULTS Initially , 146 items were identified . This number was reduced to 60 through item reduction , and the items were categorized into 4 domains : ( 1 ) symptoms and functional limitations ; ( 2 ) sports and recreational physical activities ; ( 3 ) job-related concerns ; and ( 4 ) social , emotional , and lifestyle concerns . The items were then formatted using a visual analog scale . Test-retest reliability showed Pearson correlations greater than 0.80 for 33 of the 60 questions . The intraclass correlation statistic was 0.78 , and the Cronbach α was .99 . Face validity and content validity were ensured during development , and construct validity was shown with a correlation of 0.81 to the Non-Arthritic Hip Score . Responsiveness was shown with a paired t test ( P ≤ .01 ) , effect size of 2.0 , st and ardized response mean of 1.7 , responsiveness ratio of 6.7 , and minimal clinical ly important difference of 6 points . CONCLUSIONS We have developed a new quality -of-life patient-reported outcome measure , the 33-item International Hip Outcome Tool ( iHOT-33 ) . This question naire uses a visual analog scale response format design ed for computer self-administration by young , active patients with hip pathology . Its development has followed the most rigorous methodology involving a very large number of patients . The iHOT-33 has been shown to be reliable ; shows face , content , and construct validity ; and is highly responsive to clinical change . In our opinion the iHOT-33 can be used as a primary outcome measure for prospect i ve patient evaluation and r and omized clinical trials Introduction Surgical hip dislocation ( SHD ) is an accepted st and ard to treat femoroacetabular impingement ( FAI ) . However , arthroscopic techniques have gained widespread popularity and comparable results are reported . The purpose of this prospect i ve comparative study was to test the hypothesis that , when compared to SHD , hip arthroscopy ( HA ) results in faster recovery , better short-term outcome , and equivalent morphological corrections . Material s and methods 38 patients presenting with clinical ly and morphologically verified isolated FAI were allocated to either HA or SHD . Morphological evaluation consisted of pre- and postoperative X-rays , and arthro-MRI . Demographic data , sport activities , hospital stay , complications , and the time off work were recorded . The subjective hip value , WOMAC , HHS , and hip abductor strength were measured up to 1 year . Results Shorter hospital stay and time off work , less pain at 3 months and 1 year , higher subjective hip values at 6 weeks and 3 months , and better WOMAC at 3 months were seen after HA . The HHS and the hip abductor strengths were higher in the HA group . However , morphological corrections at the head – neck-junction achieved by HA showed some overcorrection when compared to SHD . Labral refixation was performed less frequent in the HA group . Conclusion When compared to SHD , HA results in faster recovery and better short-term outcome . However , some overcorrection of the cam deformity and limited frequency of labrum refixation with HA in this study may have a negative impact on long-term outcome Background : Patient-reported outcomes ( PROs ) are considered the gold st and ard when evaluating outcomes in a surgical population . While the psychometric properties of some PROs have been tested , the properties of newer PROs in patients undergoing hip arthroscopic surgery remain somewhat unknown . Purpose : To evaluate the reliability , validity , responsiveness , and interpretability of 5 PROs ( Copenhagen Hip and Groin Outcome Score [ HAGOS ] , Hip Disability and Osteoarthritis Outcome Score [ HOOS ] , Hip Outcome Score [ HOS ] , International Hip Outcome Tool [ iHOT-33 ] , and Modified Harris Hip Score [ MHHS ] ) in a population undergoing hip arthroscopic surgery and also to provide a recommendation of the best PROs in patients undergoing hip arthroscopic surgery . Study Design : Cohort study ( diagnosis ) ; Level of evidence , 2 . Methods : Study participants were adults ( mean age , 37 ± 11 years ) who had undergone hip arthroscopic surgery 12 to 24 months previously and pain-free , healthy age-matched controls ( mean age , 35 ± 11 years ) . Baseline characteristics including age , height , weight , waist girth , physical activity , and occupation were collected for both groups . The hip arthroscopic surgery group completed the 5 PRO question naires on 3 occasions , while the healthy control group completed the PRO question naires on 1 occasion . The reliability ( test-retest reliability [ intraclass correlation coefficient , or ICC ] and minimal detectable change [ MDC ] ) , validity ( construct validity , ability to detect a difference between groups , acceptability including floor and ceiling effects ) , responsiveness , and interpretability ( minimal important change [ MIC ] ) of each measure were calculated . Results : The test-retest reliability of PROs was excellent ( ICC , 0.91 - 0.97 ) , with an MDC of < 20 % . The HOOS , HAGOS , and iHOT-33 had acceptable content validity . All PROs demonstrated construct validity and were able to detect a difference between the hip arthroscopic surgery and control groups . No measures demonstrated a floor effect ; however , the MHHS and subscales relating to activities of daily living of the HOOS , HOS , and HAGOS demonstrated a ceiling effect . The HOOS , iHOT-33 , and MHHS demonstrated adequate responsiveness , and the MIC for all measures was < 11 points of a possible 100 points . Conclusion : The PROs of the HOOS and iHOT-33 demonstrate psychometric properties that may enable research ers and clinicians to use them with confidence in a population undergoing hip arthroscopic surgery . The psychometric properties of the MHHS , HOS , and some subscales of the HAGOS are reduced , and these PROs may be less valuable in this group PURPOSE The purpose of this study was to prospect ively compare outcomes of patients receiving surgical hip dislocation and those undergoing arthroscopic treatment for femoroacetabular impingement ( FAI ) , using a matched-pair analysis . METHODS Between January 2008 and August 2011 , patients aged 30 years or younger with a diagnosis of FAI treated with surgical dislocation or arthroscopy were included . Patients were excluded with Tönnis grade 2 or greater , dysplasia , Legg-Calve-Perthes disease , and previous hip surgery . Patients treated with surgical dislocation were pair-matched to patients treated arthroscopically in a 1:2 ratio . Patient-reported outcomes were prospect ively obtained in all patients preoperatively and postoperatively at 3 months , at 1 year , at 2 years , and at latest follow-up . Alpha angles were measured preoperatively and postoperatively for both groups . Revision surgery and complications were recorded for each group . RESULTS Ten patients were included in the surgical dislocation group , and 20 pair-matched patients were included in the arthroscopic group . We obtained 100 % follow-up at a mean of 24.8 months in the open group and 25.5 months in the arthroscopic group . Preoperative scores were similar between the 2 groups ; significant improvements were made postoperatively for both groups . When we compared the 2 groups , the change in Hip Outcome Score-Sport-Specific Subscale ( 42.8 v 23.5 , P = .047 ) and 2-year Non-Arthritic Hip Score ( 94.2 v 85.7 , P = .01 ) were significantly higher in the arthroscopic group . Both groups showed a significant decrease in the alpha angle postoperatively ( P = .775 ) . CONCLUSIONS Favorable results were shown with both approaches , with significant improvement in all patient-reported outcome measures and high patient satisfaction ratings . However , arthroscopic treatment of FAI showed greater improvement in the Hip Outcome Score-Sport-Specific Subscale and a higher absolute Non-Arthritic Hip Score at an average 2-year follow-up . LEVEL OF EVIDENCE Level II , prospect i ve matched-pair comparative study BACKGROUND The patient acceptable symptom state ( PASS ) is the value beyond which patients can consider themselves well . This concept can help in interpreting results of clinical trials . OBJECTIVE To determine the PASS estimate for patients with knee and hip osteoarthritis ( OA ) by assessing pain , patient 's global assessment of disease activity , and functional impairment . METHODS A 4 week prospect i ve multicentre cohort study of 1362 out patients with knee or hip OA was carried out . Data on assessment of pain and patient 's global assessment of disease , measured on visual analogue scales , and functional impairment , measured on the Western Ontario McMaster Universities Osteoarthritis Index ( WOMAC ) function subscale , were collected at baseline and final visits . The patients assessed their satisfaction with their current state at the final visit . An anchoring method based on the patient 's opinion was used . RESULTS For patients with knee and hip OA , the estimates of PASS were , respectively , 32.3 and 35.0 mm for pain , 32.0 and 34.6 mm for patient global assessment of disease activity , and 31.0 and 34.4 points for WOMAC function score . The PASS varied moderately across the tertiles of baseline scores but not across age , disease duration , or sex . CONCLUSION The use of PASS in clinical trials would provide more meaningful results expressed as a proportion of patients in an acceptable symptom state ! [ ] [ 1 ] Rating : R and omised controlled trials are often held up as the “ gold st and ard ” of medical research , and it is commonly believed that the size of a treatment effect is exaggerated in non-r and omised studies . In these days of evidence based medicine , however , where is the empirical evidence that this is so ? A widespread criticism of r and omised controlled trials is that they are based on highly selected individuals . Are there systematic differences between patients included and excluded in such trials , and do these influence the measured treatment effect ? These are just a few … [ 1 ] : BACKGROUND In clinical trials , at the group level , results are usually reported as mean and st and ard deviation of the change in score , which is not meaningful for most readers . OBJECTIVE To determine the minimal clinical ly important improvement ( MCII ) of pain , patient 's global assessment of disease activity , and functional impairment in patients with knee and hip osteoarthritis ( OA ) . METHODS A prospect i ve multicentre 4 week cohort study involving 1362 out patients with knee or hip OA was carried out . Data on assessment of pain and patient 's global assessment , measured on visual analogue scales , and functional impairment , measured on the Western Ontario McMaster Universities Osteoarthritis Index ( WOMAC ) function subscale , were collected at baseline and final visits . Patients assessed their response to treatment on a five point Likert scale at the final visit . An anchoring method based on the patient 's opinion was used . The MCII was estimated in a subgroup of 814 patients ( 603 with knee OA , 211 with hip OA ) . RESULTS For knee and hip OA , MCII for absolute ( and relative ) changes were , respectively , ( a ) -19.9 mm ( -40.8 % ) and -15.3 mm ( -32.0 % ) for pain ; ( b ) -18.3 mm ( -39.0 % ) and -15.2 mm ( -32.6 % ) for patient 's global assessment ; ( c ) -9.1 ( -26.0 % ) and -7.9 ( -21.1 % ) for WOMAC function subscale score . The MCII is affected by the initial degree of severity of the symptoms but not by age , disease duration , or sex . CONCLUSION Using criteria such as MCII in clinical trials would provide meaningful information which would help in interpreting the results by expressing them as a proportion of improved patients PURPOSE The purpose of this prospect i ve r and omized study was to compare the outcomes of arthroscopic labral repair and selective labral debridement in female patients undergoing arthroscopy for the treatment of pincer-type or combined pincer- and cam-type femoroacetabular impingement . METHODS Between June 2007 and June 2009 , 36 female patients undergoing arthroscopic hip treatment for pincer- or combined-type femoroacetabular impingement were r and omized to 2 treatment groups at the time of surgery : labral repair or labral debridement . The repair group comprised 18 patients with a mean age of 38 ; the debridement group comprised 18 patients with a mean age of 39 . All patients underwent the same rehabilitation protocol postoperatively . At a minimum of 1 year , all patients were assessed using a vali date d Hip Outcome Score ( HOS ) to determine hip function , and also completed a simple subjective outcome measure . RESULTS All 36 patients were available for follow-up at an average time of 32 months ( range , 12 to 48 ) . In both groups , HOSs for activities of daily living ( ADL ) and sports improved significantly from before surgery to the final follow-up ( P < .05 ) . The postoperative ADL HOS was significantly better in the repair group ( 91.2 ; range , 73 to 100 ) compared with the debridement group ( 80.9 ; range , 42.6 to 100 ; P < .05 ) . Similarly , the postoperative sports HOS was significantly greater in the repair group ( 88.7 ; range , 28.6 to 100 ) than in the debridement group ( 76.3 ; range , 28.6 to 100 ; P < .05 ) . Additionally , patient subjective outcome was significantly better in the labral repair group ( P = .046 ) . CONCLUSIONS Arthroscopic treatment of femoroacetabular impingement with labral repair in female patients result ed in superior improvement in hip functional outcomes compared with labral debridement . In addition , a greater number of patients in the repair group subjectively rated their hip function as normal or nearly normal after surgery compared with the labral debridement group . LEVEL OF EVIDENCE Level I , prospect i ve r and omized study Research on surgical interventions is associated with several method ological and practical challenges of which few , if any , apply only to surgery . However , surgical evaluation is especially dem and ing because many of these challenges coincide . In this report , the second of three on surgical innovation and evaluation , we discuss obstacles related to the study design of r and omised controlled trials and non-r and omised studies assessing surgical interventions . We also describe the issues related to the nature of surgical procedures -for example , their complexity , surgeon-related factors , and the range of outcomes . Although difficult , surgical evaluation is achievable and necessary . Solutions tailored to surgical research and a framework for generating evidence on which to base surgical practice are essential |
13,798 | 18,648,135 | Nasogastric feeding appears safe and well tolerated in patients with predicted severe acute pancreatitis . | CONTEXT Nasogastric tube feeding is safe and well tolerated in most critically ill patients .
However , its safety and tolerance in the setting of severe acute pancreatitis is debatable .
OBJECTIVE We aim ed to review all available studies on nasogastric feeding in patients with severe acute pancreatitis to determine the safety and tolerance of this approach .
A further aim was to perform a meta- analysis of the available r and omized controlled trials regarding nasogastric versus nasojejunal feeding . | In the nutritional management of digestive disorders , it is important to know the relative secretory and metabolic responses to enteral and parenteral feeding . Twenty-seven healthy volunteers were studied while receiving either oral drinks or duodenal infusions of a complex formula diet , duodenal or intravenous infusions of elemental ( protein as free amino acids , low fat ) formulae , or saline . Pancreaticobiliary secretory responses were measured by nasoduodenal polyethylene glycol perfusion and aspiration , while monitoring blood hormone and nutrient levels . Diets were matched for protein ( 1.5 g x kg(-1 ) x d(-1 ) ) and energy ( 40 kcal x kg(-1 ) x d(-1 ) ) . Compared with placebo , all oroenteral diets stimulated amylase , lipase , trypsin , and bile acid secretion and increased plasma concentrations of gastrin and cholecystokinin , whereas intravenous feeding did not . The complex formula produced a similar response whether given as drinks or duodenal infusions . Changing the duodenal formula to elemental reduced enzyme secretion by 50 % , independently of CCK . Higher increases in plasma insulin , glucose , and amino acids were noted with intravenous feeding . Delivering food directly to the intestine by a feeding tube does not reduce pancreaticobiliary secretion . Enteral " elemental " formulae diminish , but only intravenous feeding avoids pancreatic stimulation . Intravenous administration impairs metabolic clearance Studies in humans have shown that pancreatic enzyme secretion is reduced during acute pancreatitis . It is not known , however , whether the reduction is due to impaired synthesis or disruption of the secretory pathway . The rate of secretion and turnover of trypsin was measured in 12 patients with acute pancreatitis of variable etiology and severity ( median Ranson 's score 2.5 , range 0 - 5 , 4 with severe necrotizing disease ) and eight healthy volunteers by 4-h primed/continuous intravenous infusions of 1-(13)C-labeled l-leucine , and collection of pancreatic secretions by duodenal perfusion and sampling . Trypsin secretion was reduced from 476 + /- 73 to 153 + /- 60 U/h ( means + /- SE , P = 0.005 ) in acute pancreatitis , with the greatest reductions being observed in patients with necrotizing disease ( 32 + /- 7 U/h , P = 0.003 ) . The time for newly labeled trypsin to first appear in digestive juice was not , however , delayed in pancreatitis patients ( 87.2 + /- 11.1 vs. 94.7 + /- 4.9 min ) ; on the contrary , there was an early appearance of newly labeled trypsin at 30 min in patients with severe necrotizing pancreatitis ( P < 0.05 ) . Calculated zymogen pool turnover was unchanged , but pool size was decreased ( P = 0.01 ) . Despite low rates of luminal secretion , trypsin continues to be synthesized in patients with acute pancreatitis . Our findings could be explained by post-Golgi leakage of enzymes from acinar cells or by loss of synthetic function in some cells with preservation in others BACKGROUND : After 50 yr in which nasoenteric feeding was considered contraindicated in acute pancreatitis ( AP ) , several clinical studies have shown that early nasojejunal ( NJ ) feeding can be achieved in most patients . A pilot study of early nasogastric ( NG ) feeding in patients with objective ly grade d severe AP proved that this approach was also feasible . A r and omized study comparing NG versus NJ feeding has been performed . METHODS : A total of 50 consecutive patients with objective ly grade d severe AP were r and omized to receive either NG or NJ feeding via a fine bore feeding tube . The end points were markers of the acute phase response APACHE II scores and C-reactive protein ( CRP ) measurements , and pain patterns by visual analogue score ( VAS ) and analgesic requirements . Complications were monitored and comparisons made of both total hospital and intensive-care stays . RESULTS : A total of 27 patients were r and omized to NG feeding and 23 to NJ . One of those in the NJ group had a false diagnosis , thereby reducing the number to 22 . Demographics were similar between the groups and no significant differences were found between the groups in APACHE II score , CRP measurement , VAS , or analgesic requirement . Clinical differences between the two groups were not significant . Overall mortality was 24.5 % with five deaths in the NG group and seven in the NJ group . CONCLUSIONS : The simpler , cheaper , and more easily used NG feeding is as good as NJ feeding in patients with objective ly grade d severe AP . This appears to be a useful and practical therapeutic approach to enteral feeding in the early management of patients with severe AP Objective : To compare the efficacy and safety of early , nasogastric enteral nutrition ( EN ) with total parenteral nutrition ( TPN ) in patients with predicted severe acute pancreatitis ( SAP ) . Summary Background Data : In SAP , the magnitude of the inflammatory response as well as increased intestinal permeability correlates with outcome . Enteral feeding has been suggested superior to parenteral feeding due to a proposed beneficial effect on the gut barrier . Methods : Fifty patients who met the inclusion criteria were r and omized to TPN or EN groups . The nutritional regimen was started within 24 hours from admission and EN was provided through a nasogastric tube . The observation period was 10 days . Intestinal permeability was measured by excretion of polyethylene glycol ( PEG ) and concentrations of antiendotoxin core antibodies ( Endocab ) . Interleukins (IL)-6 IL-8 , and C-reactive protein ( CRP ) were used as markers of the systemic inflammatory response . Morbidity and feasibility of the nutritional route were evaluated by the frequency of complications , gastrointestinal symptoms , and abdominal pain . Results : PEG , Endocab , CRP , IL-6 , APACHE II score , severity according to the Atlanta classification ( 22 patients ) , and gastrointestinal symptoms or abdominal pain did not significantly differ between the groups . The incidence of hyperglycemia was significantly higher in TPN patients ( 21 of 26 vs. 7 of 23 ; P < 0.001 ) . Total complications ( 25 vs. 52 ; P = 0.04 ) and pulmonary complications ( 10 vs. 21 ; P = 0.04 ) were significantly more frequent in EN patients , although complications were diagnosed dominantly within the first 3 days . Conclusion : In predicted SAP , nasogastric early EN was feasible and result ed in better control of blood glucose levels , although the overall early complication rate was higher in the EN group . No beneficial effects on intestinal permeability or the inflammatory response were seen by EN treatment Background : Infectious complications are the main cause of late death in patients with acute pancreatitis . Routine prophylactic antibiotic use following a severe attack has been proposed but remains controversial . On the other h and , nutritional support has recently yielded promising clinical results . The aim of study was to compare enteral vs. parenteral feeding for prevention of infectious complications in patients with predicted severe acute pancreatitis . Methods : We screened 466 consecutive patients with acute pancreatitis . A total of 70 patients with objective ly grade d severe acute pancreatitis were r and omly allocated to receive either total enteral nutrition ( TEN ) or total parenteral nutrition ( TPN ) , within 72 h of onset of symptoms . Baseline characteristics were well matched in the two groups . Results : The incidence of pancreatic infectious complications ( infected pancreatic necrosis , pancreatic abscess ) was significantly lower in the enterally fed group ( 7 vs. 16 , p = 0.02 ) . In the TEN group , 7 patients developed multiple organ failure whereas 17 parenterally fed patients developed multiple organ failure ( p = 0.02 ) . Overall mortality was 20 % with two deaths in the TEN group and twelve in the TPN group ( p < 0.01 ) . Conclusion : Early TEN could be used as prophylactic therapy for infected pancreatic necrosis since it significantly decreased the incidence of pancreatic infectious complications as well as the frequency of multiple organ failure and mortality In recent years , a number of articles have been published on the treatment of acute pancreatitis in experimental models and most of them were published about animals with mild disease . However , it is difficult to translate these results into clinical practice . For example , infliximab , a monoclonal TNF antibody , was experimentally tested in rats and it was able to significantly reduce the pathologic score and serum amylase activity , and also alleviate alveolar edema and acute respiratory distress syndrome ; no studies are available in clinical human acute pancreatitis . Another substance , such as interleukin 10 , was efficacious in decreasing the severity and mortality of lethal pancreatitis in rats , but seems to have no effect on human severe acute pancreatitis . Thus , the main problem in acute pancreatitis , especially in the severe form of the disease , is the difficulty of planning clinical studies capable of giving hard statistically significant answers regarding the benefits of the various proposed therapeutic agents previously tested in experimental setting s. According to the pathophysiology of acute pancreatitis , we may re-evaluate the efficacy of the drugs already available , such as gabexate mesilate , lexipafant and somatostatin which should be probably administered in a different manner . Of course , also in this case , we need large studies to test this hypothesis . Another great problem is prevention of the infection of pancreatic necrosis . A r and omized study has been published to test the hypothesis that probiotics and specific fibres used as supplements in early enteral nutrition may be effective in reducing pancreatic sepsis and the number of surgical interventions . A study named PROPATRIA ( Probiotic Prophylaxis in Patients with Predicted Severe Acute Pancreatitis ) has been planned to give a more robust confirmation to the previous study . Furthermore , the open question of the prevention of the fungal infection of necrosis is still being debated . Finally , the prevention of pain relapse after oral feeding in patients with mild or severe acute pancreatitis should be explored . Even if some studies exist on this issue , the question of optimal treatment is still unanswered . As in other diseases , obtaining results when treating patients with acute pancreatitis is difficult and will take continuous small steps Aims : The aim of this prospect i ve study was to assess pancreatic exocrine function in patients recovering from a first attack of acute pancreatitis , and to evaluate its relationship to severity of attack , extent of pancreatic necrosis and severity of pancreatic endocrine insufficiency . Methods : Between December 2000 and November 2001 , 23 patients were prospect ively evaluated . Pancreatic exocrine function was measured by the faecal elastase-1 test and insufficiency was classified as moderately impaired or severely impaired . Pancreatic necrosis was determined by contrast-enhanced CT scan , and its extent was categorised according to Balthazar ’s classification . The severity of pancreatic endocrine insufficiency was categorised according to insulin dependence . Attacks were classified as mild ( n = 16 ) or severe ( n = 7 ) according to the Atlanta criteria . Results : Pancreatic exocrine insufficiency was significantly more frequent in patients recovering from severe attacks than mild ( n = 6 , 86 % vs. n = 2 , 13 % ; p = 0.002 ) , and in those who developed pancreatic necrosis or pseudocyst than those who did not ( 6 of 7 patients vs. 2 of 16 patients , and 5 of 5 patients vs. 3 of 18 patients respectively ; p = 0.002 ) . The development of exocrine insufficiency correlated strongly with the extent of pancreatic necrosis ( r = –0.754 , p < 0.001 ) , and the severity of pancreatic endocrine insufficiency ( n = 4 , r = –0.453 , p = 0.03 ) . Conclusion : Pancreatic exocrine insufficiency is a common occurrence in patients recovering from severe acute pancreatitis , and its severity correlates with the extent of pancreatic necrosis and the severity of concomitant pancreatic endocrine insufficiency Summary Background . Severe acute pancreatitis may be protracted and some form of nutritional support is frequently required to maintain the patient ’s nutritional status . Recent work has suggested that enteral feeding via a jejunal route of delivery may reduce the magnitude of the inflammatory response . Insertion of nasojejunal ( NJ ) tubes in the patient with severe acute pancreatitis involves both delay and inconvenience . We undertook a prospect i ve , feasibility study to assess the safety and practicability of nasogastric ( NG ) feeding in patients with severe acute pancreatitis . Patients and Methods . Twenty-six patients with objective evidence of severe acute pancreatitis received nasogastric feeding within 48 h of admission to our unit . Results . Etiology was identified as cholelithiasis ( 18 patients ) , ethanol ( 5 ) , and miscellaneous ( 3 ) . The median Glasgow score was 4 ( range 2–7 ) , APACHE II score 10 ( 4–28 ) , and C-reactive protein concentration 286 mg/L ( 79–469 ) . Fifteen patients had pancreatic and /or peripancreatic necrosis . Eleven patients developed severe organ failure , necessitating ventilatory support . Six developed multiple organ system failure , requiring inotropic support and /or renal dialysis . There were four deaths (15.3%).Nine patients underwent early , and nine late , ERCP , respectively ; six necrosectomy ( 5 proven infected necrosis , 1 continued deterioration despite maximal support ) and 4 patients internal drainage of a pseudocyst . The feed was well-tolerated in 22 patients . In 3 patients gastric stasis proved troublesome . There was no evidence of clinical or biochemical deterioration on commencing nasogastric feeding . Conclusion . It would appear that early NG feeding is usually possible in severe acute pancreatitis . In most patients it appears safe , well-tolerated , and worthy of further study Purpose Enteral nutrition ( EN ) is effective , easy to provide , cheaper , and associated with fewer complications in comparison with parenteral nutrition in severe acute pancreatitis ( SAP ) . However , the nasogastric ( NG ) route for enteral supplements still remains to be established , and most studies have used the nasojejunal ( NJ ) route . The purpose of this study was to compare early NJ with NG feeding in SAP . Patients and Methods A total of 31 patients with SAP were r and omized to feeding by either NG ( 15 patients ) or NJ ( 16 patients ) . A semi-elemental formula was used through an enteral tube in both groups . Nutritional parameters ( anthropometry , serum prealbumin and albumin levels ) were recorded at baseline and after 7 days . Recurrence of pain and tolerance of feeding was noted . Results Recurrence of pain occurred in only 1 patient each in the 2 groups . Diarrhea occurred in 3 and 4 patients in the NJ and NG groups , respectively . There were 4 deaths in the NJ group and 5 in the NG group . Two patients in the NJ group and 1 in the NG group underwent surgery . There was no difference in the outcome measures ( ie , discharge , surgery , and death ) . There was a decline in nutritional parameters in both groups . Conclusions EN at a slow infusion is well tolerated by both NJ and NG routes in patients with SAP . Neither NJ nor NG feeding leads to recurrence or worsening of pain in SAP . Nutritional parameters remained unaffected because of inadequate calorie intake during the first week of feeding OBJECTIVE We investigated the effect of early jejunal feeding on septic complications and mortality rate in patients with acute pancreatitis in a two-phase , prospect i ve , controlled study . METHODS In the first , r and omized phase of the study , conventional parenteral nutrition was compared with early ( within 24 - 72 h after the onset of symptoms ) enteral nutrition . Of 89 patients admitted with acute pancreatitis , 48 patients were r and omized into a parenteral group ( Rindex 10 , Infusamin S , Intralipid 10 % ; 30 kcal/kg ) and 41 patients into an enteral group ( jejunal tube feeding ; Survimed OPD ; 30 kcal/kg ) . RESULTS The rate of septic complications ( infected pancreatic necrosis , abscess ) was lower in the enteral group ( P = 0.08 , chi(2 ) test ) . In the second phase of the study , early jejunal feeding was combined with prophylactic imipenem ( Tienam , 500 mg intravenously twice each day ) when necrosis of the pancreas was detected by abdominal computed tomography . When the outcomes of 92 patients in the third group were compared with those of patients in the parenteral group , the rate of septic complications decreased significantly ( P = 0.03 ) . Multiple organ failure ( P = 0.14 ) and mortality ( P = 0.13 ) tended to decrease . CONCLUSIONS We believe that the combination of early enteral nutrition and selective , adequate antibiotic prophylaxis may prevent multiple organ failure in patients with acute pancreatitis |
13,799 | 26,921,655 | Evidence surrounding these programmes is limited both in terms of long-term adherence measures and the views of participants .
However , based on limited findings there is some indication that community based group exercise programmes have long-term adherence rates of almost 70 % .
Incorporating the views of older people into programme design s may provide guidance for innovative interventions leading to sustained adherence | OBJECTIVE Lifelong physical activity provides some of the best prospect s for ageing well .
Nevertheless , people tend to become less physically active as they age .
This systematic review assessed the views and adherence of participants attending community based exercise programmes of ≥6month 's duration . | Forty-eight community living women 66–87 years old volunteered to participate in a 12-month prospect i ve , r and omized , controlled , trial . The aim was to determine if a combined weight-bearing training program twice a week would be beneficial to bone mineral density and neuromuscular function . The participants were pairwise age-matched and r and omly assigned to either an exercise group ( n=24 ) or a control group ( n=24 ) . Twenty-one subjects in the intervention group and 19 in the control group completed the study . The exercise program lasted for 50 min and consisted of a combination of strengthening , aerobic , balance and coordination exercises . The mean percentage of scheduled sessions attended for the exercise group was 67 % . At the completion of the study , the intervention group showed significant increments in bone mineral density of the Ward ’s triangle ( 8.4 % , P<0.01 ) as well as improvement in maximum walking speed ( 11.4 % , P<0.001 ) and isometric grip strength ( 9.9 % , P<0.05 ) , as compared to the control group . The conclusion was that a combined weight-bearing training program might reduce fracture risk factors by improving bone density as well as muscle strength and walking ability . This program could be suitable for older community living women in general , and might , therefore , have important implication s for fracture prevention Reports on the efficacy of physical activity intervention trials usually only include discussion of the primary outcomes . However , assessing factors such as participant retention , adherence and compliance can assist in the accurate interpretation of the overall impact of a program in terms of reach and appeal . A quasi-r and omised trial was carried out to assess and compare retention and adherence rates , and compliance with , a twice weekly resistance training program provided either individually at home or in a group format . Retirement villages ( n=6 ) were assigned to either ' Have A Try ' ( HAT , home-based ) or ' Come Have A Try ' ( CHAT , group-based ) ; both programs included nine strength and two balance exercises . The program involved a 20-week Intervention Phase a 24-week Maintenance Phase and a 20-week On-going Maintenance Phase . One hundred and nineteen participants ( mean age 80+/-6 years ) were recruited ( HAT=38 , CHAT=81 ) . There was no difference in retention rates at the end of the Intervention Phase , but significantly more HAT than CHAT participants had dropped out of the study ( p<0.01 ) after the Maintenance Phase and the On-going Maintenance Phase . During the Intervention Phase , over half the HAT and CHAT participants completed > or = 75 % of the prescribed activity sessions , but adherence was significantly greater in CHAT than HAT during the Maintenance Phase ( p<0.01 ) . Participants in CHAT were significantly more compliant than HAT participants ( p<0.05 ) . Both home- and group-based formats were successful over the short-term , but , in retirement villages , the group program had better adherence and compliance in the longer-term OBJECTIVES We assessed the impact of existing best- practice physical activity programs for older adults on physical activity participation and health-related outcomes . METHODS We used a multisite , r and omized trial with 544 older adults ( mean age 66 years ) and measures at baseline , 5 , and 10 months to test the impact of a multiple-component physical activity program compared with results for a control group that did not participate in such a program . RESULTS For adults who participated in a multiple-component physical activity program , we found statistically significant benefits at 5 and 10 months with regard to self-efficacy for exercise adherence over time ( P < .001 ) , adherence in the face of barriers ( P = .01 ) , increased upper- and lower-body strength ( P = .02 , P = .01 ) , and exercise participation ( P = .01 ) . CONCLUSIONS Best- practice community-based physical activity programs can measurably improve aspects of functioning that are risk factors for disability among older adults . US public policy should encourage these inexpensive health promotion programs Objectives The effectiveness of community level interventions depends to a great extent on adherence . Currently , information on factors related to adherence in older adults from developing countries is scarce . Our aim was to identify factors associated to adherence to a physical activity intervention in older adults from a post-transitional middle income country . Design , setting and participants Using a combination of quantitative and qualitative methods we studied 996 older Chilean subjects ( 65–67.9 years at baseline ) with low to medium socioeconomic status from 10 health centers r and omized to receive a physical activity intervention as part of the CENEX cluster trial ( IS RCT N48153354 ) . Measurements Using a multilevel regression model , the relationship between adherence ( defined a priori as attendance at a minimum of 24 physical activity classes spread over at least 12 months ) and individual , intervention-related and context ual factors was evaluated . We also conducted 40 semi-structured interviews with older adults ( n=36 ) and instructors ( n=4 ) . Transcripts of the interviews were analyzed using content analysis to identify barriers and facilitators to adherence . Results Adherence to physical activity intervention was 42.6 % ( CI 95 % 39.5 to 45.6 ) . Depression , diabetes mellitus , percentage of impoverished households and rate of arrests for violent crimes in the neighborhood predicted less adherence ( p<0.05 ) while being retired , participation in physical activity prior to the intervention , and green areas per habitant were positively associated with adherence ( p<0.05 ) . The qualitative interviews identified three primary barriers to adherence : current health problems , lack of time due to commitments for caring for family members , and being employed , and two primary facilitators to adherence : the health benefits attributed to the intervention and the opportunity the classes provided for social interaction with others . Conclusion In order to enhance effectiveness of community exercise interventions , strategies to improve participation should be targeted to older adults from deprived areas and those with psychological and medical conditions BACKGROUND Although inactivity is an important contributor to impaired functioning and disability with age , little is known concerning how improvements in physical functioning and well-being in older adults vary with the type of physical activity undertaken . METHODS One hundred three adults age 65 years and older , recruited via population -based methods , were r and omized to 12 months of community-based , moderate-intensity endurance and strengthening exercises ( Fit & Firm ) or stretching and flexibility exercises ( Stretch & Flex ) . A combination of class- and home-based exercise formats was used . Measured and self-rated physical performance along with perceived functioning and well-being were assessed pre- and postintervention . RESULTS Fit & Firm subjects showed greater 12-month improvements in both measured and self-rated endurance and strength compared to Stretch & Flex subjects . Stretch & Flex subjects reported greater improvements in bodily pain , and Stretch & Flex men evidence d greater improvements in flexibility relative to Fit & Firm subjects . Although overall exercise adherence was high in both exercise conditions ( approximately 80 % ) , subjects in both conditions showed better adherence to the home- versus class-based portions of their exercise prescriptions . CONCLUSIONS Community-based programs focusing on moderate-intensity endurance and strengthening exercises or flexibility exercises can be delivered through a combination of formats that result in improvement in important functional and well-being outcomes . This represents one of the first studies to report significant improvements in an important quality of life outcome -bodily pain-with a regular regimen of stretching and flexibility exercises in a community-based sample of older adults After a r and omized controlled trial showing that improvement on some aspects of cognitive function was related to adherence to an exercise program , determinants of adherence and maintenance were further studied . Older adults with mild cognitive impairment were contacted 6 mo after the end of exercise programs for a telephone interview addressing patterns of adherence and determinants of maintenance . Mean adherence during the trial was 53 % . About one third of participants had lapses during the trial but completed , one third had no lapses , and one third dropped out or never started . Practical barriers ( time , location ) were related to not starting and functional limitations to dropout . After the trial 25 % of participants continued the programs , 14 % reported intention to continue , and 61 % quit . Maintenance was determined by fewer health complaints , higher satisfaction with the programs , and better adherence during the programs . Although maintenance was low , this study identified several reasons and barriers to adherence and maintenance that could be addressed PURPOSE We present final outcomes from the multiple-component Fit and Strong ! intervention for older adults with lower extremity osteoarthritis . DESIGN AND METHODS A r and omized controlled trial compared the effects of this exercise and behavior-change program followed by home-based reinforcement ( n=115 ) with a wait list control ( n=100 ) at 2 , 6 , and 12 months . Fit and Strong ! combined flexibility , aerobic walking , and resistance training with education and group problem solving to enhance self-efficacy for exercise and maintenance of physical activity . All participants developed individualized plans for long-term maintenance . RESULTS Relative to controls , treatment participants experienced statistically significant improvements in self-efficacy for exercise ( p=.001 ) , minutes of exercise per week ( p=.000 ) , and lower extremity stiffness ( p=.018 ) at 2 months . These benefits were maintained at 6 months and were accompanied by increased self-efficacy for adherence to exercise over time ( p=.001 ) , reduced pain ( p=.040 ) , and a marginally significant increase in self-efficacy for arthritis pain management ( p=.052 ) . Despite a substantially smaller sample size at 12 months , significant treatment-group effects were maintained on self-efficacy for exercise ( p=.006 ) and minutes of exercise per week ( p=.001 ) , accompanied by marginally significant reductions in lower extremity stiffness ( p=.056 ) and pain ( p=.066 ) . No adverse health effects were seen . Effect sizes for self-efficacy for exercise and for maintenance of physical activity were 0.798 and 0.713 , and 0.905 and 0.669 , respectively , in the treatment group at 6 and 12 months . IMPLICATION S This consistent pattern of benefits indicates that this low-cost intervention is efficacious for older adults with lower extremity osteoarthritis Background and Purpose : Physical activity has many benefits for older adults , but adherence is often low . The purpose s of this study were to ( 1 ) identify motivators and barriers for participation in EnhanceFitness ( EF ) , a group-based exercise program ; and ( 2 ) quantitatively examine the association between motivators , barriers and individual characteristics , and ongoing participation in the program . Methods : This was a prospect i ve , cross-sectional study . We mailed a pilot , investigator-developed survey to assess motivators and barriers to exercising to 340 adults who started a new EF class , regardless of their attendance rate . We precoded surveys on the basis of class attendance , with former participants defined as having no attendance a month or more before a 4-month fitness check . Results : Of the 241 respondents ( 71 % response rate ) , 61 ( 25 % ) were precoded as former participants and 180 ( 75 % ) as current participants . The mean age of respondents was 71 years and they were predominately female ( 89 % ) . More than half of respondents were whites ( 58 % ) , and almost half were married ( 46 % ) . Former participants reported lower total motivation scores than current participants ( P < .01 ) and had a significantly higher mean total barrier score ( P < .001 ) . The effects of 5 barriers ( “ Class was too hard , ” “ Class was too easy , ” “ I do n't like to exercise , ” “ Personal illness , ” and “ Exercise caused pain ” ) and 2 motivators ( “ I want to exercise ” and “ I plan exercise as part of my day ” ) were significantly different between current and former participants . Discrete event history models show that dropout was related positively to ethnicity ( whites were more likely to drop out ) and health-related barriers . Discussion : In newly formed EF classes , participants who drop out report more program , psychosocial , and health barriers , and fewer program and psychosocial motivators . Total barrier score and health barriers significantly predict a participant 's dropping out , and white ethnicity is associated with a higher likelihood of dropping out . Conclusions : Employing strategies that address health barriers to participation could improve attendance rates for group-based exercise programs Increasing evidence suggests that physical activity can prevent some aspects of mental illness in older people such as depression , dementia and Alzheimer ’s disease . Additionally , limited research has shown that engagement in structured exercise can improve aspects of psychological well-being such as mood and self-perceptions in older adults . However , the relationship between incidental daily activity such as walking or time spent sedentary , with psychological well-being has not been investigated . The Better Ageing Project provided an opportunity to assess well-being and quality of life using st and ardised question naires with 176 adults aged 70 and over . Accelerometry was used to objective ly assess daily energy expended in physical activity at different levels of intensity . In addition , an assessment of the impact of the 12-month Better Ageing structured group exercise programme was assessed through question naires and interviews . Total daily physical activity energy expenditure ( joules/day ) and amount of time spent in activity of at least moderate intensity were weakly related ( r = 0.20–0.28 ) to quality of life , subjective well-being and physical self-perceptions . Time spent sedentary ( min/day ) was weakly and negatively related to several mental health indicators . The quantitative data showed only minor psychological benefits of the exercise intervention . In contrast , interviews with 27 research participants and 4 exercise leaders suggested that important improvements in perceived function and social benefits had been experienced |
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